A scalable and cGMP-compatible autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa.

We present Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a scalable platform producing autologous organotypic iPS cell-derived induced skin composite (iSC) grafts for definitive treatment. Clinical-grade manufacturing integrates CRISPR-mediated genetic correction with reprogramming into one step, accelerating derivation of COL7A1-edited iPS cells from patients. Differentiation into epidermal, dermal and melanocyte progenitors is followed by CD49f-enrichment, minimizing maturation heterogeneity. Mouse xenografting of iSCs from four patients with different mutations demonstrates disease modifying activity at 1 month. Next-generation sequencing, biodistribution and tumorigenicity assays establish a favorable safety profile at 1-9 months. Single cell transcriptomics reveals that iSCs are composed of the major skin cell lineages and include prominent holoclone stem cell-like signatures of keratinocytes, and the recently described Gibbin-dependent signature of fibroblasts. The latter correlates with enhanced graftability of iSCs. In conclusion, DEBCT overcomes manufacturing and safety roadblocks and establishes a reproducible, safe, and cGMP-compatible therapeutic approach to heal lesions of DEB patients.

Myeloid cell replacement is neuroprotective in chronic experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination of the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) shows promising benefits for relapsing-remitting MS in open-label clinical studies, but the cellular mechanisms underlying its therapeutic effects remain unclear. Using single-nucleus RNA sequencing, we identify a reactive myeloid cell state in chronic experimental autoimmune encephalitis (EAE) associated with neuroprotection and immune suppression. HCT in EAE mice results in an increase of the neuroprotective myeloid state, improvement of neurological deficits, reduced number of demyelinated lesions, decreased number of effector T cells and amelioration of reactive astrogliosis. Enhancing myeloid cell incorporation after a modified HCT further improved these neuroprotective effects. These data suggest that myeloid cell manipulation or replacement may be an effective therapeutic strategy for chronic inflammatory conditions of the CNS.

Early prediction of ventricular peritoneal shunt dependency in aneurysmal subarachnoid haemorrhage patients by recurrent neural network-based machine learning using routine intensive care unit data.

Aneurysmal subarachnoid haemorrhage (aSAH) can lead to complications such as acute hydrocephalic congestion. Treatment of this acute condition often includes establishing an external ventricular drainage (EVD). However, chronic hydrocephalus develops in some patients, who then require placement of a permanent ventriculoperitoneal (VP) shunt. The aim of this study was to employ recurrent neural network (RNN)-based machine learning techniques to identify patients who require VP shunt placement at an early stage. This retrospective single-centre study included all patients who were diagnosed with aSAH and treated in the intensive care unit (ICU) between November 2010 and May 2020 (n = 602). More than 120 parameters were analysed, including routine neurocritical care data, vital signs and blood gas analyses. Various machine learning techniques, including RNNs and gradient boosting machines, were evaluated for their ability to predict VP shunt dependency. VP-shunt dependency could be predicted using an RNN after just one day of ICU stay, with an AUC-ROC of 0.77 (CI: 0.75-0.79). The accuracy of the prediction improved after four days of observation (Day 4: AUC-ROC 0.81, CI: 0.79-0.84). At that point, the accuracy of the prediction was 76% (CI: 75.98-83.09%), with a sensitivity of 85% (CI: 83-88%) and a specificity of 74% (CI: 71-78%). RNN-based machine learning has the potential to predict VP shunt dependency on Day 4 after ictus in aSAH patients using routine data collected in the ICU. The use of machine learning may allow early identification of patients with specific therapeutic needs and accelerate the execution of required procedures.

Patient perception and satisfaction in awake burr hole trepanation under local anesthesia for evacuation of chronic subdural hematoma.

