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SUMMARYThe general stress response (GSR) is a widespread strategy developed by bacteria to adapt and respond to their changing environments. The GSR is induced by one or multiple simultaneous stresses, as well as during entry into stationary phase and leads to a global response that protects cells against multiple stresses. The alternative sigma factor RpoS is the central GSR regulator in E. coli and conserved in most γ-proteobacteria. In E. coli , RpoS is induced under conditions of nutrient deprivation and other stresses, primarily via the activation of RpoS translation and inhibition of RpoS proteolysis. This review includes recent advances in our understanding of how stresses lead to RpoS induction and a summary of the recent studies attempting to define RpoS-dependent genes and pathways., Competing Interests: The authors declare no conflict of interest.

Background: Acute respiratory distress syndrome (ARDS) is an important pulmonary complication in brain-injured patients receiving invasive mechanical ventilation (IMV). We aimed to evaluate the incidence and association between ARDS and clinical outcomes in patients with different forms of acute brain injury requiring IMV in the intensive care unit (ICU). Methods: This was a preplanned secondary analysis of a prospective, multicenter, international cohort study (NCT03400904). We included brain-injured patients receiving IMV for ≥ 24 h. ARDS was the main exposure of interest and was identified during index ICU admission using the Berlin definition. We examined the incidence and adjusted association of ARDS with ICU mortality, ICU length of stay, duration of IMV, and extubation failure. Outcomes were evaluated using mixed-effect logistic regression and cause-specific Cox proportional hazards models. Results: 1492 patients from 67 hospitals and 16 countries were included in the analysis, of whom 137 individuals developed ARDS (9.2% of overall cohort). Across countries, the median ARDS incidence was 5.1% (interquartile range [IQR] 0-10; range 0-27.3). ARDS was associated with increased ICU mortality (adjusted odds ratio (OR) 2.66; 95% confidence interval [CI], 1.29-5.48), longer ICU length of stay (adjusted hazard ratio [HR] 0.59; 95% CI, 0.48-0.73), and longer duration of IMV (adjusted HR 0.54; 95% CI, 0.44-0.67). The association between ARDS and extubation failure approached statistical significance (adjusted HR 1.48; 95% CI 0.99-2.21). Higher ARDS severity was associated with incrementally longer ICU length of stay and longer cumulative duration of IMV. Findings remained robust in a sensitivity analysis evaluating the magnitude of unmeasured confounding. Conclusions: In this cohort of acutely brain-injured patients, the incidence of ARDS was similar to that reported in other mixed cohorts of critically ill patients. Development of ARDS was associated with worse outcomes., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Acute respiratory distress syndrome (ARDS) is common in patients with acute brain injury admitted to the ICU. We aimed to identify factors associated with ARDS in this population., Methods: We searched MEDLINE, Embase, Cochrane Central, Scopus, and Web of Science from inception to January 14, 2022. Three reviewers independently screened articles and selected English-language studies reporting risk factors for ARDS in brain-injured adult patients. Data were extracted on ARDS incidence, adjusted and unadjusted risk factors, and clinical outcomes. Risk of bias was reported using the Quality in Prognostic Studies tool. Certainty of evidence was assessed using GRADE., Results: We selected 23 studies involving 6,961,284 patients with acute brain injury. The pooled cumulative incidence of ARDS after brain injury was 17.0% (95%CI 10.7-25.8). In adjusted analysis, factors associated with ARDS included sepsis (odds ratio (OR) 4.38, 95%CI 2.37-8.10; high certainty), history of hypertension (OR 3.11, 95%CI 2.31-4.19; high certainty), pneumonia (OR 2.69, 95%CI 2.35-3.10; high certainty), acute kidney injury (OR 1.44, 95%CI 1.30-1.59; moderate certainty), admission hypoxemia (OR 1.67, 95%CI 1.29-2.17; moderate certainty), male sex (OR 1.30, 95%CI 1.06-1.58; moderate certainty), and chronic obstructive pulmonary disease (OR 1.27, 95%CI 1.13-1.44; moderate certainty). Development of ARDS was independently associated with increased odds of in-hospital mortality (OR 3.12, 95% CI 1.39-7.00)., Conclusions: Multiple risk factors are associated with ARDS in brain-injured patients. These findings could be used to develop prognostic models for ARDS or as prognostic enrichment strategies for patient enrolment in future clinical trials., Competing Interests: Declaration of Competing Interest All authors declare they have no competing interests relevant to the submitted work. None of the authors have any financial or non-financial conflicts of interests related to the present manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale: Noninvasive respiratory support using a high-flow nasal cannula (HFNC) or noninvasive positive pressure ventilation (NIPPV) can decrease the risk of reintubation in patients being liberated from mechanical ventilation, but effects in patients with acute brain injury (ABI) are unknown. Objectives: To evaluate the association between postextubation noninvasive respiratory support and reintubation in patients with ABI being liberated from mechanical ventilation. Methods: This was a secondary analysis of a prospective, observational study of mechanically ventilated patients with ABI (clinicaltrials.gov identifier NCT03400904). The primary endpoint was reintubation during ICU admission. We used mixed-effects logistic regression models with patient-level covariates and random intercepts for hospital and country to evaluate the association between prophylactic (i.e., planned) HFNC or NIPPV and reintubation. Measurements and Main Results: 1,115 patients were included from 62 hospitals and 19 countries, of whom 267 received HFNC or NIPPV following extubation (23.9%). Compared with conventional oxygen therapy, neither prophylactic HFNC nor NIPPV was associated with decreased odds of reintubation (respectively, odds ratios of 0.97 [95% confidence interval, 0.54-1.73] and 0.63 [0.30-1.32]). Findings remained consistent in sensitivity analyses accounting for alternate adjustment procedures, missing data, shorter time frames of the primary endpoint, and competing risks precluding reintubation. In a Bayesian analysis using skeptical and data-driven priors, the probabilities of reduced reintubation ranged from 17% to 34% for HFNC and from 46% to 74% for NIPPV. Conclusions: In a large cohort of brain-injured patients undergoing liberation from mechanical ventilation, prophylactic use of HFNC and NIPPV were not associated with reintubation. Prospective trials are needed to confirm treatment effects in this population. Primary study registered with www.clinicaltrials.gov (NCT03400904).

