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Background: Targeting a cerebral perfusion pressure optimal for cerebral autoregulation (CPPopt) has been gaining more attention to prevent secondary damage after acute neurological injury. Brain tissue oxygenation (PbtO 2 ) can identify insufficient cerebral blood flow and secondary brain injury. Defining the relationship between CPPopt and PbtO 2 after aneurysmal subarachnoid hemorrhage may result in (1) mechanistic insights into whether and how CPPopt-based strategies might be beneficial and (2) establishing support for the use of PbtO 2 as an adjunctive monitor for adequate or optimal local perfusion. Methods: We performed a retrospective analysis of a prospectively collected 2-center dataset of patients with aneurysmal subarachnoid hemorrhage with or without later diagnosis of delayed cerebral ischemia (DCI). CPPopt was calculated as the cerebral perfusion pressure (CPP) value corresponding to the lowest pressure reactivity index (moving correlation coefficient of mean arterial and intracranial pressure). The relationship of (hourly) deltaCPP (CPP−CPPopt) and PbtO 2 was investigated using natural spline regression analysis. Data after DCI diagnosis were excluded. Brain tissue hypoxia was defined as PbtO 2 Results: One hundred thirty-one patients were included with a median of 44.0 (interquartile range, 20.8–78.3) hourly CPPopt/PbtO2 datapoints. The regression plot revealed a nonlinear relationship between PbtO 2 and deltaCPP ( P 2 decrease with deltaCPP 2 with deltaCPP ≥0mmHg, although there was substantial individual variation. Brain tissue hypoxia (34.6% of all measurements) was more frequent with deltaCPP Conclusions: We found a nonlinear relationship between PbtO 2 and deviation of patients’ CPP from CPPopt in aneurysmal subarachnoid hemorrhage patients in the pre-DCI period. CPP values below calculated CPPopt were associated with lower PbtO 2 . Nevertheless, the nature of PbtO 2 measurements is complex, and the variability is high. Combined multimodality monitoring with CPP/CPPopt and PbtO 2 should be recommended to redefine individual pressure targets (CPP/CPPopt) and retain the option to detect local perfusion deficits during DCI (PbtO 2 ), which cannot be fulfilled by both measurements interchangeably.

Background: Rescue treatment for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage can include induced hypertension (iHTN) and, in refractory cases, endovascular approaches, of which selective, continuous intraarterial nimodipine (IAN) is one variant. The combination of iHTN and IAN can dramatically increase vasopressor demand. In case of unsustainable doses, iHTN is often prioritized over IAN. However, evidence in this regard is largely lacking. We investigated the effects of a classical (iHTN+IAN) and modified (IAN only ) treatment protocol for refractory DCI in an observational study. Methods: Rescue treatment for DCI was initiated with iHTN (target >180 mm Hg systolic) and escalated to IAN in refractory cases. Until July 2018, both iHTN and IAN were offered in cases refractory to iHTN alone. After protocol modification, iHTN target was preemptively lowered to >120 mm Hg when IAN was initiated (IAN only ). Primary outcome was noradrenaline demand. Secondary outcomes included noradrenaline-associated complications, brain tissue oxygenation, DCI-related infarction and favorable 6-month outcome (Glasgow Outcome Scale 4–5). Results: N=29 and n=20 patients were treated according to the classical and modified protocol, respectively. Protocol modification resulted in a significant reduction of noradrenaline demand (iHTN+IAN 0.70±0.54 µg/kg per minute and IAN only 0.26±0.20 µg/kg per minute, P P P =0.95). Incidence of DCI-related infarction (45.0% versus 41.1%, odds ratio, 1.16 [0.37–3.66]; P =0.80) and favorable clinical outcome (55.6% versus 40.0%, odds ratio, 1.88 [0.55–6.39]; P =0.32) were similar. Brain tissue oxygenation was significantly higher with IANonly (26.6±12.8, 39.6±15.4 mm Hg; P Conclusions: Assuming the potential of iHTN to be exhausted in case of refractory hypoperfusion, additional IAN may serve as a last-resort measure to bridge hypoperfusion in the DCI phase. With close monitoring, preemptive lowering of pressure target after induction of IAN may be a safe alternative to alleviate total noradrenaline load and potentially reduce complication rate.

OBJECTIVE Despite the rising number of women in higher education and leadership positions, the proportional rise of female neurosurgeons still lags behind these fields. This study evaluates the gender distribution in German neurosurgical departments across all career levels, and is aimed at heightening the awareness of gender disparity and the need for improving gender equality and its related opportunities. METHODS Data on gender distribution across all professional levels in German neurosurgical departments were obtained from departmental websites as well as by email and telephone request. Results were additionally analyzed in reference to hospital ownership type of the neurosurgical departments. RESULTS A total of 140 German neurosurgical departments employing 2324 neurosurgeons were evaluated. The analysis revealed a clear preponderance of men in leadership positions. Only 9 (6.3%) of 143 department heads were women, and there were only 1 (2.4%), 17 (14.5%), and 4 (12.5%) women among 42 vice-directors, 117 chief senior physicians, and 32 managing senior physicians, respectively. Senior physicians not holding a leadership position were female in 23.1%, whereas board-certified neurosurgeons not holding a senior physician position and residents were female in 33.6% and 35.0%, respectively. Of note, the highest proportion of female department heads (15.6%) was found in private hospitals. CONCLUSIONS The number of women in leadership positions in German neurosurgical departments is dramatically low, and with increasing leadership status gender disparity increases. Mentorship, recruitment, the perception of benefits offered by diversity and programs facilitating gender equality, job sharing, parental leave policies, and onsite childcare programs are needed to turn German neurosurgical departments into modern medical departments reflecting the gender profile of the general patient population.