Evacuation of chronic subdural hematoma (CSDH) will be one of the most common neurosurgical procedures in the future in the increasingly aging societies. Performing cranial surgery on awake patients may place a psychological burden on them. Aim of this study was to evaluate the psychological distress of patients during awake CSDH relief. Patients with awake evacuation of CSDH via burr hole trepanation were included in our monocentric prospective study. Patient perception and satisfaction were measured using standardized surveys 3-5 days and 6 months after surgery. Among other questionnaires, the Hospital Anxiety and Depression and the Impact of Event Scale, were used to quantify patients' stress. A total of 50 patients (mean age 72.9 years (range 51 - 92)) were included. During surgery, 28 patients reported pain (mean 4.1 (SD 3.3)). Postoperatively, 26 patients experienced pain (mean 2.7 (SD 2.6)). Patients' satisfaction with intraoperative communication was reported with a mean of 8.3 (SD 2.1). There was a significant negative correlation between intraoperatively perceived pain and satisfaction with intraoperative communication (p = 0.023). Good intraoperative communication during evacuation of CSDH in awake patients is associated with positive patient perception and correlates with pain reduction.

Impact of pre-hospital handling and initial time to cranial computed tomography on outcome in aneurysmal subarachnoid hemorrhage patients with out-of-hospital sudden cardiac arrest-a retrospective bi-centric study.

Background: Aneurysmal subarachnoid hemorrhage (SAH) presents occasionally with cardiac arrest (CA). The impact of pre-hospital and emergency room (ER) treatment on outcome remains unclear. Therefore, we investigated the impact of pre-hospital treatment, focusing on lay cardiopulmonary resuscitation (CPR), and ER handling on the outcome of SAH patients with out-of-hospital CA (OHCA). Methods: In this bi-centric retrospective analysis, we reviewed SAH databases for OHCA and CPR from January 2011 to June 2021. Patients were analyzed for general clinical and epidemiological parameters. CPR data were obtained from ambulance reports and information on ER handling from the medical records. Data were correlated with patient survival at hospital discharge as a predefined outcome parameter. Results: Of 1,120 patients with SAH, 45 (4.0%) were identified with OHCA and CPR, 38 of whom provided all required information and were included in this study. Time to resuscitation was significantly shorter with lay resuscitation (5.3 ± 5.2 min vs. 0.3 ± 1.2 min, p = 0.003). Nineteen patients were not initially scheduled for cranial computed tomography (CCT), resulting in a significantly longer time interval to first CCT (mean ± SD: 154 ± 217 min vs. 40 ± 23 min; p < 0.001). Overall survival to discharge was 31.6%. Pre-hospital lay CPR was not associated with higher survival (p = 0.632). However, we observed a shorter time to first CCT in surviving patients (p = 0.065). Conclusions: OHCA in SAH patients is not uncommon. Besides high-quality CPR, time to diagnosis of SAH appears to play an important role. We therefore recommend considering CCT diagnostics as part of the diagnostic algorithm in patients with OHCA.

A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) remains one of the grand challenges facing human society. Much controversy exists around the complex and multifaceted pathogenesis of this prevalent disease. Given strong human genetic evidence, there is little doubt, however, that microglia play an important role in preventing degeneration of neurons. For example, loss of function of the microglial gene Trem2 renders microglia dysfunctional and causes an early-onset neurodegenerative syndrome, and Trem2 variants are among the strongest genetic risk factors for AD. Thus, restoring microglial function represents a rational therapeutic approach. Here, we show that systemic hematopoietic cell transplantation followed by enhancement of microglia replacement restores microglial function in a Trem2 mutant mouse model of AD.

