Unmasking determinants of specificity in the human kinome.

Protein kinases control cellular responses to environmental cues by swift and accurate signal processing. Breakdowns in this high-fidelity capability are a driving force in cancer and other diseases. Thus, our limited understanding of which amino acids in the kinase domain encode substrate specificity, the so-called determinants of specificity (DoS), constitutes a major obstacle in cancer signaling. Here, we systematically discover several DoS and experimentally validate three of them, named the αC1, αC3, and APE-7 residues. We demonstrate that DoS form sparse networks of non-conserved residues spanning distant regions. Our results reveal a likely role for inter-residue allostery in specificity and an evolutionary decoupling of kinase activity and specificity, which appear loaded on independent groups of residues. Finally, we uncover similar properties driving SH2 domain specificity and demonstrate how the identification of DoS can be utilized to elucidate a greater understanding of the role of signaling networks in cancer (Creixell et al., 2015 [this issue of Cell]).

Kinome-wide decoding of network-attacking mutations rewiring cancer signaling.

Cancer cells acquire pathological phenotypes through accumulation of mutations that perturb signaling networks. However, global analysis of these events is currently limited. Here, we identify six types of network-attacking mutations (NAMs), including changes in kinase and SH2 modulation, network rewiring, and the genesis and extinction of phosphorylation sites. We developed a computational platform (ReKINect) to identify NAMs and systematically interpreted the exomes and quantitative (phospho-)proteomes of five ovarian cancer cell lines and the global cancer genome repository. We identified and experimentally validated several NAMs, including PKCγ M501I and PKD1 D665N, which encode specificity switches analogous to the appearance of kinases de novo within the kinome. We discover mutant molecular logic gates, a drift toward phospho-threonine signaling, weakening of phosphorylation motifs, and kinase-inactivating hotspots in cancer. Our method pinpoints functional NAMs, scales with the complexity of cancer genomes and cell signaling, and may enhance our capability to therapeutically target tumor-specific networks.

White by Another Name? Can Anti-Christian Bias Claims Serve as a Racial Dog Whistle?

Four preregistered experiments (N = 4,307) explored whether anti-Christian bias claims can discreetly signal White allyship among Christian American adults. In Experiments 1 and 2, reading about anti-Christian bias led White, but not Black, Christians to perceive more anti-White bias. Experiments 3 and 4 demonstrate the connection between Christian and White can be leveraged by politicians in the form of a racial dog whistle. In Experiment 3, White Christians perceived a politician concerned about anti-Christian bias as caring more about anti-White bias and more willing to fight for White people (relative to a control). This politician was also perceived as less offensive than a politician concerned about anti-White bias. In Experiment 4, Black Christians perceived a politician concerned about anti-Christian bias as less offensive than one concerned about anti-White bias yet still unlikely to fight for Black people. Results suggest "anti-Christian bias" can provide a relatively palatable way to signal allegiance to White people.

Computational design of a synthetic PD-1 agonist.

Programmed cell death protein-1 (PD-1) expressed on activated T cells inhibits T cell function and proliferation to prevent an excessive immune response, and disease can result if this delicate balance is shifted in either direction. Tumor cells often take advantage of this pathway by overexpressing the PD-1 ligand PD-L1 to evade destruction by the immune system. Alternatively, if there is a decrease in function of the PD-1 pathway, unchecked activation of the immune system and autoimmunity can result. Using a combination of computation and experiment, we designed a hyperstable 40-residue miniprotein, PD-MP1, that specifically binds murine and human PD-1 at the PD-L1 interface with a Kd of ∼100 nM. The apo crystal structure shows that the binder folds as designed with a backbone RMSD of 1.3 Što the design model. Trimerization of PD-MP1 resulted in a PD-1 agonist that strongly inhibits murine T cell activation. This small, hyperstable PD-1 binding protein was computationally designed with an all-beta interface, and the trimeric agonist could contribute to treatments for autoimmune and inflammatory diseases.

Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates.