Dysfunctional cerebral autoregulation often precedes delayed cerebral ischemia (DCI). Currently, there are no data-driven techniques that leverage this information to predict DCI in real time. Our hypothesis is that information using continuous updated analyses of multimodal neuromonitoring and cerebral autoregulation can be deployed to predict DCI.Time series values of intracranial pressure, brain tissue oxygenation, cerebral perfusion pressure (CPP), optimal CPP (CPPOpt), ΔCPP (CPP - CPPOpt), mean arterial pressure, and pressure reactivity index were combined and summarized as vectors. A validated temporal signal angle measurement was modified into a classification algorithm that incorporates hourly data. The time-varying temporal signal angle measurement (TTSAM) algorithm classifies DCI at varying time points by vectorizing and computing the angle between the test and reference time signals. The patient is classified as DCI+ if the error between the time-varying test vector and DCI+ reference vector is smaller than that between the time-varying test vector and DCI- reference vector. Finally, prediction at time point t is calculated as the majority voting over all the available signals. The leave-one-patient-out cross-validation technique was used to train and report the performance of the algorithms. The TTSAM and classifier performance was determined by balanced accuracy, F1 score, true positive, true negative, false positive, and false negative over time.One hundred thirty-one patients with aneurysmal subarachnoid hemorrhage who underwent multimodal neuromonitoring were identified from two centers (Columbia University: 52 [39.7%], Aachen University: 79 [60.3%]) and included in the analysis. Sixty-four (48.5%) patients had DCI, and DCI was diagnosed 7.2 ± 3.3 days after hemorrhage. The TTSAM algorithm achieved a balanced accuracy of 67.3% and an F1 score of 0.68 at 165 h (6.9 days) from bleed day with a true positive of 0.83, false positive of 0.16, true negative of 0.51, and false negative of 0.49.A TTSAM algorithm using multimodal neuromonitoring and cerebral autoregulation calculations shows promise to classify DCI in real time.

OBJECTIVES: The recommendation of induced hypertension for delayed cerebral ischemia treatment after aneurysmal subarachnoid hemorrhage has been challenged recently and ideal pressure targets are missing. A new concept advocates an individual cerebral perfusion pressure where cerebral autoregulation functions best to ensure optimal global perfusion. We characterized optimal cerebral perfusion pressure at time of delayed cerebral ischemia and tested the conformity of induced hypertension with this target value. DESIGN: Retrospective analysis of prospectively collected data. SETTING: University hospital neurocritical care unit. PATIENTS: Thirty-nine aneurysmal subarachnoid hemorrhage patients with invasive neuromonitoring (20 with delayed cerebral ischemia, 19 without delayed cerebral ischemia). INTERVENTIONS: Induced hypertension greater than 180 mm Hg systolic blood pressure. MEASUREMENTS AND MAIN RESULTS: Changepoint analysis was used to calculate significant changes in cerebral perfusion pressure, optimal cerebral perfusion pressure, and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure 48 hours before delayed cerebral ischemia diagnosis. Optimal cerebral perfusion pressure increased 30 hours before the onset of delayed cerebral ischemia from 82.8 +/- 12.5 to 86.3 +/- 11.4 mm Hg (p < 0.05). Three hours before delayed cerebral ischemia, a changepoint was also found in the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure (decrease from -0.2 +/- 11.2 to -7.7 +/- 7.6 mm Hg; p < 0.05) with a corresponding increase in pressure reactivity index (0.09 +/- 0.33 to 0.19 +/- 0.37; p < 0.05). Cerebral perfusion pressure at time of delayed cerebral ischemia was lower than in patients without delayed cerebral ischemia in a comparable time frame (cerebral perfusion pressure delayed cerebral ischemia 81.4 +/- 8.3 mm Hg, no delayed cerebral ischemia 90.4 +/- 10.5 mm Hg; p < 0.05). Inducing hypertension resulted in a cerebral perfusion pressure above optimal cerebral perfusion pressure (+12.4 +/- 8.3 mm Hg; p < 0.0001). Treatment response (improvement of delayed cerebral ischemia: induced hypertension(+) [n = 15] or progression of delayed cerebral ischemia: induced hypertension(-) [n = 5]) did not correlate to either absolute values of cerebral perfusion pressure or optimal cerebral perfusion pressure, nor the resulting difference (cerebral perfusion pressure [p = 0.69]; optimal cerebral perfusion pressure [p = 0.97]; and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure [p = 0.51]). CONCLUSIONS: At the time of delayed cerebral ischemia occurrence, there is a significant discrepancy between cerebral perfusion pressure and optimal cerebral perfusion pressure with worsening of autoregulation, implying inadequate but identifiable individual perfusion. Standardized induction of hypertension resulted in cerebral perfusion pressures that exceeded individual optimal cerebral perfusion pressure in delayed cerebral ischemia patients. The potential benefit of individual blood pressure management guided by autoregulation-based optimal cerebral perfusion pressure should be explored in future intervention studies.