Acute low-pressure hydrocephalus in aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Acute and chronic hydrocephalus are common pathologies after aneurysmal subarachnoid hemorrhage (SAH). Generally, the presence of acute hydrocephalus is associated with elevated intracranial pressure (ICP) treated with a ventricular drain. Subsequently, however, pronounced hydrocephalus without elevated ICP may develop in some patients with SAH in the postacute phase. This is described as acute low-pressure hydrocephalus (aLPH), and there are very limited data in the literature of this pathology. The aim of this study was to evaluate the rate of and factors associated with aLPH and describe its clinical course. METHODS: In this retrospective single-center cohort study, the frequency and clinical characteristics of SAH-associated aLPH were investigated. Acute LPH was defined as an increase in ventricular size as measured by the Evans index, ICP within the normal range (< 5 mm Hg) at the time of ventricular enlargement, and timely neurological improvement after indwelling ventricular CSF drainage with negative pressure up to 5 cm H2O below normal level. Demographic and SAH-specific factors in patients with SAH treated using an external ventricular drain were extracted from the electronic medical chart and further analyzed. RESULTS: From November 2010 to May 2020, 15 (3.7.%) of 406 patients with SAH fulfilled the criteria for aLPH. Acute LPH was diagnosed after an average of 13.1 ± 7.7 days. The presence of IVH and its extension were associated with the occurrence of aLPH. After undergoing the transient phase of aLPH, these patients subsequently developed a chronic, typical malresorptive hydrocephalus requiring a ventriculoperitoneal shunt more often (66.7% vs 17.4%, p < 0.001) and stayed longer in the intensive care unit (27 vs 20.5 days, p = 0.043) and in the hospital (36.4 vs 26.3 days, p = 0.004). CONCLUSIONS: Acute LPH is a rare pathology in patients with SAH and negatively impacts the clinical course. It should be especially considered in patients with a lack of neurological improvement, an increase in ventricular width, and normal ICP values, so that forced CSF drainage is implemented.

Augmentation of a neuroprotective myeloid state by hematopoietic cell transplantation.

Multiple sclerosis (MS) is an autoimmune disease associated with inflammatory demyelination in the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) is under investigation as a promising therapy for treatment-refractory MS. Here we identify a reactive myeloid state in chronic experimental autoimmune encephalitis (EAE) mice and MS patients that is surprisingly associated with neuroprotection and immune suppression. HCT in EAE mice leads to an enhancement of this myeloid state, as well as clinical improvement, reduction of demyelinated lesions, suppression of cytotoxic T cells, and amelioration of reactive astrogliosis reflected in reduced expression of EAE-associated gene signatures in oligodendrocytes and astrocytes. Further enhancement of myeloid cell incorporation into the CNS following a modified HCT protocol results in an even more consistent therapeutic effect corroborated by additional amplification of HCT-induced transcriptional changes, underlining myeloid-derived beneficial effects in the chronic phase of EAE. Replacement or manipulation of CNS myeloid cells thus represents an intriguing therapeutic direction for inflammatory demyelinating disease.

Corticosteroid-Dependent Leukocytosis Masks the Predictive Potential of White Blood Cells for Delayed Cerebral Ischemia and Ventriculoperitoneal Shunt Dependency in Aneurysmatic Subarachnoid Hemorrhage.

A multitude of pathological and inflammatory processes determine the clinical course after aneurysmal subarachnoid hemorrhage (aSAH). However, our understanding of predictive factors and therapeutic consequences is limited. We evaluated the predictive value of clinically relevant factors readily available in the ICU setting, such as white blood cell (WBC) count and CRP, for two of the leading comorbidities, delayed cerebral ischemia (DCI) and ventriculoperitoneal (VP) shunt dependency in aSAH patients with and without corticosteroid treatment. We conducted a retrospective analysis of 484 aSAH patients admitted to our institution over an eight-year period. Relevant clinical factors affecting the risk of DCI and VP shunt dependency were identified and included in a multivariate logistic regression model. Overall, 233/484 (48.1%) patients were treated with corticosteroids. Intriguingly, predictive factors associated with the occurrence of DCI differed significantly depending on the corticosteroid treatment status (dexamethasone group: Hunt and Hess grade (p = 0.002), endovascular treatment (p = 0.016); no-dexamethasone group: acute hydrocephalus (p = 0.018), peripheral leukocyte count 7 days post SAH (WBC at day 7) (p = 0.009)). Similar disparities were found for VP shunt dependency (dexamethasone group: acute hydrocephalus (p = 0.002); no-dexamethasone group: WBC d7 (p = 0.036), CRP peak within 72 h (p = 0.015)). Our study shows that corticosteroid-induced leukocytosis negates the predictive prognostic potential of systemic inflammatory markers for DCI and VP shunt dependency, which has previously been neglected and should be accounted for in future studies.