Many tumors become addicted to autophagy for survival, suggesting inhibition of autophagy as a potential broadly applicable cancer therapy. ULK1/Atg1 is the only serine/threonine kinase in the core autophagy pathway and thus represents an excellent drug target. Despite recent advances in the understanding of ULK1 activation by nutrient deprivation, how ULK1 promotes autophagy remains poorly understood. Here, we screened degenerate peptide libraries to deduce the optimal ULK1 substrate motif and discovered 15 phosphorylation sites in core autophagy proteins that were verified as in vivo ULK1 targets. We utilized these ULK1 substrates to perform a cell-based screen to identify and characterize a potent ULK1 small molecule inhibitor. The compound SBI-0206965 is a highly selective ULK1 kinase inhibitor in vitro and suppressed ULK1-mediated phosphorylation events in cells, regulating autophagy and cell survival. SBI-0206965 greatly synergized with mechanistic target of rapamycin (mTOR) inhibitors to kill tumor cells, providing a strong rationale for their combined use in the clinic.

Homing in: Mechanisms of Substrate Targeting by Protein Kinases.

Protein phosphorylation is the most common reversible post-translational modification in eukaryotes. Humans have over 500 protein kinases, of which more than a dozen are established targets for anticancer drugs. All kinases share a structurally similar catalytic domain, yet each one is uniquely positioned within signaling networks controlling essentially all aspects of cell behavior. Kinases are distinguished from one another based on their modes of regulation and their substrate repertoires. Coupling specific inputs to the proper signaling outputs requires that kinases phosphorylate a limited number of sites to the exclusion of hundreds of thousands of off-target phosphorylation sites. Here, we review recent progress in understanding mechanisms of kinase substrate specificity and how they function to shape cellular signaling networks.

The Impact of Internal Medicine Clerkship Characteristics and NBME Subject Exams on USMLE Step 2 Clinical Knowledge Exam Performance.

BACKGROUND: Residency program directors will likely emphasize the United States Medical Licensing Exam (USMLE) Step 2 clinical knowledge (CK) exam more during residency application given the recent USMLE Step 1 transition to pass/fail scoring. We examined how internal medicine clerkship characteristics and NBME subject exam scores affect USMLE Step 2 CK performance. DESIGN: The authors used univariable and multivariable generalized estimating equations to determine associations between Step 2 CK performance and internal medicine clerkship characteristics and NBME subject exams. The sample had 21,280 examinees' first Step 2 CK scores for analysis. RESULTS: On multivariable analysis, Step 1 performance (standardized ß = 0.45, p < .001) and NBME medicine subject exam performance (standardized ß = 0.40, p < .001) accounted for approximately 60% of the variance in Step 2 CK performance. Students who completed the internal medicine clerkship last in the academic year scored lower on Step 2 CK (Mdiff = -3.17 p < .001). Students who had a criterion score for passing the NBME medicine subject exam scored higher on Step 2 CK (Mdiff = 1.10, p = .03). There was no association between Step 2 CK performance and other internal medicine clerkship characteristics (all p > 0.05) nor with the total NBME subject exams completed (ß=0.05, p = .78). CONCLUSION: Despite similarities between NBME subject exams and Step 2 CK, the authors did not identify improved Step 2 CK performance for students who had more NBME subject exams. The lack of association of Step 2 CK performance with many internal medicine clerkship characteristics and more NBME subject exams has implications for future clerkship structure and summative assessment. The improved Step 2 CK performance in students that completed their internal medicine clerkship earlier warrants further study given the anticipated increase in emphasis on Step 2 CK.

Comprehensive profiling of the STE20 kinase family defines features essential for selective substrate targeting and signaling output.

Specificity within protein kinase signaling cascades is determined by direct and indirect interactions between kinases and their substrates. While the impact of localization and recruitment on kinase-substrate targeting can be readily assessed, evaluating the relative importance of direct phosphorylation site interactions remains challenging. In this study, we examine the STE20 family of protein serine-threonine kinases to investigate basic mechanisms of substrate targeting. We used peptide arrays to define the phosphorylation site specificity for the majority of STE20 kinases and categorized them into four distinct groups. Using structure-guided mutagenesis, we identified key specificity-determining residues within the kinase catalytic cleft, including an unappreciated role for the kinase ß3-αC loop region in controlling specificity. Exchanging key residues between the STE20 kinases p21-activated kinase 4 (PAK4) and Mammalian sterile 20 kinase 4 (MST4) largely interconverted their phosphorylation site preferences. In cells, a reprogrammed PAK4 mutant, engineered to recognize MST substrates, failed to phosphorylate PAK4 substrates or to mediate remodeling of the actin cytoskeleton. In contrast, this mutant could rescue signaling through the Hippo pathway in cells lacking multiple MST kinases. These observations formally demonstrate the importance of catalytic site specificity for directing protein kinase signal transduction pathways. Our findings further suggest that phosphorylation site specificity is both necessary and sufficient to mediate distinct signaling outputs of STE20 kinases and imply broad applicability to other kinase signaling systems.