PURPOSE OF REVIEW: Individualizing cerebral perfusion pressure based on cerebrovascular autoregulation assessment is a promising concept for neurological injuries where autoregulation is typically impaired. The purpose of this review is to describe the status quo of autoregulation-guided protocols and discuss steps towards clinical use. RECENT FINDINGS: Retrospective studies have indicated an association of impaired autoregulation and poor clinical outcome in traumatic brain injury (TBI), hypoxic-ischemic brain injury (HIBI) and aneurysmal subarachnoid hemorrhage (aSAH). The feasibility and safety to target a cerebral perfusion pressure optimal for cerebral autoregulation (CPPopt) after TBI was recently assessed by the COGITATE trial. Similarly, the feasibility to calculate a MAP target (MAPopt) based on near-infrared spectroscopy was demonstrated for HIBI. Failure to meet CPPopt is associated with the occurrence of delayed cerebral ischemia in aSAH but interventional trials in this population are lacking. No level I evidence is available on potential effects of autoregulation-guided protocols on clinical outcomes. SUMMARY: The effect of autoregulation-guided management on patient outcomes must still be demonstrated in prospective, randomized, controlled trials. Selection of disease-specific protocols and endpoints may serve to evaluate the overall benefit from such approaches.

Introduction Robin sequence (RS) is a leading cause of obstructive sleep apnea (OSA) in newborns. Most studies have focused on understanding anatomic factors leading to OSA and changes in apnea–hypopnea index (AHI) on polysomnography (PSG) beyond the neonatal period. This study aims to define age-related OSA features between patients with RS, without RS and healthy controls using PSG-based analyses of respiratory arousal responses and gas-exchange parameters. Design Retrospective comparison of PSG features in a total of 48 children encompassing three groups: (a) infants with RS (n = 24, Results OSA sleep-stage specific indexes (rapid eye movement [REM] vs non-REM[NREM]) as well as position-specific indexes (supine vs nonsupine) were similar in individuals with and without RS. Relative to the non-RS groups, infants with RS have more sustained hypoxemia (time with SpO2 < 90%) and reduced arousal responses to OSA demonstrated by higher OAHI/respiratory arousal indexes. OAHI/respiratory arousal indexes significantly correlated with the severity of hypoxemia in infants with RS. Conclusion Infants with RS and OSA show reduced arousal responses to apneic events, which correlates with higher hypoxemia severity. OAHI/respiratory arousal indexes in RS may identify high-risk individuals with upper airway obstruction and reduced arousal protective responses.

Background and Purpose: Aneurysmal subarachnoid hemorrhage is a devastating disease leaving surviving patients often severely disabled. Delayed cerebral ischemia (DCI) has been identified as one of the main contributors to poor clinical outcome after subarachnoid hemorrhage. The objective of this review is to summarize existing clinical evidence assessing the diagnostic value of invasive neuromonitoring (INM) in detecting DCI and provide an update of evidence since the 2014 consensus statement on multimodality monitoring in neurocritical care. Methods: Three invasive monitoring techniques were targeted in the data collection process: brain tissue oxygen tension (p ti O 2 ), cerebral microdialysis, and electrocorticography. Prospective and retrospective studies as well as case series (≥10 patients) were included as long as monitoring was used to detect DCI or guide DCI treatment. Results: Forty-seven studies reporting INM in the context of DCI were included (p ti O 2 : N=21; cerebral microdialysis: N=22; electrocorticography: N=4). Changes in brain oxygen tension are associated with angiographic vasospasm or reduction in regional cerebral blood flow. Metabolic monitoring with trend analysis of the lactate to pyruvate ratio using cerebral microdialysis, identifies patients at risk for DCI. Clusters of cortical spreading depolarizations are associated with clinical neurological worsening and cerebral infarction in selected patients receiving electrocorticography monitoring. Conclusions: Data supports the use of INM for the detection of DCI in selected patients. Generalizability to all subarachnoid hemorrhage patients is limited by design bias of available studies and lack of randomized trials. Continuous data recording with trend analysis and the combination of INM modalities can provide tailored treatment support in patients at high risk for DCI. Future trials should test interventions triggered by INM in relation to cerebral infarctions.

