MorphoSeq: Full Single-Cell Transcriptome Dynamics Up to Gastrulation in a Chordate.

Single-cell RNA sequencing (scRNA-seq) provides a leap forward in resolving cellular diversity and developmental trajectories but fails to comprehensively delineate the spatial organization and precise cellular makeup of individual embryos. Here, we reconstruct from scRNA-seq and light sheet imaging data a canonical digital embryo that captures the genome-wide gene expression trajectory of every single cell at every cell division in the 18 lineages up to gastrulation in the ascidian Phallusia mammillata. By using high-coverage scRNA-seq, we devise a computational framework that stratifies single cells of individual embryos into cell types without prior knowledge. Unbiased transcriptome data analysis mapped each cell's physical position and lineage history, yielding the complete history of gene expression at the genome-wide level for every single cell in a developing embryo. A comparison of individual embryos reveals both extensive reproducibility between symmetric embryo sides and a large inter-embryonic variability due to small differences in embryogenesis timing.

Riboregulation of Enolase 1 activity controls glycolysis and embryonic stem cell differentiation.

Differentiating stem cells must coordinate their metabolism and fate trajectories. Here, we report that the catalytic activity of the glycolytic enzyme Enolase 1 (ENO1) is directly regulated by RNAs leading to metabolic rewiring in mouse embryonic stem cells (mESCs). We identify RNA ligands that specifically inhibit ENO1's enzymatic activity in vitro and diminish glycolysis in cultured human cells and mESCs. Pharmacological inhibition or RNAi-mediated depletion of the protein deacetylase SIRT2 increases ENO1's acetylation and enhances its RNA binding. Similarly, induction of mESC differentiation leads to increased ENO1 acetylation, enhanced RNA binding, and inhibition of glycolysis. Stem cells expressing mutant forms of ENO1 that escape or hyper-activate this regulation display impaired germ layer differentiation. Our findings uncover acetylation-driven riboregulation of ENO1 as a physiological mechanism of glycolytic control and of the regulation of stem cell differentiation. Riboregulation may represent a more widespread principle of biological control.

Evolution of superconductivity in twisted graphene multilayers.

The group of moiré graphene superconductors keeps growing, and by now it contains twisted graphene multilayers as well as untwisted stacks. We analyze here the contribution of long-range charge fluctuations in the superconductivity of twisted double bilayers and helical trilayers, and compare the results to twisted bilayer graphene. A diagrammatic approach which depends on a few, well-known parameters is used. We find that the critical temperature and the order parameter differ significantly between twisted double bilayers and helical trilayers on one hand, and twisted bilayer graphene on the other. This trend, consistent with experiments, can be associated with the role played by moiré Umklapp processes in the different systems.

Microfluidic study of retention and elimination of abnormal red blood cells by human spleen with implications for sickle cell disease.

The spleen clears altered red blood cells (RBCs) from circulation, contributing to the balance between RBC formation (erythropoiesis) and removal. The splenic RBC retention and elimination occur predominantly in open circulation where RBCs flow through macrophages and inter-endothelial slits (IESs). The mechanisms underlying and interconnecting these processes significantly impact clinical outcomes. In sickle cell disease (SCD), blockage of intrasplenic sickled RBCs is observed in infants splenectomized due to acute splenic sequestration crisis (ASSC). This life-threatening RBC pooling and organ swelling event is plausibly triggered or enhanced by intra-tissular hypoxia. We present an oxygen-mediated spleen-on-a-chip platform for in vitro investigations of the homeostatic balance in the spleen. To demonstrate and validate the benefits of this general microfluidic platform, we focus on SCD and study the effects of hypoxia on splenic RBC retention and elimination. We observe that RBC retention by IESs and RBC-macrophage adhesion are faster in blood samples from SCD patients than those from healthy subjects. This difference is markedly exacerbated under hypoxia. Moreover, the sickled RBCs under hypoxia show distinctly different phagocytosis processes from those non-sickled RBCs under hypoxia or normoxia. We find that reoxygenation significantly alleviates RBC retention at IESs, and leads to rapid unsickling and fragmentation of the ingested sickled RBCs inside macrophages. These results provide unique mechanistic insights into how the spleen maintains its homeostatic balance between splenic RBC retention and elimination, and shed light on how disruptions in this balance could lead to anemia, splenomegaly, and ASSC in SCD and possible clinical manifestations in other hematologic diseases.