Background: There is insufficient evidence to guide ventilatory targets in acute brain injury (ABI). Recent studies have shown associations between mechanical power (MP) and mortality in critical care populations. We aimed to describe MP in ventilated patients with ABI, and evaluate associations between MP and clinical outcomes., Methods: In this preplanned, secondary analysis of a prospective, multi-center, observational cohort study (ENIO, NCT03400904), we included adult patients with ABI (Glasgow Coma Scale ≤ 12 before intubation) who required mechanical ventilation (MV) ≥ 24 h. Using multivariable log binomial regressions, we separately assessed associations between MP on hospital day (HD)1, HD3, HD7 and clinical outcomes: hospital mortality, need for reintubation, tracheostomy placement, and development of acute respiratory distress syndrome (ARDS)., Results: We included 1217 patients (mean age 51.2 years [SD 18.1], 66% male, mean body mass index [BMI] 26.3 [SD 5.18]) hospitalized at 62 intensive care units in 18 countries. Hospital mortality was 11% (n = 139), 44% (n = 536) were extubated by HD7 of which 20% (107/536) required reintubation, 28% (n = 340) underwent tracheostomy placement, and 9% (n = 114) developed ARDS. The median MP on HD1, HD3, and HD7 was 11.9 J/min [IQR 9.2-15.1], 13 J/min [IQR 10-17], and 14 J/min [IQR 11-20], respectively. MP was overall higher in patients with ARDS, especially those with higher ARDS severity. After controlling for same-day pressure of arterial oxygen/fraction of inspired oxygen (P/F ratio), BMI, and neurological severity, MP at HD1, HD3, and HD7 was independently associated with hospital mortality, reintubation and tracheostomy placement. The adjusted relative risk (aRR) was greater at higher MP, and strongest for: mortality on HD1 (compared to the HD1 median MP 11.9 J/min, aRR at 17 J/min was 1.22, 95% CI 1.14-1.30) and HD3 (1.38, 95% CI 1.23-1.53), reintubation on HD1 (1.64; 95% CI 1.57-1.72), and tracheostomy on HD7 (1.53; 95%CI 1.18-1.99). MP was associated with the development of moderate-severe ARDS on HD1 (2.07; 95% CI 1.56-2.78) and HD3 (1.76; 95% CI 1.41-2.22)., Conclusions: Exposure to high MP during the first week of MV is associated with poor clinical outcomes in ABI, independent of P/F ratio and neurological severity. Potential benefits of optimizing ventilator settings to limit MP warrant further investigation., (© 2023. The Author(s).)

A series of landmark experiments conducted throughout the 20 th century progressively localized the regions involved in consciousness to the reticular activating system (RAS) and its ascending projections. The first description of the RAS emerged in 1949 through seminal experiments performed by Moruzzi and Magoun in feline brainstems; additional experiments in the 1950s revealed connections between the RAS and the thalamus and neocortical structures. This knowledge has allowed for the explanation of disorders of consciousness with exquisite anatomic precision. The clinical relevance of the RAS is further apparent in modern definitions of brain death/death by neurologic criteria (BD/DNC), which require demonstration of the complete and permanent loss of capacity for consciousness as one of their core criteria. BD/DNC is currently understood across jurisdictions in terms of "whole brain" and "brainstem" formulations. Although their clinical examination between formulations is indistinguishable, policies for BD/DNC declaration may differ in the rare scenario of patients with isolated infratentorial brain injuries, in which ancillary testing is advised in the whole brain formulation but not the brainstem formulation. Canadian guidelines acknowledge that the distinction between whole brain and brainstem formulations is unclear with respect to clinical implications for patients with isolated infratentorial injuries. This has led to variability in Canadian clinicians' use of ancillary testing when the mechanism of BD/DNC is suspected to be an isolated infratentorial injury. The present narrative review highlights these concepts and explores implications for determination of BD/DNC in Canada, with specific emphasis on the RAS and its relevance to both formulations., (© 2023. The Author(s).)

Purpose of Review: Recent studies have focused on identifying optimal targets and strategies of mechanical ventilation in patients with acute brain injury (ABI). The present review will summarize these findings and provide practical guidance to titrate ventilatory settings at the bedside, with a focus on managing potential brain-lung conflicts., Recent Findings: Physiologic studies have elucidated the impact of low tidal volume ventilation and varying levels of positive end expiratory pressure on intracranial pressure and cerebral perfusion. Epidemiologic studies have reported the association of different thresholds of tidal volume, plateau pressure, driving pressure, mechanical power, and arterial oxygen and carbon dioxide concentrations with mortality and neurologic outcomes in patients with ABI. The data collectively make clear that injurious ventilation in this population is associated with worse outcomes; however, optimal ventilatory targets remain poorly defined., Summary: Although direct data to guide mechanical ventilation in brain-injured patients is accumulating, the current evidence base remains limited. Ventilatory considerations in this population should be extrapolated from high-quality evidence in patients without brain injury - keeping in mind relevant effects on intracranial pressure and cerebral perfusion in patients with ABI and individualizing the chosen strategy to manage brain-lung conflicts where necessary., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

There are two anatomic formulations of death by neurologic criteria accepted worldwide: whole-brain death and brainstem death. As part of the Canadian Death Definition and Determination Project, we convened an expert working group and performed a narrative review of the literature. Infratentorial brain injury (IBI) with an unconfounded clinical assessment consistent with death by neurologic criteria represents a nonrecoverable injury. The clinical determination of death cannot distinguish between IBI and whole-brain cessation of function. Current clinical, functional, and neuroimaging assessments cannot reliably confirm the complete and permanent destruction of the brainstem. No patient with isolated brainstem death has been reported to recover consciousness and all patients have died. Studies suggest a significant majority of isolated brainstem death will evolve into whole-brain death, influenced by time/duration of somatic support and impacted by ventricular drainage and/or posterior fossa decompressive craniectomy. Acknowledging variability in intensive care unit (ICU) physician opinion on this matter, a majority of Canadian ICU physicians would perform ancillary testing for death determination by neurologic criteria in the context of IBI. There is currently no reliable ancillary test to confirm complete destruction of the brainstem; ancillary testing currently includes evaluation of both infratentorial and supratentorial flow. Acknowledging international variability in this regard, the existing evidence reviewed does not provide sufficient confidence that the clinical exam in IBI represents a complete and permanent destruction of the reticular activating system and thus the capacity for consciousness. On this basis, IBI consistent with clinical signs of death by neurologic criteria without significant supratentorial involvement does not fulfill criteria for death in Canada and ancillary testing is required., (© 2023. The Author(s).)