Neurocritical care 35(1), 172-183 (2021). doi:10.1007/s12028-020-01169-x, Published by Springer, New York, NY

Homozygous mutation in arteriovenous malformation (AVM) causative genes in a fraction of endothelial cells (ECs) causes brain AVMs (bAVMs). Heterozygous mutation of an AVM causative gene, endoglin, in bone marrow (BM) caused capillary dysplasia in mouse brain. We hypothesize that homozygous mutation of activin receptor-like kinase 1 (Alk1, another AVM causative gene) in BM derived ECs (BMDECs) is sufficient to cause bAVM in brain angiogenic region, Alk1(−) ECs can clonally expand in bAVM, and the burden of Alk1(−) ECs correlates with bAVM severity. The BMs of PdgfbiCreER;Alk1(2f/2f);Ai14 mice with EC-specific tamoxifeninducible Cre and Alk1 floxed alleles were transplanted into wild-type mice to analyze the role of BMDECs in bAVM development. PdgfbiCreER;Alk1(2f/2f);confetti(+/−) mice with Cre-regulated confetti transgene were used to study EC clonal expansion. BAVMs were induced by intra-brain injection of an adeno-associated viral vector expressing vascular endothelial growth factor followed with intra-peritoneal injection of tamoxifen. Wild-type mice transplanted with PdgfbiCreER;Alk1(2f/2f);Ai14 BM developed bAVMs after bAVM induction. Recombined BMDECs were detected in bAVMs. The presence of clusters of ECs expressing same confetti color in bAVMs suggests that Alk1(−) ECs have been clonally expanded. Increasing tamoxifen dose increased the number of Alk1(−) ECs and abnormal vessels in bAVMs of PdgfbiCreER;Alk1(2f/2f) mice. Our data indicated that homozygous mutation of Alk1 in BMDECs is sufficient to cause bAVM development in brain angiogenic region; clonal expansion of Alk1(−) ECs provides a likely mechanism for how a fraction of mutant ECs causes bAVM; and the burden of Alk1(−) ECs correlates with AVM severity.

Neurosurgical review 44(6), 3547-3556 (2021). doi:10.1007/s10143-021-01541-1, Published by Springer, Berlin ; Heidelberg ; New York

Background and Purpose: Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage negatively impacts long-term recovery but is often detected too late to prevent damage. We aim to develop hourly risk scores using routinely collected clinical data to detect DCI. Methods: A DCI classification model was trained using vital sign measurements (heart rate, blood pressure, respiratory rate, and oxygen saturation) and demographics routinely collected for clinical care. Twenty-two time-varying physiological measures were computed including mean, SD, and cross-correlation of heart rate time series with each of the other vitals. Classification was achieved using an ensemble approach with L2-regularized logistic regression, random forest, and support vector machines models. Classifier performance was determined by area under the receiver operating characteristic curves and confusion matrices. Hourly DCI risk scores were generated as the posterior probability at time t using the Ensemble classifier on cohorts recruited at 2 external institutions (n=38 and 40). Results: Three hundred ten patients were included in the training model (median, 54 years old [interquartile range, 45–65]; 80.2% women, 28.4% Hunt and Hess scale 4–5, 38.7% Modified Fisher Scale 3–4); 101 (33%) developed DCI with a median onset day 6 (interquartile range, 5–8). Classification accuracy before DCI onset was 0.83 (interquartile range, 0.76–0.83) area under the receiver operating characteristic curve. Risk scores applied to external institution datasets correctly predicted 64% and 91% of DCI events as early as 12 hours before clinical detection, with 2.7 and 1.6 true alerts for every false alert. Conclusions: An hourly risk score for DCI derived from routine vital signs may have the potential to alert clinicians to DCI, which could reduce neurological injury.

Acta neurochirurgica (2022). doi:10.1007/s00701-022-05250-6, Published by Springer, Wien [u.a.]

BH3-mimetics inhibiting anti-apoptotic BCL-2 proteins represent a novel and promising class of antitumor drugs. While the BCL-2 inhibitor venetoclax is already approved by the Food and Drug Administration, BCL-XL and MCL-1 inhibitors are currently in early clinical trials. To predict side effects of therapeutic MCL-1 inhibition on the human hematopoietic system, we used RNA interference and the small molecule inhibitor S63845 on cord blood-derived CD34+ cells. Both approaches resulted in almost complete depletion of human hematopoietic stem and progenitor cells. As a consequence, maturation into the different hematopoietic lineages was severely restricted and CD34+ cells expressing MCL-1 shRNA showed a very limited engraftment potential upon xenotransplantation. In contrast, mature blood cells survived normally in the absence of MCL-1. Combined inhibition of MCL-1 and BCL-XL resulted in synergistic effects with relevant loss of colony-forming hematopoietic stem and progenitor cells already at inhibitor concentrations of 0.1 mM each, indicating “synthetic lethality” of the two BH3- mimetics in the hematopoietic system.