Function-guided proximity mapping unveils electrophilic-metabolite sensing by proteins not present in their canonical locales.

Enzyme-assisted posttranslational modifications (PTMs) constitute a major means of signaling across different cellular compartments. However, how nonenzymatic PTMs-despite their direct relevance to covalent drug development-impinge on cross-compartment signaling remains inaccessible as current target-identification (target-ID) technologies offer limited spatiotemporal resolution, and proximity mapping tools are also not guided by specific, biologically-relevant, ligand chemotypes. Here we establish a quantitative and direct profiling platform (Localis-rex) that ranks responsivity of compartmentalized subproteomes to nonenzymatic PTMs. In a setup that contrasts nucleus- vs. cytoplasm-specific responsivity to reactive-metabolite modification (hydroxynonenylation), ∼40% of the top-enriched protein sensors investigated respond in compartments of nonprimary origin or where the canonical activity of the protein sensor is inoperative. CDK9-a primarily nuclear-localized kinase-was hydroxynonenylated only in the cytoplasm. Site-specific CDK9 hydroxynonenylation-which we identified in untreated cells-drives its nuclear translocation, downregulating RNA-polymerase-II activity, through a mechanism distinct from that of commonly used CDK9 inhibitors. Taken together, this work documents an unmet approach to quantitatively profile and decode localized and context-specific signaling/signal-propagation programs orchestrated by reactive covalent ligands.

Revisiting the significance of keratin expression in complex epithelia.

A large group of keratin genes (n=54 in the human genome) code for intermediate filament (IF)-forming proteins and show differential regulation in epithelial cells and tissues. Keratin expression can be highly informative about the type of epithelial tissue, differentiation status of constituent cells and biological context (e.g. normal versus diseased settings). The foundational principles underlying the use of keratin expression to gain insight about epithelial cells and tissues primarily originated in pioneering studies conducted in the 1980s. The recent emergence of single cell transcriptomics provides an opportunity to revisit these principles and gain new insight into epithelial biology. Re-analysis of single-cell RNAseq data collected from human and mouse skin has confirmed long-held views regarding the quantitative importance and pairwise regulation of specific keratin genes in keratinocytes of surface epithelia. Furthermore, such analyses confirm and extend the notion that changes in keratin gene expression occur gradually as progenitor keratinocytes commit to and undergo differentiation, and challenge the prevailing assumption that specific keratin combinations reflect a mitotic versus a post-mitotic differentiating state. Our findings provide a blueprint for similar analyses in other tissues, and warrant a more nuanced approach in the use of keratin genes as biomarkers in epithelia.

Shaping epithelial lumina under pressure.

The formation of fluid- or gas-filled lumina surrounded by epithelial cells pervades development and disease. We review the balance between lumen pressure and mechanical forces from the surrounding cells that governs lumen formation. We illustrate the mechanical side of this balance in several examples of increasing complexity, and discuss how recent work is beginning to elucidate how nonlinear and active mechanics and anisotropic biomechanical structures must conspire to overcome the isotropy of pressure to form complex, non-spherical lumina.

The risk of hospitalization for psychotic disorders following hospitalization for COVID-19: a French nationwide longitudinal study.

COVID-19, like other infectious diseases, may be a risk factor for psychotic disorders. We aimed to compare the proportions of hospitalizations for psychotic disorders in the 12 months following discharge from hospital for either COVID-19 or for another reason in the adult general population in France during the first wave of the pandemic. We conducted a retrospective longitudinal nationwide study using the national French administrative healthcare database. Psychotic disorders were first studied as a whole, and then chronic and acute disorders separately. The role of several adjustment factors, including sociodemographics, a history of psychotic disorder, the duration of the initial hospitalization, and the level of care received during that hospitalization, were also analyzed. Between 1 January 2020 and 30 June 2020, a total of 14,622 patients were hospitalized for psychotic disorders in the 12 months following discharge from hospital for either COVID-19 or another reason. Initial hospitalization for COVID-19 (vs. another reason) was associated with a lower rate of subsequent hospitalization for psychotic disorders (0.31% vs. 0.51%, odds ratio (OR) = 0.60, 95% confidence interval (CI) [0.53-0.67]). This was true for both chronic and acute disorders, even after adjusting for the various study variables. Importantly, a history of psychotic disorder was a major determinant of hospitalization for psychotic disorders (adjusted OR = 126.56, 95% CI [121.85-131.46]). Our results suggest that, in comparison to individuals initially hospitalized for another reason, individuals initially hospitalized for COVID-19 present a lower risk of hospitalization for first episodes of psychotic symptoms/disorders or for psychotic relapse in the 12 months following discharge. This finding contradicts the hypothesis that there is a higher risk of psychotic disorders after a severe COVID-19.