Objective: Extubation failure in brain-injured patients is associated with increased morbidity. Our objective was to systematically review prognostic factors associated with extubation failure in acutely brain-injured adult patients receiving invasive ventilation in an ICU., Data Sources: MEDLINE, Embase, and Cochrane Central were searched from inception to January 31, 2022., Study Selection: Two reviewers independently screened citations and selected English-language cohort studies and randomized trials examining the association of prognostic factors with extubation failure. Studies were considered if they included greater than or equal to 80% adult patients with acute brain injury admitted to the ICU and mechanically ventilated for greater than or equal to 24 hours., Data Extraction: Two reviewers extracted data on population, prognostic factors, extubation outcomes, and risk of bias (using the quality in prognostic factors tool)., Data Synthesis: In the primary analysis, adjusted odds ratios (aOR) for each prognostic factor were pooled using random-effects models. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. The search identified 7,626 citations, of which 21 studies met selection criteria. Moderate-certainty evidence suggested increased risk of extubation failure with older age (aOR, 3.0 for upper vs lower tertile; 95% CI, 1.78-5.07) and longer duration of mechanical ventilation (aOR, 3.47 for upper vs lower tertile; 95% CI, 1.68-7.19). Presence of cough (aOR, 0.40; 95% CI, 0.28-0.57) and intact swallow (aOR, 0.34; 95% CI, 0.21-0.54) probably decreased risk of extubation failure (moderate certainty). Associations of other factors with extubation failure were informed by low or very low certainty evidence., Conclusions: Patient age, duration of mechanical ventilation, and airway reflexes were associated with extubation failure in brain-injured patients with moderate certainty. Future studies are needed to determine the optimal application of these variables in clinical practice., Competing Interests: Dr. Robba reports being a lecturer for Masimo. Dr. Schultz attended a workshop organized by Hamilton in 2018. Lodging expenses were covered for the invited experts and speakers received a speaker’s fee of CHF 800. Dr. Schultz is also the Team Leader of Medical Affairs at Hamilton Medical AG, Switzerland, since 2022. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Importance: Many conventional end points in randomized clinical trials of interventions for critically ill patients do not account for patient-centered concerns such as time at home, physical function, and quality of life after critical illness., Objective: To establish whether days alive and at home at day 90 (DAAH90) is associated with long-term survival and functional outcomes in mechanically ventilated patients., Design, Setting, and Participants: The RECOVER prospective cohort study was conducted from February 2007 to March 2014, using data from 10 intensive care units (ICUs) in Canada. Patients were included in the baseline cohort if they were aged 16 years or older and underwent invasive mechanical ventilation for 7 or more days. The follow-up cohort analyzed here comprised RECOVER patients who were alive and had functional outcomes ascertained at 3, 6, and 12 months. Secondary data analysis occurred from July 2021 to August 2022., Exposures: Composite of survival and days alive and at home at day 90 after ICU admission (DAAH90)., Main Outcomes and Measures: Functional outcomes at 3, 6, and 12 months were evaluated with the Functional Independence Measure (FIM), the 6-Minute Walk Test (6MWT), the Medical Research Council (MRC) Scale for Muscle Strength, and the 36-Item Short Form Health Survey physical component summary (SF-36 PCS). Mortality was evaluated at 1 year from ICU admission. Ordinal logistic regression was used to describe the association between DAAH90 tertiles and outcomes. Cox proportional hazards regression models were used to examine the independent association of DAAH90 tertiles with mortality., Results: The baseline cohort comprised 463 patients. Their median age was 58 years (IQR, 47-68 years), and 278 patients (60.0%) were men. In these patients, Charlson Comorbidity Index score, Acute Physiology and Chronic Health Evaluation II score, ICU intervention (eg, kidney replacement therapy or tracheostomy), and ICU length of stay were independently associated with lower DAAH90. The follow-up cohort comprised 292 patients. Their median age was 57 years (IQR, 46-65 years), and 169 patients (57.9%) were men. Among patients who survived to day 90, lower DAAH90 was associated with higher mortality at 1 year after ICU admission (tertile 1 vs tertile 3: adjusted hazard ratio [HR], 0.18 [95% CI, 0.07-0.43]; P < .001). At 3 months of follow-up, lower DAAH90 was independently associated with lower median scores on the FIM (tertile 1 vs tertile 3, 76 [IQR, 46.2-101] vs 121 [IQR, 112-124.2]; P = .04), 6MWT (tertile 1 vs tertile 3, 98 [IQR, 0-239] vs 402 [IQR, 300-494]; P < .001), MRC (tertile 1 vs tertile 3, 48 [IQR, 32-54] vs 58 [IQR, 51-60]; P < .001), and SF-36 PCS (tertile 1 vs tertile 3, 30 [IQR, 22-38] vs 37 [IQR, 31-47]; P = .001) measures. Among patients who survived to 12 months, being in tertile 3 vs tertile 1 for DAAH90 was associated with higher FIM score at 12 months (estimate, 22.4 [95% CI, 14.8-30.0]; P < .001), but this association was not present for ventilator-free days (estimate, 6.0 [95% CI, -2.2 to 14.1]; P = .15) or ICU-free days (estimate, 5.9 [95% CI, -2.1 to 13.8]; P = .15) at day 28., Conclusions and Relevance: In this study, lower DAAH90 was associated with greater long-term mortality risk and worse functional outcomes among patients who survived to day 90. These findings suggest that the DAAH90 end point reflects long-term functional status better than standard clinical end points in ICU studies and may serve as a patient-centered end point in future clinical trials.

Objectives: Balancing the risks of hypotension and vasopressor-associated adverse effects is a daily challenge in ICUs. We conducted a systematic review with meta-analysis to examine the effect of lower versus higher exposure to vasopressor therapy on mortality among adult ICU patients with vasodilatory hypotension., Data Sources: We searched Ovid Medline, Embase, and the Cochrane Central Register of Controlled Trials for studies published from inception to October 15, 2021., Study Selection: We included randomized controlled trials of lower versus higher exposure to vasopressor therapy in adult ICU patients with vasodilatory hypotension without language or publication status limits., Data Extraction: The primary outcome was 90-day all-cause mortality, with seven prespecified subgroups. Secondary outcomes included shorter- and longer-term mortality, use of life-sustaining therapies, vasopressor-related complications, neurologic outcome, and quality of life at longest reported follow-up. We conducted random-effects meta-analyses to calculate summary effect measures across individual studies (risk ratio [RR] for dichotomous variables, mean difference for continuous variables, both with 95% CIs). The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation. We registered this review on the International Prospective Register of Systematic Reviews (CRD42021224434)., Data Synthesis: Of 3,403 records retrieved, 68 full-text articles were reviewed and three eligible studies included. Lower exposure to vasopressors probably lowers 90-day mortality but this is based on moderate-certainty evidence, lowered for imprecision (RR, 0.94; 95% CI, 0.87-1.02). There was no credible subgroup effect. Lower vasopressor exposure may also decrease the risk of supraventricular arrhythmia (odds ratio, 0.55; 95% CI, 0.36-0.86; low certainty)., Conclusions: In patients with vasodilatory hypotension who are started on vasopressors, moderate-certainty evidence from three randomized trials showed that lower vasopressor exposure probably lowers mortality. However, additional trial data are needed to reach an optimal information size to detect a clinically important 10% relative reduction in mortality with this approach., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Patients with traumatic brain injury (TBI) frequently require invasive mechanical ventilation and admission to an intensive care unit. Ventilation of patients with TBI poses unique clinical challenges, and careful attention is required to ensure that the ventilatory strategy (including selection of appropriate tidal volume, plateau pressure, and positive end-expiratory pressure) does not cause significant additional injury to the brain and lungs. Selection of ventilatory targets may be guided by principles of lung protection but with careful attention to relevant intracranial effects. In patients with TBI and concomitant acute respiratory distress syndrome (ARDS), adjunctive strategies include sedation optimization, neuromuscular blockade, recruitment maneuvers, prone positioning, and extracorporeal life support. However, these approaches have been largely extrapolated from studies in patients with ARDS and without brain injury, with limited data in patients with TBI. This narrative review will summarize the existing evidence for mechanical ventilation in patients with TBI. Relevant literature in patients with ARDS will be summarized, and where available, direct data in the TBI population will be reviewed. Next, practical strategies to optimize the delivery of mechanical ventilation and determine readiness for extubation will be reviewed. Finally, future directions for research in this evolving clinical domain will be presented, with considerations for the design of studies to address relevant knowledge gaps., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Kaposi's sarcoma-associated herpesvirus (KSHV) causes several human diseases including Kaposi's sarcoma (KS), a leading cause of cancer in Africa and in patients with AIDS. KS tumor cells harbor KSHV predominantly in a latent form, while typically <5% contain lytic replicating virus. Because both latent and lytic stages likely contribute to cancer initiation and progression, continued dissection of host regulators of this biological switch will provide insights into fundamental pathways controlling the KSHV life cycle and related disease pathogenesis. Several cellular protein kinases have been reported to promote or restrict KSHV reactivation, but our knowledge of these signaling mediators and pathways is incomplete. We employed a polypharmacology-based kinome screen to identifiy specific kinases that regulate KSHV reactivation. Those identified by the screen and validated by knockdown experiments included several kinases that enhance lytic reactivation: ERBB2 (HER2 or neu ), ERBB3 (HER3), ERBB4 (HER4), MKNK2 (MNK2), ITK, TEC, and DSTYK (RIPK5). Conversely, ERBB1 (EGFR1 or HER1), MKNK1 (MNK1) and FRK (PTK5) were found to promote the maintenance of latency. Mechanistic characterization of ERBB2 pro-lytic functions revealed a signaling connection between ERBB2 and the activation of CREB1, a transcription factor that drives KSHV lytic gene expression. These studies provided a proof-of-principle application of a polypharmacology-based kinome screen for the study of KSHV reactivation and enabled the discovery of both kinase inhibitors and specific kinases that regulate the KSHV latent-to-lytic replication switch., Author Summary: Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, a cancer particularly prevalent in Africa. In cancer cells, the virus persists in a quiescent form called latency, in which only a few viral genes are made. Periodically, the virus switches into an active replicative cycle in which most of the viral genes are made and new virus is produced. What controls the switch from latency to active replication is not well understood, but cellular kinases, enzymes that control many cellular processes, have been implicated. Using a cell culture model of KSHV reactivation along with an innovative screening method that probes the effects of many cellular kinases simultaneously, we identified drugs that significantly limit KSHV reactivation, as well as specific kinases that either enhance or restrict KSHV replicative cycle. Among these were the ERBB kinases which are known to regulate growth of cancer cells. Understanding how these and other kinases contribute to the switch leading to production of more infectious virus helps us understand the mediators and mechanisms of KSHV diseases. Additionally, because kinase inhibitors are proving to be effective for treating other diseases including some cancers, identifying ones that restrict KSHV replicative cycle may lead to new approaches to treating KSHV-related diseases.