Extracorporeal membrane oxygenation in traumatic brain injury - A retrospective, multicenter cohort study.

INTRODUCTION: Patients with traumatic brain injury (TBI) regularly require intensive care with prolonged invasive ventilation. Consequently, these patients are at increased risk of pulmonary failure, potentially requiring extracorporeal membrane oxygenation (ECMO). The aim of this work was to provide an overview of ECMO treatment in TBI patients based upon data captured into the TraumaRegister DGU® (TR-DGU). METHODS: A retrospective multi-center cohort analysis of patients registered in the TR-DGU was conducted. Adult patients with relevant TBI (AISHead ≥3) who had been treated in German, Austrian, or Swiss level I or II trauma centers using ECMO therapy between 2015 and 2019 were included. A multivariable logistic regression analysis was used to identify risk factors for the need for ECMO treatment. RESULTS: 12,247 patients fulfilled the inclusion criteria. The overall rate of ECMO treatment was 1.1% (134 patients). Patients on ECMO had an overall hospital mortality rate of 38% (51/134 patients) while 13% (1523/12,113 patients) of TBI patients without ECMO therapy died. Male gender (p = 0.014), AISChest 3+ (p<0.001), higher Injury Severity Score (p<0.001) and packed red blood cell (pRBC) transfusion (p<0.001) were associated with ECMO treatment. CONCLUSION: ECMO therapy is a potentially lifesaving modality for the treatment of moderate-to-severe TBI when combined with severe chest trauma and pulmonary failure. The in-hospital mortality is increased in this high-risk population, but the majority of patients is surviving.

Diffusion tensor imaging changes in patients with glioma-associated seizures.

INTRODUCTION: Structural white matter changes associated with certain epilepsy subtypes have been demonstrated using diffusion tensor imaging (DTI). This observational study aims to identify potential water diffusion abnormalities in glioma patients with associated seizures. METHODS: Two cohorts from two centers were analyzed independently: (A) Prospectively recruited patients diagnosed with glioma who received preoperative DTI to measure mean diffusivity (MD) and fractional anisotropy (FA) in regions-of-interest (ROIs) including the marginal tumor zone (TU), adjacent peritumoral white matter as well as distant ipsilateral and contralateral white matter and cortex. Data were compared between patients with and without seizures and tested for statistical significance. (B) A retrospective cohort using an alternative technical approach sampling ROIs in contrast enhancement, necrosis, non-enhancing tumor, marginal non-enhancing tumor zone, peritumoral tissue, edema and non-tumorous tissue. RESULTS: (A) The prospective study cohort consisted of 23 patients with 12 (52.2%) presenting with a history of seizures. There were no significant seizure-associated differences in MD or FA for non-tumor white matter or cortical areas. MD-TU was significantly lower in patients with seizures (p = 0.005). (B) In the retrospective cohort consisting of 46 patients with a seizure incidence of 50.0%, significantly decreased normalized values of MD were observed for non-enhancing tumor regions of non-glioblastoma multiforme (GBM) cases in patients with seizures (p = 0.022). CONCLUSION: DTI analyses in glioma patients demonstrated seizure-associated diffusion restrictions in certain tumor-related areas. No other structural abnormalities in adjacent or distant white matter or cortical regions were detected.

Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1.

Immunotherapy with anti-GD2 antibodies has advanced the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse, and little is known about mechanisms of resistance to anti-GD2 therapy. Here, we show that reduced GD2 expression was significantly correlated with the mesenchymal cell state in neuroblastoma and that a forced adrenergic-to-mesenchymal transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2-expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.

Hyperoxia is Dose-Dependently Associated with an Increase of Unfavorable Outcomes in Ventilated Patients with Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cohort Study.