Background and Purpose: Homozygous mutation in arteriovenous malformation (AVM) causative genes in a fraction of endothelial cells (ECs) causes brain AVMs (bAVMs). Heterozygous mutation of endoglin, an AVM causative gene, in bone marrow (BM) caused capillary dysplasia in mouse brain. We tested if (1) homozygous mutation of activin receptor-like kinase 1 ( Alk1, another AVM causative gene) in BM derived ECs (BMDECs) can cause bAVM in brain angiogenic region, (2) Alk1 - ECs clonally expand in bAVM, and (3) the burden of Alk1 - ECs correlates with bAVM severity. Methods: The BMs of Pdgfb iCreER; Alk1 2 f/2f ;Ai14 mice with EC-specific tamoxifen-inducible Cre and Alk1 floxed alleles were transplanted into wild-type mice to analyze the role of BMDECs in bAVM development. Pdgfb iCreER; Alk1 2 f/2f ;confetti +/- mice with Cre-regulated confetti transgene were used to study EC clonal expansion. Brain AVMs were induced by intra-brain injection of an adeno-associated viral vector expressing vascular endothelial growth factor followed by intra-peritoneal injection of tamoxifen. Results: Wild-type mice transplanted with Pdgfb iCreER; Alk1 2 f/2f ;Ai14 BM developed bAVMs after bAVM induction. Recombined BMDECs were detected in bAVMs. The presence of clusters of ECs expressing same confetti color in bAVMs suggests that Alk1 - ECs had been clonally expanded. Increasing tamoxifen dose increased the number of Alk1 - ECs and abnormal vessels in bAVMs of Pdgfb iCreER; Alk1 2 f/2f mice. Conclusion: Homozygous mutation of Alk1 in BMDECs is sufficient to cause bAVM development in brain angiogenic region; clonal expansion of Alk1 - ECs provides a likely mechanism for how a fraction of mutant ECs causes bAVM; and the burden of Alk1 - ECs correlates with AVM severity.

Neurocritical care 36(3), 702-714 (2022). doi:10.1007/s12028-022-01466-7, Published by Springer, New York, NY

Neurocritical care (2022). doi:10.1007/s12028-022-01545-9, Published by Springer, New York, NY

Objective—Direct oral anticoagulants (DOAC) are replacing vitamin K antagonists (VKA) for the prevention of ischemic stroke and venous thromboembolism. We set out to assess the effect of prior treatment with DOAC and VKA in patients with aneurysmal subarachnoid hemorrhage (SAH). Methods—Consecutive SAH patients treated at two (Aachen, Germany and Helsinki, Finland) university hospitals were considered for inclusion. To assess the association between anticoagulant treatments on SAH severity measure by modified Fisher grading (mFisher) and outcome as measured by the Glasgow outcome scale (GOS, 6 months), DOAC- and VKA-treated patients were compared against age- and sex-matched SAH controls without anticoagulants. Results—During the inclusion timeframes, 964 SAH patients were treated in both centers. At the time point of aneurysm rupture, nine patients (0.93%) were on DOAC treatment, and 15 (1.6%) patients were on VKA. These were matched to 34 and 55 SAH age- and sex-matched controls, re-spectively. Overall, 55.6% of DOAC-treated patients suffered poor-grade (WFNS4–5) SAH compared to 38.2% among their respective controls (p = 0.35); 53.3% of patients on VKA suffered poor-grade SAH compared to 36.4% in their respective controls (p = 0.23). Neither treatment with DOAC (aOR 2.70, 95%CI 0.30 to 24.23; p = 0.38), nor VKA (aOR 2.78, 95%CI 0.63 to 12.23; p = 0.18) were inde-pendently associated with unfavorable outcome (GOS1–3) after 12 months. Conclusions—Iatrogenic coagulopathy caused by DOAC or VKA was not associated with more severe radiological or clinical subarachnoid hemorrhage or worse clinical outcome in hospitalized SAH patients.

Background: An acute respiratory distress syndrome (ARDS) is caused by the increased amounts of pro-inflammatory cytokines and neutrophil-mediated tissue injury. To date, there is no effective treatment for the ARDS available, while the need for one is growing due to the most severe complications of the current coronavirus disease-2019 (COVID-19) pandemic. The human astrocytes (AstroRx) have shown immunomodulatory properties in the central nervous system (CNS). This study aimed to evaluate the capacity of astrocytes to decrease lung inflammation and to be applied as a treatment therapy in ARDS.Methods: First, we assessed the ability of clinical-grade AstroRx to suppress T-cell proliferation in a mixed lymphocyte reaction test. Next, we tested the therapeutical potential of AstroRx cells in a lipopolysaccharide (LPS)-based ARDS mouse model by injecting AstroRx intravenously (i.v). We determined the degree of lung injury by using a severity scoring scale of 0–2, based on the American Thoracic Society. The scoring measured the presence of neutrophils, fibrin deposits, and the thickening of alveolar walls. The state of inflammation was further assessed by quantifying the immune-cell infiltration to the bronchoalveolar lavage fluid (BALF) and by the presence of proinflammatory cytokines and chemokines in the BALF and serum.Results: We detected that AstroRx cells were capable to suppress T-cell proliferation in vitro after exposure to the mitogen concanavalin A (ConA). In vivo, AstroRx cells were able to lower the degree of lung injury in LPS-treated animals compared with the sham injected animals (P = 0.039). In this study, 30% of AstroRx treated mice showed no lung lesions (responder mice), these mice presented a steady number of eosinophils, T cells, and neutrophils comparable with the level of naïve control mice. The inflammatory cytokines and chemokines, such as TNFα, IL1b, IL-6, and CXCL1, were also kept in check in responder AstroRx-treated mice and were not upregulated as in the sham-injected mice (P < 0.05). As a result, the LPS-treated ARDS mice had a higher survival rate when they were treated with AstroRx.Conclusions: Our results demonstrate that the immunosuppressive activity of AstroRx cells support the application of AstroRx cells as a cell therapy treatment for ARDS. The immunoregulatory activity may also be a part of the mechanism of action of AstroRx reported in the amyotrophic lateral sclerosis (ALS) neurodegenerative disease.