A recombinant humanized monoclonal antibody (mAb) Eculizumab, C5-complement cascade inhibitor, is an important treatment of complement-based diseases recommended by international guidelines. Elizaria® Drug Product (DP), developed by IBC Generium, Russia, is the world's first registered biosimilar of eculizumab (Soliris®, Alexion Pharmaceuticals). Using sensitive state-of-the-art analytical techniques extensive similarity assessment has been conducted to demonstrate the structural and functional similarity of original Soliris® (Eculizumab Reference Product, RP) and the biosimilar Elizaria®, focusing on the physicochemical and biological quality attributes, including those known to affect the mechanisms of action. A multitude of analyses revealed that amino acid sequence is identical, the higher order structures, post-translational modifications, purity, and product variants are highly similar between Elizaria® DP and Eculizumab RP, except for minor differences in the relative abundance of the charge variants and glycan moieties considered not clinically significant. The results demonstrate that Elizaria® is highly analytically similar to Eculizumab RP in terms of physicochemical properties and biological activities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Neurocritical care patients are at risk of stress-induced gastrointestinal ulceration. We performed a systematic review and meta-analysis of stress ulcer prophylaxis (SUP) in critically ill adults admitted with a primary neurologic injury., Materials and Methods: We included randomized controlled trials (RCTs) comparing SUP with histamine-2-receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) to placebo/no prophylaxis, as well as to each other. The primary outcome was in-ICU gastrointestinal bleeding (GIB). Predefined secondary outcomes were all-cause 30-day mortality, ICU length of stay (LOS), nosocomial pneumonia, and other complications., Results: We identified 14 relevant trials enrolling 1036 neurocritical care patients; 11 trials enrolling 930 patients were included in the meta-analysis. H2RAs resulted in a lower incidence of GIB as compared to placebo or no prophylaxis (Risk ratio [RR] 0.42, 95% CI 0.30-0.58; p < 0.001); PPIs with a lower risk of GIB compared to placebo/no prophylaxis (RR 0.37, 95% CI 0.23-0.59; p < 0.001). No significant difference was observed in GIB comparing PPIs with H2RAs (RR 0.53, 95% CI 0.26-1.06; p = 0.07; I 2 = 0%)., Conclusions: In neurocritical care patients, the overall high or unclear risk of bias of individual trials, the low event rates, and modest sample sizes preclude strong clinical inferences about the utility of SUP., Competing Interests: Declaration of Competing Interest The authors have no conflict of interests to report relevant to this study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Humoral immunity to factor VIII (FVIII) represents a significant challenge for the treatment of patients with hemophilia A. Current paradigms indicate that neutralizing antibodies against FVIII (inhibitors) occur through a classical CD4 T cell, germinal center (GC) dependent process. However, clinical observations suggest that the nature of the immune response to FVIII may differ between patients. While some patients produce persistent low or high inhibitor titers, others generate a transient response. Moreover, FVIII reactive memory B cells are only detectable in some patients with sustained inhibitor titers. The determinants regulating the type of immune response a patient develops, let alone how the immune response differs in these patients remains incompletely understood. One hypothesis is that polymorphisms within immunoregulatory genes alter the underlying immune response to FVIII, and thereby the inhibitor response. Consistent with this, studies report that inhibitor titers to FVIII differ in animals with the same F8 pathogenic variant but completely distinct backgrounds; though, how these genetic disparities affect the immune response to FVIII remains to be investigated. Given this, we sought to mechanistically dissect how genetics impact the underlying immune response to FVIII. In particular, as the risk of producing inhibitors is weakly associated with differences in HLA, we hypothesized that genetic factors other than HLA influence the immune response to FVIII and downstream inhibitor formation. Our data demonstrate that FVIII deficient mice encoding the same MHC and F8 variant produce disparate inhibitor titers, and that the type of inhibitor response formed associates with the ability to generate GCs. Interestingly, the formation of antibodies through a GC or non-GC pathway does not appear to be due to differences in CD4 T cell immunity, as the CD4 T cell response to an immunodominant epitope in FVIII was similar in these mice. These results indicate that genetics can impact the process by which inhibitors develop and may in part explain the apparent propensity of patients to form distinct inhibitor responses. Moreover, these data highlight an underappreciated immunological pathway of humoral immunity to FVIII and lay the groundwork for identification of biomarkers for the development of approaches to tolerize against FVIII., Competing Interests: SM serves on the advisory board for Genentech, Sanofi Genzyme, Takeda, Biomarin, and CSL Behring. SM consults for Pfizer and Spark, as well as receives research funding from Octapharma, Genentech. RJ is the CEO and part-owner of Biconcavity Inc, as well as owns stock in BioMarin Pharmaceutical Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Patel, Lundgren, Baldwin, Cox, Parker, Healey, Jajosky, Zerra, Josephson, Doering, Stowell and Meeks.)