Eco-anxiety: Towards a medical model and the new framework of ecolalgia.

INTRODUCTION: In the context of global warming, new terms emerged in the global media and in the psychology field to embody the negative feelings which come along with climate change such as 'eco-anxiety' or 'solastalgia'. The pathological character of these emotions is denied although medical opinion is often required for helping people to handle them. Also, no proper medical framework in the field exists to study and care for these patients. METHODS: In this narrative review, we aim to (1) analyse the concept of eco-anxiety by focusing on its history and developed concepts, (2) summarize the different scales built to assess eco-anxiety and (3) propose a new medical framework. RESULTS: We came out with a framework based on the transformation of a physiological adaptative behaviour the 'eco-distress'. It is composed of three dimensions: eco-anger, eco-grief and eco-worry, it is not debilitating in daily life and promotes coping strategies such as management of negative emotions and pro-environmental behaviours (PEB). It can transform itself into a pathological state, the 'ecolalgia', composed of two core dimensions: eco-anxiety and eco-depression, leading to functional impairment and decrease in PEB. If ecolalgia maintains over 15 days, we propose to consider it as a full psychiatric disorder needing medical advice. CONCLUSION: This new framework enables a novel approach that is necessary for the improved management of mental health issues related to climate change.

Study of the different sleep disturbances during the prodromal phase of depression and mania in bipolar disorders.

BACKGROUND: One of the challenges in bipolar disorder (BD) lies in early detection of the illness and its recurrences, to improve prognosis. Sleep disturbances (SD) have been proposed as reliable predictive markers of conversion. While preliminary studies have explored the relationship between SD and the onset of mood episodes, the results remain heterogeneous and a few have specifically examined patients' perception of prodromal symptoms and their progression until the episode occurs. Identifying prodromes represents a crucial clinical challenge, as it enables early intervention, thereby reducing the severity of BD. Therefore, the objective of this study is to better characterize and evaluate the progressive nature of SD as prodromal symptoms of mood episodes, and patients' perception of it. METHODS: Patients diagnosed with BD, either hospitalized or seeking treatment for a (hypo)manic or depressive episode benefited from standardized questionnaires, structured interviews, and self-report questionnaires to evaluate SD prior to the current episode, as well as sociodemographic and clinical information. RESULTS: Out of the 41 patients included, 59% spontaneously reported SD prior to the episode, appearing 90 days before depression and 35 days before mania (pre-indexed/spontaneous reports: 51.22% insomnia complaints, 4.88% hypersomnolence complaints, 7.32% parasomnias, 2.44% sleep movements). After inquiry about specific SD, the percentage of patients reporting prodromal SD increased significantly to 83%, appearing 210 days before depression and 112.5 days before mania (post-indexed reports: 75.61% presented with insomnia complaints appearing 150 days before depression and 20 days before mania, 46.34% had hypersomnolence complaints appearing 60 days before depression, 43.9% had parasomnias appearing 210 days before depression and 22.5 days before mania, 36.59% had sleep movements appearing 120 days before depression and 150 days before mania). Of note, bruxism appeared in 35% of patients before mania, and restless legs syndrome in 20% of patients before depression. CONCLUSION: This study highlights the very high prevalence of SD prior to a mood episode in patients with BD with differences between depressive and manic episodes. The more systematic screening of sleep alterations of the prodromal phase improved the recognition and characterization of different symptoms onset by patients. This underscores the need for precise questioning regarding sleep patterns in patients, to better identify the moment of transition toward a mood episode, referred to as "Chronos syndrome". The study emphasizes the importance of educating patients about the disorder and its sleep prodromal symptoms to facilitate early intervention and prevent recurrences.

Insomnia, poor sleep quality and perinatal suicidal risk: A systematic review and meta-analysis.