BACKGROUND: Adequate oxygenation in patients with aneurysmal subarachnoid hemorrhage (SAH) is imperative. However, hyperoxia increases formation of reactive oxygen species and may be associated with a dose-dependent toxicity. We postulated a threshold for arterial partial pressure of oxygen (paO2) above which toxicity effects precipitate and sought to study the effects on 30-day mortality, favorable outcome at discharge and at 3 months, and delayed cerebral ischemia. METHODS: In this retrospective single-center cohort study, patients with SAH and mechanical ventilation > 72 h were included. Oxygen integrals were calculated above the following thresholds: 80, 100, 120, and 150 mm Hg and time-weighted mean paO2. All calculations were done from admission to end of day 1, day 3, and day 14. We conducted multivariable logistic regression analyses adjusted for age, sex, duration of ventilation, and Hunt and Hess grade. Time-weighted mean paO2 was categorized by quartiles. Favorable outcome was defined as Glasgow Outcome Scale scores of 4 and 5. RESULTS: From November 2010 to February 2021, 282 of 549 patients fulfilled the inclusion criteria. Odds ratios for 30-day mortality increased dose dependently and were as follows: 1.07 (95% confidence interval [CI] 1.03-1.11; p = 0.001) for each 1 mm Hg per day above 80 mm Hg; 1.16 (95% CI 1.07-1.27), above 100 mm Hg; 1.36 (95% CI 1.15-1.61), above 120 mm Hg; and 1.59 (95% CI 1.22-2.08), above 150 mm Hg (all p < 0.001) at day 14. For favorable outcome at 3 months, odds ratios were 0.96 (95% CI 0.92-0.99) for each 1 mm Hg per day above 80 mm Hg; 0.90 (95% CI 0.84-0.98), above 100 mm Hg; 0.83 (95% CI 0.72-0.97), above 120 mm Hg; and 0.77 (95% CI 0.61-0.97), above 150 mm Hg (all p < 0.05). For time-weighted mean paO2, lowest 30-day mortality and highest favorable outcome at 3 months were found in the second quartile (78-85 mm Hg). Thirty-day mortality increased above 93 mm Hg (fourth quartile), with an odds ratio of 3.4 (95% CI 1.4-8.4, p = 0.007). Odds ratios for favorable outcome at 3 months were 0.28 (95% CI 0.12-0.69), 0.27 (95% CI 0.11-0.67), and 0.24 (95% CI 0.10-0.59) for the first, third, and fourth quartiles, respectively (all p < 0.01). No significant association was found at day 1 and day 3, for favorable outcome at discharge, or for delayed cerebral ischemia. CONCLUSIONS: Integrals above the defined paO2 thresholds were dose-dependently associated with an increase in mortality in ventilated patients with SAH. When we considered time-weighted mean paO2, unfavorable outcomes and 30-day mortality were more frequent both below and above a certain range. Unfavorable outcomes increased in paO2 ranges usually defined as normoxia. This emphasizes the necessity to further characterize oxygenation thresholds in ventilated patients with SAH in prospective clinical studies.

False-positive results in transcranial motor evoked potentials for outcome prognostication during surgery for supratentorial lesions.

During monitoring of motor evoked potentials (MEP) elicited by transcranial electrical stimulation (TES) for prognostication of postoperative motor deficit, significant MEP changes without postoperative deterioration of motor function represent false-positive results. We aimed to investigate this phenomenon in a large series of patients who underwent resection of supratentorial lesions. TES was applied in 264 patients during resection of motor-eloquent supratentorial lesions. MEP were recorded bilaterally from arm, leg, and/ or facial muscles. The threshold criterion was applied assessing percentage increase in threshold level, which was considered significant if being > 20% higher on affected side than on the unaffected side. Subcortical stimulation was additionally applied to estimate the distance to corticospinal tract. Motor function was evaluated at 24 h after surgery and at 3-month follow-up. Patients with false-positive results were analyzed regarding tumor location, tumor volume, and characteristics of the monitoring. MEP were recorded from 399 muscles (264 arm muscles, 75 leg muscles, and 60 facial muscles). Motor function was unchanged postoperatively in 359 muscles in 228 patients. Among these cases, the threshold level did not change significantly in 354 muscles in 224 patients, while it increased significantly in the remaining 5 muscles in 4 patients (abductor pollicis brevis in all four patients and orbicularis oris in one patient), leading to a false-positive rate of 1.1%. Tumor volume, opening the ventricle, and negative subcortical stimulation did not significantly correlate with false-positive results, while the tumor location in the parietal lobe dorsal to the postcentral gyrus correlated significantly (p = 0.012, odds ratio 11.2, 95% CI 1.8 to 69.8). False-negative results took place in 1.1% of cases in a large series of TES-MEP monitoring using the threshold criterion. Tumor location in the parietal lobe dorsal to the postcentral gyrus was the only predictor of false-positive results.