Advances in the development of novel treatment options for hemophilia A are prevalent. However, the anti-factor VIII (FVIII) neutralizing antibody (inhibitor) response to existing FVIII products remains a major treatment challenge. Although some novel products are designed to function in the presence of inhibitors, they do not specific address the immunogenicity risk or mechanistic causes of inhibitor development, which remain unclear. Furthermore, most preclinical studies supporting clinical gene therapy programs have reported immunogenicity signals in animal models, especially at higher vector doses and sometimes using multiple vector designs. In these settings, immunogenicity risk factor determination, comparative immunogenicity of competing vector designs, and the potential for obtaining meaningful prognostic data remain relatively unexplored. Additionally, there remains the opportunity to investigate clinical gene therapy as an alternative to standard immune tolerance induction therapy. The current study was designed to address these issues through longitudinal dose-response evaluation of 4 adeno-associated viral (AAV) vector candidates encoding 2 different FVIII transgenes in a murine model of hemophilia A. Plasma FVIII activity and anti-FVIII antibody data were used to generate a pharmacokinetic model that (1) identifies initial AAV-FVIII product expression kinetics as the dominant risk factor for inhibitor development, (2) predicts a therapeutic window where immune tolerance is achieved, and (3) demonstrates evidence of gene therapy-based immune tolerance induction. Although there are known limitations to the predictive value of preclinical immunogenicity testing, these studies can uncover or support the development of design principles that can guide the development of safe and effective genetic medicines., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose of Review: The principle of optimizing oxygen delivery to the injured brain rests on the premise that both hypoxia and hyperoxia are important mediators of secondary brain injury and should be avoided. This rationale has prompted a move towards incorporating oxygenation endpoints into the management of neurocritical care patients, particularly those with traumatic brain injury. The present review will seek to describe clinical strategies to optimize oxygenation in the acutely brain-injured patient, drawing upon relevant physiologic principles and clinical data, where it exists., Recent Findings: A phase II randomized trial found that a protocolized approach to improving oxygen delivery resulted in less duration of brain hypoxia and a trend towards lower mortality among patients with severe traumatic brain injury. Recent clinical protocols have been published to guide oxygen delivery based on core physiologic principles: increasing oxygen supply via modulation of mean arterial pressure and intracranial pressure, blood oxygen carrying capacity, and cerebral vasoreactivity; and decreasing oxygen demand via sedation, pharmacologic coma, and hypothermia., Summary: Although there is growing interest in the use of brain tissue oxygenation as a resuscitative endpoint, many of these therapies are based on physiologic principles with little robust clinical evidence to guide their application. Clinicians must be mindful of this and balance the putative benefits of improving oxygenation against the risks associated with the use of such therapies., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Patients with acute neurologic injuries frequently require mechanical ventilation due to diminished airway protective reflexes, cardiopulmonary failure secondary to neurologic insults, or to facilitate gas exchange to precise targets. Mechanical ventilation enables tight control of oxygenation and carbon dioxide levels, enabling clinicians to modulate cerebral hemodynamics and intracranial pressure with the goal of minimizing secondary brain injury. In patients with acute spinal cord injuries, neuromuscular conditions, or diseases of the peripheral nerve, mechanical ventilation enables respiratory support under conditions of impending or established respiratory failure. Noninvasive ventilatory approaches may be carefully considered for certain disease conditions, including myasthenia gravis and amyotrophic lateral sclerosis, but may be inappropriate in patients with Guillain-Barré syndrome or when relevant contra-indications exist. With regard to discontinuing mechanical ventilation, considerable uncertainty persists about the best approach to wean patients, how to identify patients ready for extubation, and when to consider primary tracheostomy. Recent consensus guidelines highlight these and other knowledge gaps that are the focus of active research efforts. This chapter outlines important general principles to consider when initiating, titrating, and discontinuing mechanical ventilation in patients with acute neurologic injuries. Important disease-specific considerations are also reviewed where appropriate., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Medical images support diagnostic care and research in medicine. The acquisition and availability of medical images in digital form can facilitate quick diagnosis, ease of access, continuity of care, analysis and contribute to modern medical research. Digital Imaging and Communications in Medicine (DICOM) is a universal standard that promises standardized representation and exchange of medical images and related information from various radiological and waveform sources. DICOM software development kits or tools or libraries make it easier to implement DICOM standard in healthcare applications. There are several such API libraries available from different providers that promise DICOM integration. In this paper, we explore available DICOM API libraries and conduct a comparative study between a set of selected libraries on the four major criteria (DICOM features, technical aspects, the robustness of the library, and the level of user support available). The aim is to provide a complete picture of options available that can help in finding a best-fit open-source DICOM standard integration API library for developing standardized and interoperable healthcare applications.

Background: Patients with acute traumatic cervical or high thoracic level spinal cord injury (SCI) typically require mechanical ventilation (MV) during their acute admission. Placement of a tracheostomy is preferred when prolonged weaning from MV is anticipated. However, the optimal timing of tracheostomy placement in patients with acute traumatic SCI remains uncertain. We systematically reviewed the literature to determine the effects of early versus late tracheostomy or prolonged intubation in patients with acute traumatic SCI on important clinical outcomes., Methods: Six databases were searched from their inception to January 2020. Conference abstracts from relevant proceedings and the gray literature were searched to identify additional studies. Data were obtained by two independent reviewers to ensure accuracy and completeness. The quality of observational studies was evaluated using the Newcastle Ottawa Scale., Results: Seventeen studies (2,804 patients) met selection criteria, 14 of which were published after 2009. Meta-analysis showed that early tracheostomy was not associated with decreased short-term mortality (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.39-1.79; p = 0.65; n = 2,072), but was associated with a reduction in MV duration (mean difference [MD], 13.1 days; 95% CI, -6.70 to -21.11; p = 0.0002; n = 855), intensive care unit length of stay (MD, -10.20 days; 95% CI, -4.66 to -15.74; p = 0.0003; n = 855), and hospital length of stay (MD, -7.39 days; 95% CI, -3.74 to -11.03; p < 0.0001; n = 423). Early tracheostomy was also associated with a decreased incidence of ventilator-associated pneumonia and tracheostomy-related complications (RR, 0.86; 95% CI, 0.75-0.98; p = 0.02; n = 2,043 and RR, 0.64; 95% CI, 0.48-0.84; p = 0.001; n = 812 respectively). The majority of studies ranked as good methodologic quality on the Newcastle Ottawa Scale., Conclusion: Early tracheostomy in patients with acute traumatic SCI may reduce duration of mechanical entilation, length of intensive care unit stay, and length of hospital stay. Current studies highlight the lack of high-level evidence to guide the optimal timing of tracheostomy in acute traumatic SCI. Future research should seek to understand whether early tracheostomy improves patient comfort, decreases duration of sedation, and improves long-term outcomes., Level of Evidence: Systematic Review, level III., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Surgery of Trauma.)