Suicidal risk in mothers is a public health priority. Risk factors include biological, psychological and psychosocial factors. Among the biological factors, the role of sleep disturbances as potential contributors to increased suicidal risk during the peripartum period is becoming apparent. To explore this further, we conducted a systematic review following the PRISMA criteria. Currently, 10 studies have examined the role of insomnia and poor sleep quality in suicidal risk during the peripartum period and have involved 807,760 women. The data showed that disturbed sleep and poor sleep quality increase the risk of suicidal ideation in both pregnant women with and without perinatal depression. The results of the meta-analysis indicated that insomnia and poor sleep quality increase the odds of suicidal risk in pregnant women by more than threefold (OR = 3.47; 95% CI: 2.63-4.57). Specifically, the odds ratio (OR) for poor sleep quality was 3.72 (95% CI: 2.58-5.34; p < 0.001), and for insomnia symptoms, after taking into account perinatal depression, was 4.76 (95% CI: 1.83-12.34; p < 0.001). These findings emphasise the importance of assessing and addressing sleep disturbances during the peripartum period to mitigate their adverse effects on peripartum psychopathology and suicidal risk.

Exploring emotional regulation in insomnia with and without major depressive episode.

Previous studies have highlighted the pivotal role of emotional regulation impairment in the progression of depressive and insomnia disorders, individually. Nevertheless, to date, no study has undertaken a direct comparison of the emotional profiles in individuals experiencing insomnia with or without major depressive episode (MDE). In this study, our objective was to closely examine multiple aspects of emotional regulation among individuals experiencing insomnia, with or without concurrent depression. This descriptive observational study involved 57 participants, comprising 27 individuals with comorbid chronic insomnia and MDE, and 30 with chronic insomnia alone. All participants completed self-questionnaires assessing aspects of emotional regulation: the Affect Intensity Measure (intensity), Affective Lability Scale (lability), Temperament Evaluation of Memphis Pisa Paris and San Diego Autoquestionnaire (temperament), Cognitive Emotion Regulation Questionnaire (cognitive strategies), and Multidimensional Assessment of Thymic States (reactivity). There were statistically significant differences between the group with insomnia with MDE and insomnia without MDE in terms of anxiety/depression lability. Discrepancies also manifested in terms of activation or inhibition in motor activity and motivation. Additionally, a noteworthy variance in cognitive strategies for emotional regulation was observed, specifically in self-blame and catastrophising. From a cognitive perspective, patients with insomnia and a MDE exhibited a greater inclination towards self-blame and catastrophising, in contrast to those with insomnia only. Behaviourally, the former group demonstrated heightened inhibition of motivation and motor activity. These findings underscore the importance of larger-scale investigations to validate these insights and pave the way for clinical prospects centred around emotional regulation, ultimately fostering personalised treatments for insomnia.

The electroretinography to identify biomarkers of idiopathic hypersomnia and narcolepsy type 1.

Hypersomnia spectrum disorders are underdiagnosed and poorly treated due to their heterogeneity and absence of biomarkers. The electroretinography has been proposed as a proxy of central dysfunction and has proved to be valuable to differentiate certain psychiatric disorders. Hypersomnolence is a shared core feature in central hypersomnia and psychiatric disorders. We therefore aimed to identify biomarkers by studying the electroretinography profile in patients with narcolepsy type 1, idiopathic hypersomnia and in controls. Cone, rod and retinal ganglion cells electrical activity were recorded with flash-electroretinography in non-dilated eye of 31 patients with idiopathic hypersomnia (women 84%, 26.6 ± 5.9 years), 19 patients with narcolepsy type 1 (women 63%, 36.6 ± 12.7 years) and 43 controls (women 58%, 30.6 ± 9.3 years). Reduced cone a-wave amplitude (p = 0.039) and prolonged cone (p = 0.022) and rod b-wave (p = 0.009) latencies were observed in patients with narcolepsy type 1 as compared with controls, while prolonged photopic negative response-wave latency (retinal ganglion cells activity) was observed in patients with idiopathic hypersomnia as compared with controls (p = 0.033). The rod and cone b-wave latency clearly distinguished narcolepsy type 1 from idiopathic hypersomnia and controls (area under the curve > 0.70), and the photopic negative response-wave latency distinguished idiopathic hypersomnia and narcolepsy type 1 from controls with an area under the curve > 0.68. This first original study shows electroretinography anomalies observed in patients with hypersomnia. Narcolepsy type 1 is associated with impaired cone and rod responses, whereas idiopathic hypersomnia is associated with impaired retinal ganglion cells response, suggesting different phototransduction alterations in both hypersomnias. Although these results need to be confirmed with a larger sample size, the electroretinography may be a promising tool for clinicians to differentiate hypersomnia subtypes.