Study Objectives Several birth cohorts have defined the pivotal role of early lower respiratory tract infections (LRTI) in the inception of pediatric respiratory conditions. However, the association between early LRTI and the development of obstructive sleep apnea (OSA) in children has not been established. Methods To investigate whether early LRTIs increase the risk of pediatric OSA, we analyzed clinical data in children followed during the first 5 years in the Boston Birth Cohort (n = 3114). Kaplan–Meier survival estimates and Cox proportional hazards models adjusted by pertinent covariates were used to evaluate the risk of OSA by the age of 5 years between children with LRTI during the first 2 years of life in comparison to those without LRTI during this period. Results Early life LRTI increased the risk of pediatric OSA independently of other pertinent covariates and risk factors (hazard ratio, 1.53; 95% CI, 1.15 to 2.05). Importantly, the association between LRTI and pediatric OSA was limited to LRTIs occurring during the first 2 years of life. Complementarily to this finding, we observed that children who had severe respiratory syncytial virus bronchiolitis during infancy had two times higher odds of OSA at 5 years in comparison with children without this exposure (odds ratio, 2.09; 95% CI, 1.12 to 3.88). Conclusions Children with severe LRTIs in early life have significantly increased risk of developing OSA during the first 5 years of life. Our results offer a new paradigm for investigating novel mechanisms and interventions targeting the early pathogenesis of OSA in the pediatric population.

Introduction Prader Willi Syndrome (PWS) is a rare genetic disorder characterized by infantile hypotonia, hyperphagia leading to early childhood obesity, and short stature. PWS patients are at risk for multiple sleep abnormalities including increased risk of obstructive sleep apnea, central sleep apnea, and excessive daytime sleepiness. The limited studies reviewing PSGs in pediatric PWS patients showed varying results. Our study aim is to characterize sleep characteristics in pediatric patients with PWS. Methods We conducted a retrospective chart review of pediatric patients with a genetically confirmed diagnosis of Prader Willi Syndrome from 2007 to 2015. In lab polysomnograms were scored using the AASM criteria for pediatric sleep studies. Data was collected on sleep architecture parameters and compared to normative data available for pediatric polysomnography. Given large variability in sleep architecture during infancy, subjects were divided into two age groups (< 1 years old, 1-19 years old). Results Fifty-one PSGs were reviewed of which 31 (60.7%) belong to males and 20 (39.3%) belong to females. Forty-one PSGs were initial studies and 11 were repeat studies. Age at the time of sleep study ranged from 11 days to 19 years old. 8 (15%) subjects were less than 1 years old and 44 (84%) were 1 year and older. For subjects less than one year old, mean sleep onset latency (min) was 21±33.4, REM onset latency (min) 35±27.2, SWS(%) 43.3±10.2, REM(%) 35.3±7.35, arousal index 9.7±11.9, wake after sleep onset (WASO) (min) 59.5±11.4 and sleep efficiency 82.4±9.4. For the 1-19 year age group, mean sleep onset latency (min) was 24.5±23.1, REM onset latency (min) 104± 59.9, SWS (%) 21.4±7.11, REM (%) 21.3±6.9, arousal index 7.3±5.4, WASO (min) 46.5±36.10 and sleep efficiency was 85.7±9.0. Conclusion In our population of PWS patients, REM onset latency was not decreased as shown in previous studies. Sleep efficiency was decreased. Other sleep parameters fell within normal range. Additional data on signs of excessive daytime sleepiness and sleep disordered breathing in this population is needed to understand if EDS persists with decreased sleep efficiency and otherwise normal sleep parameters and/or with OSA. Support (If Any)

OBJECTIVE Initiation of continuous positive airway pressure (CPAP) in children with severe obstructive sleep apnea syndrome (OSAS) is challenging and the distinct features of the subset of children requiring CPAP are poorly defined. Asthma often coexists with OSAS in children. The goal of this study was to explore the influence of asthma in the need for CPAP therapy in children with severe OSAS. HYPOTHESIS Asthmatic children with severe OSAS have higher probability of needing CPAP than children with severe OSAS without asthma. METHODS Cross-sectional study of clinical presentation, individual risk factors, and initial overnight polysomnogram (PSG) parameters in children with severe OSAS. Severe OSAS was defined as an obstructive apnea hypopnea index ≥10/h. The association between asthma and CPAP initiation was studied individually and adjusted by pertinent covariates. RESULTS Four hundred eligible children (mean age 7 years, ±SD 5.3) with severe OSAS were enrolled and 133 individuals (33%) were identified to have asthma. The proportion of children needing CPAP was significantly higher in asthmatics with severe OSAS (29%) compared to those with OSAS alone (14%) (P

Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. The pathogenesis of bAVM has not been fully understood. Animal models are important tools for dissecting bAVM pathogenesis and testing new therapies. We have developed several mouse bAVM models using genetically modified mice. However, due to the body size, mouse bAVM models have some limitations. Recent studies identified somatic mutations in sporadic human bAVM. To develop a feasible tool to create sporadic bAVM in rodent and animals larger than rodent, we made tests using the CRISPR/Cas9 technique to induce somatic gene mutations in mouse brain in situ. Two sequence-specific guide RNAs (sgRNAs) targeting mouse Alk1 exons 4 and 5 were cloned into pAd-Alk1e4sgRNA + e5sgRNA-Cas9 plasmid. These sgRNAs were capable to generate mutations in Alk1 gene in mouse cell lines. After packaged into adenovirus, Ad-Alk1e4sgRNA + e5sgRNA-Cas9 was co-injected with an adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF) into the brains of wild-type C57BL/6J mice. Eight weeks after viral injection, bAVMs were detected in 10 of 12 mice. Compared to the control (Ad-GFP/AAV-VEGF-injected) brain, 13% of Alk1 alleles were mutated and Alk1 expression was reduced by 26% in the Ad-Alk1e4sgRNA + e5sgRNA-Cas9/AAV-VEGF-injected brains. Around the Ad-Alk1e4sgRNA + e5sgRNA-Cas9/AAV-VEGF injected site, Alk1-null endothelial cells were detected. Our data demonstrated that CRISPR/Cas9 is a feasible tool for generating bAVM model in animals.

The urea-creatinine ratio (UCR) has been proposed as potential biomarker for critical illness-associated catabolism. Its role in the context of aneurysmal subarachnoid hemorrhage (aSAH) remains to be elucidated, which was the aim of the present study.We enrolled 66 patients with aSAH with normal renal function and 36 patients undergoing elective cardiac surgery as a control group for the effects of surgery. In patients with aSAH, the predictive or diagnostic value of early (day 0-2) and critical (day 5-7) UCRs was assessed with regard to delayed cerebral ischemia (DCI), DCI-related infarction, and clinical outcome after 12 months.Preoperatively, UCR was similar both groups. Within 2 days postoperatively, UCRs increased significantly in patients in the elective cardiac surgery group (P0.001) but decreased back to baseline on day 5-7 (P = 0.245), whereas UCRs in patients with aSAH increased to significantly greater levels on day 5-7 (P = 0.028). Greater early or critical UCRs were associated with poor clinical outcomes (P = 0.015) or DCI (P = 0.011), DCI-related infarction (P = 0.006), and poor clinical outcomes (P 0.001) respectively. In multivariate analysis, there was an independent association between greater early UCRs and poor clinical outcomes (P = 0.026).In this exploratory study of UCR in the context of aSAH, greater early values were predictive for a poor clinical outcome after 12 months, whereas greater critical values were associated with DCI, DCI-related infarctions, and poor clinical outcomes. The clinical implications as well as the pathophysiologic relevance of protein catabolism should be explored further in the context of aSAH.

Adrenomedullin (ADM) has been identified as a promising biomarker of mortality and outcome in sepsis, heart failure and after major surgery. A recently developed assay specific for bioactive adrenomedullin (bio-ADM) has not yet been assessed in aneurysmal subarachnoid hemorrhage (aSAH). The objective of this prospective trial was to assess the time course of bio-ADM after aSAH in relation to the development of delayed cerebral ischemia (DCI) and its association with clinical outcome.Bio-ADM levels in plasma and cerebrospinal fluid (CSF) were measured during five predefined epochs, for up to 21 days in 30 aSAH patients: early, (day 0 to day 3); acute, (day 4 to day 8); early critical, (day 9 to day 12); late critical, (day 13 to day 15), and late (day 16 to day 21). DCI was diagnosed clinically or based on multimodal monitoring and imaging, and the occurrence of DCI-related cerebral infarction, and outcome after 12 months (extended Glasgow outcome scale), was noted.Higher median bio-ADM levels in plasma during the acute phase were predictive of long-term unfavorable outcome (AUC = 0.97; 95% CI 0.91 to 1.00; p 0.001). Early critical bio-ADM levels during DCI were lower in CSF and confirmed DCI occurrence (AUC = 0.80; 95% CI 0.59 to 1.00; p = 0.044).The dynamics of bio-ADM levels in CSF present a fairly different course compared to plasma with observed higher bio-ADM concentrations in patients spared from DCI and/or developing favorable outcome.