Objectives: To identify whether factors associated with withholding extubation in the ICU also predict the risk of extubation failure., Design: Retrospective cohort study., Setting: Eight medical-surgical ICUs in Toronto., Patients: Adult patients receiving invasive mechanical ventilation, with a first successful spontaneous breathing trial within 28 days of initial ICU admission., Interventions: None., Measurements and Main Results: The primary end point had three mutually exclusive levels, including: 1) withholding extubation after a successful spontaneous breathing trial, 2) extubation failure within 48 hours, and 3) successful extubation. Among 9,910 patients, 38% of patients were not extubated within 24 hours of their first successful spontaneous breathing trial. A total of 12.9% of patients who were promptly extubated failed within the next 48 hours. Several discrepancies were evident in the association of factors with risk of withholding extubation and extubation failure. Specifically, both age and female sex were associated with withholding extubation (odds ratio, 1.07; 95% CI, 1.03-1.11; and odds ratio, 1.13; 95% CI, 1.02-1.26, respectively) but not a higher risk of failed extubation (odds ratio, 0.99; 95% CI, 0.93-1.05; and odds ratio, 0.93; 95% CI, 0.77-1.11, respectively). Conversely, both acute cardiovascular conditions and intubation for hypoxemic respiratory failure were associated with a higher risk of failed extubation (odds ratio, 1.32; 95% CI, 1.06-1.66; and odds ratio, 1.46; 95% CI, 1.16-1.82, respectively) but not a higher odds of a withheld extubation attempt (odds ratio, 0.79; 95% CI, 0.68-0.91; and odds ratio, 1.07; 95% CI, 0.93-1.23, respectively)., Conclusions: Several factors showed discordance between the decision to withhold extubation and the risk of extubation failure. This discordance may lead to longer duration of mechanical ventilation or higher reintubation rates. Improving the decision-making behind extubation may help to reduce both exposure to invasive mechanical ventilation and extubation failure., Competing Interests: Dr. Ferreyro is supported by a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research. Dr. Angriman is supported by a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Purpose: We systematically reviewed existing critical care electroencephalography (EEG) educational programs for non-neurologists, with the primary goal of reporting the content covered, methods of instruction, overall duration, and participant experience. Our secondary goals were to assess the impact of EEG programs on participants' core knowledge, and the agreement between non-experts and experts for seizure identification., Source: Major databases were searched from inception to 30 August 2020. Randomized controlled trials, cohort studies, and descriptive studies were all considered if they reported an EEG curriculum for non-neurologists in a critical care setting. Data were presented thematically for the qualitative primary outcome and a meta-analysis using a random effects model was performed for the quantitative secondary outcomes., Principal Findings: Twenty-nine studies were included after reviewing 7,486 citations. Twenty-two studies were single centre, 17 were from North America, and 16 were published after 2016. Most EEG studies were targeted to critical care nurses (17 studies), focused on processed forms of EEG with amplitude-integrated EEG being the most common (15 studies), and were shorter than one day in duration (24 studies). In pre-post studies, EEG programs significantly improved participants' knowledge of tested material (standardized mean change, 1.79; 95% confidence interval [CI], 0.86 to 2.73). Agreement for seizure identification between non-experts and experts was moderate (Cohen's kappa = 0.44; 95% CI, 0.27 to 0.60)., Conclusions: It is feasible to teach basic EEG to participants in critical care settings from different clinical backgrounds, including physicians and nurses. Brief training programs can enable bedside providers to recognize high-yield abnormalities such as non-convulsive seizures., (© 2021. Canadian Anesthesiologists' Society.)

Hematopoietic stem and progenitor cell (HSPC) lentiviral gene therapy is a promising strategy toward a lifelong cure for hemophilia A (HA). The primary risks associated with this approach center on the requirement for pre-transplantation conditioning necessary to make space for, and provide immune suppression against, stem cells and blood coagulation factor VIII, respectively. Traditional conditioning agents utilize genotoxic mechanisms of action, such as DNA alkylation, that increase risk of sterility, infection, and developing secondary malignancies. In the current study, we describe a non-genotoxic conditioning protocol using an immunotoxin targeting CD117 (c-kit) to achieve endogenous hematopoietic stem cell depletion and a cocktail of monoclonal antibodies to provide transient immune suppression against the transgene product in a murine HA gene therapy model. This strategy provides high-level engraftment of hematopoietic stem cells genetically modified ex vivo using recombinant lentiviral vector (LV) encoding a bioengineered high-expression factor VIII variant, termed ET3. Factor VIII procoagulant activity levels were durably elevated into the normal range and phenotypic correction achieved. Furthermore, no immunological rejection or development of anti-ET3 immunity was observed. These preclinical data support clinical translation of non-genotoxic antibody-based conditioning in HSPC LV gene therapy for HA., Competing Interests: C.B.D. and H.T.S. are co-founders of Expression Therapeutics and own equity in the company. Expression Therapeutics owns the intellectual property associated with ET3. G.D. is an employee of Expression Therapeutics and owns equity in the company. S.C. serves on the advisory committee on emapalumab for Sobi. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. A.L.R., C.P., T.S.L., K.A.K., J.T.Z., and J.S.A. declare no competing interests., (© 2021 The Authors.)

Management of patients with severe or critical COVID-19 is mainly modeled after care of patients with severe pneumonia or acute respiratory distress syndrome from other causes. These models are based on evidence that primarily originates from investigations in high-income countries, but it may be impractical to apply these recommendations to resource-restricted settings in low- and middle-income countries (LMICs). We report on a set of pragmatic recommendations for microbiology and laboratory testing, imaging, and the use of diagnostic and prognostic models in patients with severe COVID-19 in LMICs. For diagnostic testing, where reverse transcription-PCR (RT-PCR) testing is available and affordable, we recommend using RT-PCR of the upper or lower respiratory specimens and suggest using lower respiratory samples for patients suspected of having COVID-19 but have negative RT-PCR results for upper respiratory tract samples. We recommend that a positive RT-PCR from any anatomical source be considered confirmatory for SARS-CoV-2 infection, but, because false-negative testing can occur, recommend that a negative RT-PCR does not definitively rule out active infection if the patient has high suspicion for COVID-19. We suggest against using serologic assays for the detection of active or past SARS-CoV-2 infection, until there is better evidence for its usefulness. Where available, we recommend the use of point-of-care antigen-detecting rapid diagnostic testing for SARS-CoV-2 infection as an alternative to RT-PCR, only if strict quality control measures are guaranteed. For laboratory testing, we recommend a baseline white blood cell differential platelet count and hemoglobin, creatinine, and liver function tests and suggest a baseline C-reactive protein, lactate dehydrogenase, troponin, prothrombin time (or other coagulation test), and D-dimer, where such testing capabilities are available. For imaging, where availability of standard thoracic imaging is limited, we suggest using lung ultrasound to identify patients with possible COVID-19, but recommend against its use to exclude COVID-19. We suggest using lung ultrasound in combination with clinical parameters to monitor progress of the disease and responses to therapy in COVID-19 patients. We currently suggest against using diagnostic and prognostic models as these models require extensive laboratory testing and imaging, which often are limited in LMICs.

The therapeutic options for COVID-19 patients are currently limited, but numerous randomized controlled trials are being completed, and many are on the way. For COVID-19 patients in low- and middle-income countries (LMICs), we recommend against using remdesivir outside of a clinical trial. We recommend against using hydroxychloroquine ± azithromycin or lopinavir-ritonavir. We suggest empiric antimicrobial treatment for likely coinfecting pathogens if an alternative infectious cause is likely. We suggest close monitoring without additional empiric antimicrobials if there are no clinical or laboratory signs of other infections. We recommend using oral or intravenous low-dose dexamethasone in adults with COVID-19 disease who require oxygen or mechanical ventilation. We recommend against using dexamethasone in patients with COVID-19 who do not require supplemental oxygen. We recommend using alternate equivalent doses of steroids in the event that dexamethasone is unavailable. We also recommend using low-dose corticosteroids in patients with refractory shock requiring vasopressor support. We recommend against the use of convalescent plasma and interleukin-6 inhibitors, such as tocilizumab, for the treatment of COVID-19 in LMICs outside of clinical trials.