The Cerebral Collateral Cascade: Comprehensive Blood Flow in Ischemic Stroke.

BACKGROUND AND PURPOSE: Robust cerebral collaterals are associated with favorable outcomes in patients with acute ischemic stroke due to large vessel occlusion treated by thrombectomy. However, collateral status assessment mostly relies on single imaging biomarkers and a more comprehensive holistic approach may provide deeper insights into the biology of collateral perfusion on medical imaging. Comprehensive collateralization is defined as blood flow of cerebral arteries through the brain tissue and into draining veins. We hypothesized that a comprehensive analysis of the cerebral collateral cascade (CCC) on an arterial, tissue and venous level would predict clinical and radiological outcomes. MATERIALS AND METHODS: Multicenter retrospective cohort study of acute stroke patients undergoing thrombectomy triage. CCC was determined by quantifying pial arterial collaterals, tissue-level collaterals, and venous outflow. Pial arterial collaterals were determined by CT angiography, tissue-level collaterals were assessed on CT perfusion. Venous outflow was assessed on CT angiography using the cortical vein opacification score. 3 groups were defined: CCC+ (good pial collaterals, tissue-level collaterals, and venous outflow), CCC- (poor pial collaterals, tissue-level collaterals, and venous outflow) and CCCmixed (remainder of patients). Primary outcome was functional independence (modified Rankin Scale: 0-2) at 90-days. Secondary outcome was final infarct volume. RESULTS: 647 patients met inclusion criteria: 176 CCC+, 345 CCC mixed and 126 CCC-. Multivariable ordinal logistic regression showed that CCC+ predicted good functional outcomes (OR=18.9 [95% CI 8-44.5]; p<0.001) compared to CCC- and CCCmixed patients. CCCmixed patients likely had better functional outcomes compared to CCC- patients (OR=2.5 [95% CI 1.2-5.4]; p=0.014). Quantile regression analysis (50th percentile) showed that CCC+ (ß: -78.5, 95% CI -96.0- -61.1; p<0.001) and CCCmixed (ß: -64.0, 95% CI -82.4- -45.6; p<0.001) profiles were associated with considerably lower final infarct volumes compared to CCC- profiles. CONCLUSION: Comprehensive assessment of the collateral blood flow cascade in acute stroke patients is a strong predictor of clinical and radiological outcomes in patients treated by thrombectomy.

Treatment of a genetic brain disease by CNS-wide microglia replacement.

Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.

A recurrent machine learning model predicts intracranial hypertension in neurointensive care patients.

The evolution of intracranial pressure (ICP) of critically ill patients admitted to a neurointensive care unit (ICU) is difficult to predict. Besides the underlying disease and compromised intracranial space, ICP is affected by a multitude of factors, many of which are monitored on the ICU, but the complexity of the resulting patterns limits their clinical use. This paves the way for new machine learning techniques to assist clinical management of patients undergoing invasive ICP monitoring independent of the underlying disease. An institutional cohort (ICP-ICU) of patients with invasive ICP monitoring (n = 1346) was used to train recurrent machine learning models to predict the occurrence of ICP increases of ≥22 mmHg over a long (>2 h) time period in the upcoming hours. External validation was performed on patients undergoing invasive ICP measurement in two publicly available datasets [Medical Information Mart for Intensive Care (MIMIC, n = 998) and eICU Collaborative Research Database (n = 1634)]. Different distances (1-24 h) between prediction time point and upcoming critical phase were evaluated, demonstrating a decrease in performance but still robust AUC-ROC with larger distances (24 h AUC-ROC: ICP-ICU 0.826 ± 0.0071, MIMIC 0.836 ± 0.0063, eICU 0.779 ± 0.0046, 1 h AUC-ROC: ICP-ICU 0.982 ± 0.0008, MIMIC 0.965 ± 0.0010, eICU 0.941 ± 0.0025). The model operates on sparse hourly data and is stable in handling variable input lengths and missingness through its nature of recurrence and internal memory. Calculation of gradient-based feature importance revealed individual underlying decisions for our long short time memory-based model and thereby provided improved clinical interpretability. Recurrent machine learning models have the potential to be an effective tool for the prediction of ICP increases with high translational potential.