A combined computational and experimental investigation of the filtration function of splenic macrophages in sickle cell disease.

Being the largest lymphatic organ in the body, the spleen also constantly controls the quality of red blood cells (RBCs) in circulation through its two major filtration components, namely interendothelial slits (IES) and red pulp macrophages. In contrast to the extensive studies in understanding the filtration function of IES, fewer works investigate how the splenic macrophages retain the aged and diseased RBCs, i.e., RBCs in sickle cell disease (SCD). Herein, we perform a computational study informed by companion experiments to quantify the dynamics of RBCs captured and retained by the macrophages. We first calibrate the parameters in the computational model based on microfluidic experimental measurements for sickle RBCs under normoxia and hypoxia, as those parameters are not available in the literature. Next, we quantify the impact of key factors expected to dictate the RBC retention by the macrophages in the spleen, namely, blood flow conditions, RBC aggregation, hematocrit, RBC morphology, and oxygen levels. Our simulation results show that hypoxic conditions could enhance the adhesion between the sickle RBCs and macrophages. This, in turn, increases the retention of RBCs by as much as four-fold, which could be a possible cause of RBC congestion in the spleen of patients with SCD. Our study on the impact of RBC aggregation illustrates a 'clustering effect', where multiple RBCs in one aggregate can make contact and adhere to the macrophages, leading to a higher retention rate than that resulting from RBC-macrophage pair interactions. Our simulations of sickle RBCs flowing past macrophages for a range of blood flow velocities indicate that the increased blood velocity could quickly attenuate the function of the red pulp macrophages on detaining aged or diseased RBCs, thereby providing a possible rationale for the slow blood flow in the open circulation of the spleen. Furthermore, we quantify the impact of RBC morphology on their tendency to be retained by the macrophages. We find that the sickle and granular-shaped RBCs are more likely to be filtered by macrophages in the spleen. This finding is consistent with the observation of low percentages of these two forms of sickle RBCs in the blood smear of SCD patients. Taken together, our experimental and simulation results aid in our quantitative understanding of the function of splenic macrophages in retaining the diseased RBCs and provide an opportunity to combine such knowledge with the current knowledge of the interaction between IES and traversing RBCs to apprehend the complete filtration function of the spleen in SCD.

Retention of uninfected red blood cells causing congestive splenomegaly is the major mechanism of anemia in malaria.

Splenomegaly frequently occurs in patients with Plasmodium falciparum (Pf) or P. vivax (Pv) malarial anemia, but mechanisms underlying this co-occurrence are unclear. In malaria-endemic Papua, Indonesia, we prospectively analyzed red blood cell (RBC) concentrations in the spleen and spleen-mimetic retention in 37 subjects splenectomized for trauma or hyperreactive splenomegaly, most of whom were infected with Plasmodium. Splenomegaly (median 357 g [range: 80-1918 g]) was correlated positively with the proportion of red-pulp on histological sections (median 88.1% [range: 74%-99.4%]; r = .59, p = .0003) and correlated negatively with the proportion of white-pulp (median 8.3% [range: 0.4%-22.9%]; r = -.50, p = .002). The number of RBC per microscopic field (>95% uninfected) was correlated positively with spleen weight in both Pf-infected (r = .73; p = .017) and Pv-infected spleens (r = .94; p = .006). The median estimated proportion of total-body RBCs retained in Pf-infected spleens was 8.2% (range: 1.0%-33.6%), significantly higher than in Pv-infected (2.6% [range: 0.6%-23.8%]; p = .015) and PCR-negative subjects (2.5% [range: 1.0%-3.3%]; p = .006). Retained RBCs accounted for over half of circulating RBC loss seen in Pf infections. The proportion of total-body RBC retained in Pf- and Pv-infected spleens correlated negatively with hemoglobin concentrations (r = -.56, p = .0003), hematocrit (r = -.58, p = .0002), and circulating RBC counts (r = -.56, p = .0003). Splenic CD71-positive reticulocyte concentrations correlated with spleen weight in Pf (r = 1.0; p = .003). Retention rates of peripheral and splenic RBCs were correlated negatively with circulating RBC counts (r = -.69, p = .07 and r = -.83, p = .008, respectively). In conclusion, retention of mostly uninfected RBC in the spleen, leading to marked congestion of the red-pulp, was associated with splenomegaly and is the major mechanism of anemia in subjects infected with Plasmodium, particularly Pf.