As some patients infected with the novel coronavirus progress to critical illness, a subset will eventually develop shock. High-quality data on management of these patients are scarce, and further investigation will provide valuable information in the context of the pandemic. A group of experts identify a set of pragmatic recommendations for the care of patients with SARS-CoV-2 and shock in resource-limited environments. We define shock as life-threatening circulatory failure that results in inadequate tissue perfusion and cellular dysoxia/hypoxia, and suggest that it can be operationalized via clinical observations. We suggest a thorough evaluation for other potential causes of shock and suggest against indiscriminate testing for coinfections. We suggest the use of the quick Sequential Organ Failure Assessment (qSOFA) as a simple bedside prognostic score for COVID-19 patients and point-of-care ultrasound (POCUS) to evaluate the etiology of shock. Regarding fluid therapy for the treatment of COVID-19 patients with shock in low-middle-income countries, we favor balanced crystalloids and recommend using a conservative fluid strategy for resuscitation. Where available and not prohibited by cost, we recommend using norepinephrine, given its safety profile. We favor avoiding the routine use of central venous or arterial catheters, where availability and costs are strong considerations. We also recommend using low-dose corticosteroids in patients with refractory shock. In addressing targets of resuscitation, we recommend the use of simple bedside parameters such as capillary refill time and suggest that POCUS be used to assess the need for further fluid resuscitation, if available.

Background: Use of electroencephalography (EEG) is currently recommended by the American Clinical Neurophysiology Society for a wide range of indications, including diagnosis of nonconvulsive status epilepticus and evaluation of unexplained disorders of consciousness. Data interpretation usually occurs by expert personnel (e.g., epileptologists, neurophysiologists), with information relayed to the primary care team. However, data cannot always be read in time-sensitive fashion, leading to potential delays in EEG interpretation and patient management. Multiple training programs have recently been described to enable non-experts to rapidly interpret EEG at the bedside. A comprehensive review of these training programs, including the tools used, outcomes obtained, and potential pitfalls, is currently lacking. Therefore, the optimum training program and implementation strategy remain unknown., Methods: We will conduct a systematic review of descriptive studies, case series, cohort studies, and randomized controlled trials assessing training programs for EEG interpretation by non-experts. Our primary objective is to comprehensively review educational programs in this domain and report their structure, patterns of implementation, limitations, and trainee feedback. Our secondary objective will be to compare the performance of non-experts for EEG interpretation with a gold standard (e.g., interpretation by a certified electroencephalographers). Studies will be limited to those performed in acute care settings in both adult and pediatric populations (intensive care unit, emergency department, or post-anesthesia care units). Comprehensive search strategies will be developed for MEDLINE, EMBASE, WoS, CINAHL, and CENTRAL to identify studies for review. The gray literature will be scanned for further eligible studies. Two reviewers will independently screen the search results to identify studies for inclusion. A standardized data extraction form will be used to collect important data from each study. If possible, we will attempt to meta-analyze the quantitative data. If heterogeneity between studies is too high, we will present meaningful quantitative comparisons of secondary outcomes as per the synthesis without meta-analysis (SWiM) reporting guidelines., Discussion: We will aim to summarize the current literature in this domain to understand the structure, patterns, and pitfalls of EEG training programs for non-experts. This review is undertaken with a view to inform future education designs, potentially enabling rapid detection of EEG abnormalities, and timely intervention by the treating physician., Prospero Registration: Submitted and undergoing review. Registration ID: CRD42020171208 .

The use of extracorporeal membrane oxygenation (ECMO) is increasing globally, although mortality in this setting remains high. Patients on ECMO may be potential organ donors in the context of withdrawal of life-sustaining measures (WLSM) or neurologic determination of death (NDD). Nevertheless, there are currently no Canadian standards to guide clinicians on NDD or WLSM for the purposes of organ donation in this patient population. Apnea testing remains fundamental to determining NDD and is an area where ECMO may alter routine procedures. In this review, we outline protocols for the performance of apnea testing and WLSM for patients supported with ECMO, highlighting important technical and physiologic considerations that may affect the determination of death. In addition, we review important considerations for NDD in ECMO, including management of potential confounders, strategies for controlling oxygen and carbon dioxide levels during apnea testing, and the appropriate use of ancillary tests to support NDD. In the context of ECMO support, there is limited evidence to guide NDD and WLSM for the purposes of organ donation. Drawing upon extensive clinical experience, we provide protocols for these processes and review other important considerations in an effort to maximize donor potential in this growing patient population.

The use of standardized management protocols (SMPs) may improve patient outcomes for some critical care diseases. Whether SMPs improve outcomes after subarachnoid hemorrhage (SAH) is currently unknown. We aimed to study the effect of SMPs on 6-month mortality and neurologic outcomes following SAH. A systematic review of randomized control trials (RCTs) and observational studies was performed by searching multiple indexing databases from their inception through January 2019. Studies were limited to adult patients (age ≥ 18) with non-traumatic SAH reporting mortality, neurologic outcomes, delayed cerebral ischemia (DCI) and other important complications. Data on patient and SMP characteristics, outcomes and methodologic quality were extracted into a pre-piloted collection form. Methodologic quality of observational studies was assessed using the Newcastle-Ottawa scale, and RCT quality was reported as per the Cochrane risk of bias tool. A total of 11,260 studies were identified, of which 37 (34 full-length articles and 3 abstracts) met the criteria for inclusion. Two studies were RCTs and 35 were observational. SMPs were divided into four broad domains: management of acute SAH, early brain injury, DCI and general neurocritical care. The most common SMP design was control of DCI, with 22 studies assessing this domain of care. Overall, studies were of low quality; most described single-center case series with small patient sizes. Definitions of key terms and outcome reporting practices varied significantly between studies. DCI and neurologic outcomes in particular were defined inconsistently, leading to significant challenges in their interpretation. Given the substantial heterogeneity in reporting practices between studies, a meta-analysis for 6-month mortality and neurologic outcomes could not be performed, and the effect of SMPs on these measures thus remains inconclusive. Our systematic review highlights the need for large, rigorous RCTs to determine whether providing standardized, best-practice management through the use of a protocol impacts outcomes in critically ill patients with SAH.Trial registration Registration number: CRD42017069173.

Neutralizing antibodies to factor VIII (fVIII), referred to as "inhibitors," remain the most challenging complication post-fVIII replacement therapy. Preclinical development of novel fVIII products involves studies incorporating hemophilia A (HA) and wild-type animal models. Though immunogenicity is a critical aspect of preclinical pharmacology studies, gene therapy studies tend to focus on fVIII expression levels without major consideration for immunogenicity. Therefore, little clarity exists on whether preclinical testing can be predictive of clinical immunogenicity risk. Despite this, but perhaps due to the potential for transformative benefits, clinical gene therapy trials have progressed rapidly. In more than two decades, no inhibitors have been observed. However, all trials are conducted in previously treated patients without a history of inhibitors. The current review thus focuses on our understanding of preclinical immunogenicity for HA gene therapy candidates and the potential indication for inhibitor treatment, with a focus on product- and platform-specific determinants, including fVIII transgene sequence composition and tissue/vector biodistribution. Currently, the two leading clinical gene therapy vectors are adeno-associated viral (AAV) and lentiviral (LV) vectors. For HA applications, AAV vectors are liver-tropic and employ synthetic, high-expressing, liver-specific promoters. Factors including vector serotype and biodistribution, transcriptional regulatory elements, transgene sequence, dosing, liver immunoprivilege, and host immune status may contribute to tipping the scale between immunogenicity and tolerance. Many of these factors can also be important in delivery of LV-fVIII gene therapy, especially when delivered intravenously for liver-directed fVIII expression. However, ex vivo LV-fVIII targeting and transplantation of hematopoietic stem and progenitor cells (HSPC) has been demonstrated to achieve durable and curative fVIII production without inhibitor development in preclinical models. A critical variable appears to be pre-transplantation conditioning regimens that suppress and/or ablate T cells. Additionally, we and others have demonstrated the potential of LV-fVIII HSPC and liver-directed AAV-fVIII gene therapy to eradicate pre-existing inhibitors in murine and canine models of HA, respectively. Future preclinical studies will be essential to elucidate immune mechanism(s) at play in the context of gene therapy for HA, as well as strategies for preventing adverse immune responses and promoting immune tolerance even in the setting of pre-existing inhibitors., (Copyright © 2020 Patel, Lundgren, Spencer and Doering.)