Introduction Aneurysmal subarachnoid hemorrhage (aSAH) is associated with early and delayed brain injury due to several underlying and interrelated processes, which include inflammation, oxidative stress, endothelial, and neuronal apoptosis. Treatment with melatonin, a cytoprotective neurohormone with anti-inflammatory, anti-oxidant and anti-apoptotic effects, has been shown to attenuate early brain injury (EBI) and to prevent delayed cerebral vasospasm in experimental aSAH models. Less is known about the role of endogenous melatonin for aSAH outcome and how its production is altered by the pathophysiological cascades initiated during EBI. In the present observational study, we analyzed changes in melatonin levels during the first three weeks after aSAH. Materials and methods Daytime (from 11:00 am to 05:00 pm) melatonin levels were measured by enzyme-linked immunosorbent assay (ELISA) in serum samples obtained from 30 patients on the day of aSAH onset (d0) and in five pre-defined time intervals during the early (d1–4), critical (d5–8, d9–12, d13–15) and late (d16–21) phase. Perioperative daytime melatonin levels determined in 30 patients who underwent elective open aortic surgery served as a control for the acute effects of surgical treatment on melatonin homeostasis. Results There was no difference between serum melatonin levels measured in the control patients and on the day of aSAH onset (p = 0.664). However, aSAH was associated with a sustained up-regulation that started during the critical phase (d9–12) and progressed to the late phase (d16–21), during which almost 80% of the patients reached daytime melatonin levels above 5 pg/ml. In addition, subgroup analyses revealed higher melatonin levels on d5–8 in patients with a poor clinical status on admission (p = 0.031), patients with anterior communicating artery aneurysms (p = 0.040) and patients without an external ventricular drain (p = 0.018), possibly pointing to a role of hypothalamic dysfunction. Conclusion Our observations in a small cohort of patients provide first evidence for a delayed up-regulation of circulatory daytime melatonin levels after aSAH and a role of aneurysm location for higher levels during the critical phase. These findings are discussed in terms of previous results about stress-induced melatonin production and the role of hypothalamic and brainstem involvement for melatonin levels after aSAH.

Introduction Delayed cerebral ischemia (DCI) is a common complication after aneurysmal subarachnoid hemorrhage (aSAH) that can culminate in secondary brain damage. Although it remains one of the main preventable causes of aSAH-related morbidity, there is still a lack of prognostic criteria for identification of patients at risk of developing DCI. Because elevated circulatory levels of the enzyme dipeptidyl peptidase 3 (cDPP3) were recently identified as a potential biomarker for outcome prediction in critically ill patients, we evaluated the time-course of changes in cDPP3 levels after aSAH. Materials and methods cDPP3 levels were quantified in serum obtained from 96 confirmed aSAH patients during the early (EP: d1–4), critical (CP: d5–8, d9–12, d13–15) and late (LP: d16–21) phase after aSAH onset. Associations between cDPP3 levels and demographic or clinical parameters were evaluated. The relations between cDPP3 levels and DCI, DCI-related infarctions and long-term clinical outcomes were examined by receiver operating characteristics (ROC) curve analysis and multivariate logistic regression. Results Significantly higher cDPP3 levels during CP (d5–8, d9–12, d13–15) were observed in patients with poor clinical (p Conclusion Our results provide first evidence that cDPP3 could serve as a promising biomarker for early diagnosis of DCI-related infarctions in poor grade aSAH patients.

Telemedicine and remote monitoring are valuable tools to address inadequate obstructive sleep apnea compliance during the current pandemic.

Introduction Prader Willi Syndrome (PWS) is a rare genetic disorder characterized by infantile hypotonia, hyperphagia leading to early childhood obesity, and multiple sleep abnormalities including increased risk of obstructive sleep apnea, central sleep apnea, and excessive daytime sleepiness. PWS patients have been reported to have a shorter lifespan with respiratory related causes as a common cause of death. Limited data exists on PSGs in pediatric PWS patients. Our aim was to compare respiratory parameters in different age groups. Methods We conducted a retrospective chart review of pediatric patients with a genetically confirmed diagnosis of Prader Willi Syndrome from 2007 to 2015. In lab polysomnograms were scored using the AASM criteria for pediatric sleep studies. As central apneas are more commonly seen in infancy with PWS, we categorized patients into < 1 years old and 1-19 years old for comparison. Results Fifty-one PSGs were reviewed of which 31 (60.7%) were males and 20 (39.3%) were females. Forty-one PSGs were initial studies and 11 were repeat studies. Age at time of sleep study ranged from 11 days-19 years old. 8 (15%) subjects were < 1 years old and 44 (84%) were 1-19 years old. For patients < 1 year old, mean obstructive hypopnea index (OAHI) was 5.65±3.7, central index (CI)2.2±2.5, mean SpO2(%) 98±.4, SpO2 nadir 86±5.8, and % of time with SpO2 < 90% .16±.314. For patients 1-19 years old, mean (OAHI) was 8.7±13.4, (CI) 0.8±1.25, mean SpO2 96±3.0, SpO2 nadir 81±.10, and % of time with SpO2 < 90% .03±.10. The OAHI trended up in the 1-19 year old group but results were not significant, CI decreased in the 1-19 year old group 2.2 vs 0.8 p < .04. Conclusion Our study demonstrated similar results to prior studies in pediatric PWS with an increase in OAHI and decrease in CI with age. SPO2 nadir decreased in the 1-19 year old group but these results were not significant. Ongoing research at our center is looking at possible contributing factors including BMI percentile, GH therapy, and adenotonsillectomy to better understand our findings. Support (If Any)