Exploring actigraphy as a digital phenotyping measure: A study on differentiating psychomotor agitation and retardation in depression.

INTRODUCTION: Psychomotor activity stands out as a crucial symptom in characterizing behaviors associated with depression. This study aims to explore the potential of actigraphy as a tool for digital phenotyping in characterizing symptoms of psychomotor agitation and retardation, which are clinically challenging dimensions to capture, in patients diagnosed with major depressive episode (MDE) according to DSM-5 criteria. METHODS: We compared rest-activity circadian rhythm biomarkers measured by the Motion Watch 8 actigraphy between 58 (78.4%) patients with MDE and psychomotor retardation (PMR), and 16 (21.6%) patients with MDE and psychomotor agitation (PMA), according to DSM-5 criteria. RESULTS: Actigraphy allowed to objectively report PMA through heightened activity over a 24-h period, while PMR manifests as reduced activity during the most active 10 h. Lower rest-activity rhythm (RAR) amplitude in PMR was accompanied by increased irregularities in intra- and inter-day rhythms. Interestingly, actigraphy emerges as an objective tool to measure the characteristics of the active and rest periods, free from the confounding effects of sleep disturbances. Indeed, no differences in sleep disturbances were identified between patients exhibiting psychomotor agitation and those displaying PMR. CONCLUSION: Digital phenotyping through actigraphy may aid in distinguishing psychomotor retardation and psychomotor agitation allowing for a more precise characterization of the depression phenotype. When integrated with clinical assessment, measurements from actigraphy could offer additional insights into activity rhythms alongside subjective assessments and hold the potential to augment existing clinical decision-making processes in psychiatry.

A role for keratin 17 during DNA damage response and tumor initiation.

High levels of the intermediate filament protein keratin 17 (K17) are associated with poor prognoses for several human carcinomas. Studies in mouse models have shown that K17 expression is positively associated with growth, survival, and inflammation in skin and that lack of K17 delays onset of tumorigenesis. K17 occurs in the nucleus of human and mouse tumor keratinocytes where it impacts chromatin architecture, gene expression, and cell proliferation. We report here that K17 is induced following DNA damage and promotes keratinocyte survival. The presence of nuclear K17 is required at an early stage of the double-stranded break (DSB) arm of the DNA damage and repair (DDR) cascade, consistent with its ability to associate with key DDR effectors, including γ-H2A.X, 53BP1, and DNA-PKcs. Mice lacking K17 or with attenuated K17 nuclear import showed curtailed initiation in a two-step skin carcinogenesis paradigm. The impact of nuclear-localized K17 on DDR and cell survival provides a basis for the link between K17 induction and poor clinical outcomes for several human carcinomas.

Protocol and validity testing of femoroacetabular posterior translation with dynamic hip ultrasonography.

OBJECTIVE: To describe femoroacetabular posterior translation (FAPT) using dynamic hip ultrasonography (DHUS), and to determine the inter- and intra-rater reliability of hip ultrasound measurements of FAPT. MATERIALS AND METHODS: The study design was a feasibility study of 13 healthy young adults (26 hips) using test-retest analysis. The data was collected prospectively over a 2-week time period. Three DHUS measurements (posterior neutral (PN), flexion, adduction, and internal rotation (PFADIR), and stand and load (PStand) were measured by four independent raters (2 senior who divided the cohort, 1 intermediate, 1 junior) at two time points for bilateral hips of each participant. Reliability was assessed by calculating the intraclass correlation coefficient (ICC) along with 95% confidence intervals (CIs) for each rater and across all raters. RESULTS: A total of 468 US scans were completed. The mean age of the cohort was 25.7 years (SD 5.1 years) and 54% were female. The inter-rater reliability was excellent for PFADIR (ICC 0.85 95% CI 0.76-0.91), good for PN (ICC 0.69 95% CI 0.5-0.81), and good for PStand (ICC 0.72 95% CI 0.55-0.83). The intra-rater reliability for all raters was good for PFADIR (ICC 0.60 95% CI 0.44-0.73), fair for PN (ICC 0.42 95% CI 0.21-0.59), and fair for PStand (ICC 0.42 95% CI 0.22-0.59). CONCLUSION: This is the first study to present a protocol using dynamic ultrasonography to measure FAPT. DHUS measure for FAPT was shown to be reliable across raters with varying levels of ultrasound experience.