Background and Objective: Motor Imagery (MI) based Brain-Computer-Interface (BCI) is a rising support system that can assist disabled people to communicate with the real world, without any external help. It serves as an alternative communication channel between the user and computer. Electroencephalogram (EEG) recordings prove to be an appropriate choice for imaging MI tasks in a BCI system as it provides a non-invasive way for completing the task. The reliability of a BCI system confides on the efficiency of the assessment of different MI tasks., Methods: The present work proposes a new approach for the classification of distinct MI tasks based on EEG signals using the flexible analytic wavelet transform (FAWT) technique. The FAWT decomposes the EEG signal into sub-bands and temporal moment-based features are extracted from the sub-bands. Feature normalization is applied to minimize the bias nature of classifier. The FAWT-based features are utilized as inputs to multiple classifiers. Ensemble learning method based Subspace k-Nearest Neighbour (kNN) classifier is established as the best and robust classifier for the distinction of the right hand (RH) and right foot (RF) MI tasks., Results: The sub-band (SB) wise features are tested on multiple classifiers and best performance parameters are obtained using the ensemble method based subspace kNN classifier. The best results of parameters are obtained for fourth SB as accuracy 99.33%, sensitivity 99%, specificity 99.6%, F1-Score 0.9925, and kappa value 0.9865. The other sub-bands are also attained significant results using subspace KNN classifier., Conclusions: The proposed work explores the utility of FAWT based features for the classification of RH and RF MI tasks EEG signals. The suggested work highlights the effectiveness of multiple classifiers for classification MI-tasks. The proposed method shows better performance in comparison to state-of-arts methods. Thus, the potential to implement a BCI system for controlling wheelchairs, robotic arms, etc., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Physical actions classification of surface electromyography (sEMG) signal is required in applications like prosthesis, and robotic control etc. In this paper, tunable-Q factor wavelet transform (TQWT) based algorithm is proposed for the classification of physical actions such as clapping, hugging, bowing, handshaking, standing, running, jumping, waving, seating, and walking. sEMG signal is decomposed into sub-bands by TQWT. Various features are extracted from each different band and statistical analysis is performed. These features are fed into multi-class least squares support vector machine classifier using two non-linear kernel functions, morlet wavelet function, and radial basis function. The proposed method is an attempt for classifying physical actions using TQWT and its performance and results are promising and have high classification accuracy of 97.74% for sub-band eight with morlet kernel function., (© Springer Nature Switzerland AG 2019.)

Background and Objective: The recognition of emotional states is a crucial step in the development of a brain-computer interface (BCI) system. Emotion recognition system finds applications in medical science for the impaired and disabled people. Electroencephalography assesses the neurophysiology of the brain for recognition of different emotional states., Methods: The audio-video stimulus based experimental setup is arranged for the electroencephalogram (EEG) recordings of happy, fear, sad, and relax emotions and a two-stage filtering method is proposed for the recognition of emotion EEG signals. At the first stage, a correlation-criterion is suggested for removal of noisy intrinsic mode functions (IMFs) from the IMFs obtained by applying the empirical mode decomposition on the raw EEG signal. The noise-free IMFs are used to reconstruct the denoised EEG signal with improved stationarity characteristics. The denoised EEG signal is further decomposed into modes using the variational mode decomposition (VMD). At the second stage, the instantaneous-frequency based filtering of VMD modes is performed and filtered modes are retained for the reconstruction of denoised EEG signal with the desired frequency range. After two-stage filtering, the non-linear measures of filtered EEG signals are used as input features to multi-class least squares support vector machine (MC-LS-SVM) classifier for emotion recognition., Results: The different kernel functions are tested in MC-LS-SVM classifier for emotion recognition. The Morlet wavelet (MW) kernel function provides the best individual classification accuracies for happy, fear, sad, and relax emotions as 92.79%, 87.62%, 88.98%, and 93.13%, respectively. The MW-kernel function also obtained the best overall accuracy of 90.63%, F1-score 0.9064, and kappa value 0.8751., Conclusions: The Audio-video stimulus based emotion EEG-dataset is recorded. A new filtering method is proposed for EEG signals. The proposed method provides better emotion recognition performance as compared to the state-of-the-art methods and classifies emotions using single-bipolar EEG channel, which can greatly reduce the complexity of emotion-recognition based BCI systems., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: The relationship between posterior shoulder instability and increased glenoid retroversion has been documented. Posterior open wedge glenoid osteotomy is a possible treatment option for patients with increased glenoid retroversion, but outcomes in the literature are limited. Therefore, the purpose of this study was to report the clinical and radiological outcomes following posterior glenoid osteotomy., Methods: Patients that underwent posterior glenoid osteotomy for posterior shoulder instability with a GR angle of more than or equal to 10°, and were at least 12 months out from surgery, were included in the study. General data, medical history, and radiographic data such as the pre- and postoperative glenoid retroversion angle were extracted from the patients' hospital documentation notes. To evaluate the postoperative outcome, the Rowe standard rating scale for shoulder instability and the Oxford shoulder instability score were collected retrospectively., Results: A total of 12 shoulders (11 patients) could be included. The mean pre-operative glenoid retroversion was 23.3° (range 12°-35°) and this reduced significantly (p = 0.003) to a mean of 13° (range 1°-28°) postoperatively. At a mean follow-up of 19.8 months (range 14-36), the median Rowe score was 90 points (range 45-100 points) and the median Oxford instability score was 44 points (range 21-48 points). There were no postoperative re-dislocations or revision surgeries; however, one patient reported signs of recurrent shoulder instability and four asymptomatic glenoid neck fractures occurred., Conclusion: Open wedge posterior glenoid osteotomy provides reliable clinical results with a low rate of clinical failure in a stringently selected patient cohort at short-term follow-up. However, due to the risk of potentially severe complications, we advocate this procedure for experienced shoulder surgeons only, who are familiar with its anatomical and technical considerations., Level of Evidence: IV (case series).

Neuromuscular disorder is a muscular and nervous disorder resulting in muscular weakness and progressively damages nervous control, such as amyotrophic lateral sclerosis (ALS) and myopathy (MYO). Its diagnosis can be possible by classification of ALS, MYO, and normal electromyogram (EMG) signals. In this paper, an effective method based on variational mode decomposition (VMD) is proposed for identification of neuromuscular disorder of EMG signals. VMD is an adaptive signal decomposition which decomposes EMG signals nonrecursively into band-limited functions or modes. These modes are used for extraction of spectral features, particularly spectral flatness, spectral spread, spectral decrease and statistical features like kurtosis, mean absolute deviation, and interquartile range. The extracted features are fed to the extreme learning machine classifier in order to classify neuromuscular disorder of EMG signals. The performance of obtained results shows that the method used provides a better classification for neuromuscular disorder of EMG signals as compared to existing methods.