Multiparametric Monitoring of Early Pathophysiological Changes in a Porcine Model of Sequential Focal and Global Cerebral Ischemia.

OBJECTIVE: Large animal models of cerebral ischemia have the potential to increase the translational value of stroke research. This study aims to measure early changes of brain tissue oxygen pressure (ptiO2) and cerebral blood flow (CBF) to characterize a porcine model of sequential middle cerebral artery occlusion (MCAO) and common carotid artery occlusion (CCAO). METHODS: Eight juvenile German Landrace pigs received unilateral MCAO via a frontotemporal approach under continuous intraparenchymal multiparametric monitoring. Insufficient reduction (i.e., <50% in both ptiO2 and CBF) was followed by additional bilateral CCAO. Neurodegenerative changes were detected by Fluoro-Jade B (FJB) staining. RESULTS: Only 1 of 8 animals demonstrated a decrease of >50% in both ptiO2 and CBF after MCAO. Additional CCAO in 7 pigs led to a significant reduction of both ipsilateral and contralateral ptiO2 (P < 0.01) but not of CBF. There was no difference in ptiO2 and FJB positive area between hemispheres in this group. Measurement of ptiO2 correlated negatively with the FJB positive area (P < 0.05). CONCLUSIONS: Intraparenchymal multiparametric measurements of acute changes in ptiO2 and CBF were variable after MCAO. Bilateral CCAO led to a consistent decrease in ptiO2 and correlated with early degenerative histologic changes, but CBF did not. Real-time procedural ptiO2 monitoring could provide useful guidance in large animal ischemia models. Feasibility in the context of global cerebral hypoperfusion is demonstrated.

Traumatic brain injury with concomitant injury to the spleen: characteristics and mortality of a high-risk trauma cohort from the TraumaRegister DGU®.

PURPOSE: Based on the hypothesis that systemic inflammation contributes to secondary injury after initial traumatic brain injury (TBI), this study aims to describe the effect of splenectomy on mortality in trauma patients with TBI and splenic injury. METHODS: A retrospective cohort analysis of patients prospectively registered into the TraumaRegister DGU® (TR-DGU) with TBI (AISHead ≥ 3) combined with injury to the spleen (AISSpleen ≥ 1) was conducted. Multivariable logistic regression modeling was performed to adjust for confounding factors and to assess the independent effect of splenectomy on in-hospital mortality. RESULTS: The cohort consisted of 1114 patients out of which 328 (29.4%) had undergone early splenectomy. Patients with splenectomy demonstrated a higher Injury Severity Score (median: 34 vs. 44, p < 0.001) and lower Glasgow Coma Scale (median: 9 vs. 7, p = 0.014) upon admission. Splenectomized patients were more frequently hypotensive upon admission (19.8% vs. 38.0%, p < 0.001) and in need for blood transfusion (30.3% vs. 61.0%, p < 0.001). The mortality was 20.7% in the splenectomy group and 10.3% in the remaining cohort. After adjustment for confounding factors, early splenectomy was not found to exert a significant effect on in-hospital mortality (OR 1.29 (0.67-2.50), p = 0.45). CONCLUSION: Trauma patients with TBI and spleen injury undergoing splenectomy demonstrate a more severe injury pattern, more compromised hemodynamic status and higher in-hospital mortality than patients without splenectomy. Adjustment for confounding factors reveals that the splenectomy procedure itself is not independently associated with survival.