NnU-Net versus mesh growing algorithm as a tool for the robust and timely segmentation of neurosurgical 3D images in contrast-enhanced T1 MRI scans.

PURPOSE: This study evaluates the nnU-Net for segmenting brain, skin, tumors, and ventricles in contrast-enhanced T1 (T1CE) images, benchmarking it against an established mesh growing algorithm (MGA). METHODS: We used 67 retrospectively collected annotated single-center T1CE brain scans for training models for brain, skin, tumor, and ventricle segmentation. An additional 32 scans from two centers were used test performance compared to that of the MGA. The performance was measured using the Dice-Sørensen coefficient (DSC), intersection over union (IoU), 95th percentile Hausdorff distance (HD95), and average symmetric surface distance (ASSD) metrics, with time to segment also compared. RESULTS: The nnU-Net models significantly outperformed the MGA (p < 0.0125) with a median brain segmentation DSC of 0.971 [95CI: 0.945-0.979], skin: 0.997 [95CI: 0.984-0.999], tumor: 0.926 [95CI: 0.508-0.968], and ventricles: 0.910 [95CI: 0.812-0.968]. Compared to the MGA's median DSC for brain: 0.936 [95CI: 0.890, 0.958], skin: 0.991 [95CI: 0.964, 0.996], tumor: 0.723 [95CI: 0.000-0.926], and ventricles: 0.856 [95CI: 0.216-0.916]. NnU-Net performance between centers did not significantly differ except for the skin segmentations Additionally, the nnU-Net models were faster (mean: 1139 s [95CI: 685.0-1616]) than the MGA (mean: 2851 s [95CI: 1482-6246]). CONCLUSIONS: The nnU-Net is a fast, reliable tool for creating automatic deep learning-based segmentation pipelines, reducing the need for extensive manual tuning and iteration. The models are able to achieve this performance despite a modestly sized training set. The ability to create high-quality segmentations in a short timespan can prove invaluable in neurosurgical settings.

Predictive Models of Long-Term Outcome in Patients with Moderate to Severe Traumatic Brain Injury are Biased Toward Mortality Prediction.

BACKGROUND: The prognostication of long-term functional outcomes remains challenging in patients with traumatic brain injury (TBI). Our aim was to demonstrate that intensive care unit (ICU) variables are not efficient to predict 6-month functional outcome in survivors with moderate to severe TBI (msTBI) but are mostly associated with mortality, which leads to a mortality bias for models predicting a composite outcome of mortality and severe disability. METHODS: We analyzed the data from the multicenter randomized controlled Continuous Hyperosmolar Therapy in Traumatic Brain-Injured Patients trial and developed predictive models using machine learning methods and baseline characteristics and predictors collected during ICU stay. We compared our models' predictions of 6-month binary Glasgow Outcome Scale extended (GOS-E) score in all patients with msTBI (unfavorable GOS-E 1-4 vs. favorable GOS-E 5-8) with mortality (GOS-E 1 vs. GOS-E 2-8) and binary functional outcome in survivors with msTBI (severe disability GOS-E 2-4 vs. moderate to no disability GOS-E 5-8). We investigated the link between ICU variables and long-term functional outcomes in survivors with msTBI using predictive modeling and factor analysis of mixed data and validated our hypotheses on the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. RESULTS: Based on data from 370 patients with msTBI and classically used ICU variables, the prediction of the 6-month outcome in survivors was inefficient (mean area under the receiver operating characteristic 0.52). Using factor analysis of mixed data graph, we demonstrated that high-variance ICU variables were not associated with outcome in survivors with msTBI (p = 0.15 for dimension 1, p = 0.53 for dimension 2) but mostly with mortality (p < 0.001 for dimension 1), leading to a mortality bias for models predicting a composite outcome of mortality and severe disability. We finally identified this mortality bias in the IMPACT model. CONCLUSIONS: We demonstrated using machine learning-based predictive models that classically used ICU variables are strongly associated with mortality but not with 6-month outcome in survivors with msTBI, leading to a mortality bias when predicting a composite outcome of mortality and severe disability.