Residency match interview scheduling: quantifying the applicant experience.

BACKGROUND: The process of offering and scheduling residency interviews varies widely among programmes. Applicants report distress and have advocated for reform. However, there is a paucity of quantitative data to characterise applicant concerns. OBJECTIVE: We quantified the interview scheduling experience for US allopathic medical students in the 2020 main residency match. METHODS: An anonymous, 13 question survey was sent to student representatives from each Association of American Medical Colleges member institution. Recipients were asked to forward the survey to their entire fourth-year class. RESULTS: Of 4314 applicants to whom the survey was sent, 786 (18.2%) responded. Overall, 20.4% reported missing the opportunity to interview at a programme because they did not have adequate time to respond to an invitation; applicants into surgical specialties were significantly more likely than their non-surgical peers to report this experience (26.4% vs 18.4%, p<0.05). Most (57.4%) respondents scheduled an interview knowing they would likely cancel it in the future. The most commonly cited reason for this behaviour was concern that applicants would not receive invitations from other programmes (85.6%). A majority (56.4%) of respondents did not believe the match interview process functions based on equity and merit. CONCLUSIONS: About one in five respondents missed the opportunity to interview at a programme because they did not respond to an invitation in time. Most respondents scheduled interviews knowing that they were likely to cancel them in the future. Standardisation of the interview invitation timeline would address these concerns.

Medical Student Attitudes toward USMLE Step 1 and Health Systems Science - A Multi-Institutional Survey.

Phenomenon: Because of its importance in residency selection, the United States Medical Licensing Examination Step 1 occupies a critical position in medical education, stimulating national debate about appropriate score use, equitable selection criteria, and the goals of undergraduate medical education. Yet, student perspectives on these issues and their implications for engagement with health systems science-related curricular content are relatively underexplored. Approach: We conducted an online survey of medical students at 19 American allopathic medical schools from March-July, 2019. Survey items were designed to elicit student opinions on the Step 1 examination and the impact of the examination on their engagement with new, non-test curricular content related to health systems science. Findings: A total of 2856 students participated in the survey, representing 23.5% of those invited. While 87% of students agreed that doing well on the Step 1 exam was their top priority, 56% disagreed that studying for Step 1 had a positive impact on engagement in the medical school curriculum. Eighty-two percent of students disagreed that Step 1 scores should be the top item residency programs use to offer interviews. When asked whether Step 1 results should be reported pass/fail with no numeric score, 55% of students agreed, while 33% disagreed. The majority of medical students agreed that health systems science topics were important but disagreed that studying for Step 1 helped learn this content. Students reported being more motivated to study a topic if it was on the exam, part of a course grade, prioritized by residency program directors, or if it would make them a better physician in the future. Insights: These results confirm the primacy of the United States Medical Licensing Examination Step 1 exam in preclinical medical education and demonstrate the need to balance the objectives of medical licensure and residency selection with the goals of the broader medical profession. The survey responses suggest several potential solutions to increase student engagement in health systems science curricula which may be especially important after Step 1 examination results are reported as pass/fail.

LI-RADS Treatment Response Algorithm: Performance and Diagnostic Accuracy.

Background In 2017, the Liver Imaging Reporting and Data System (LI-RADS) included an algorithm for the assessment of hepatocellular carcinoma (HCC) treated with local-regional therapy. The aim of the algorithm was to enable standardized evaluation of treatment response to guide subsequent therapy. However, the performance of the algorithm has not yet been validated in the literature. Purpose To evaluate the performance of the LI-RADS 2017 Treatment Response algorithm for assessing the histopathologic viability of HCC treated with bland arterial embolization. Materials and Methods This retrospective study included patients who underwent bland arterial embolization for HCC between 2006 and 2016 and subsequent liver transplantation. Three radiologists independently assessed all treated lesions by using the CT/MRI LI-RADS 2017 Treatment Response algorithm. Radiology and posttransplant histopathology reports were then compared. Lesions were categorized on the basis of explant pathologic findings as either completely (100%) or incompletely (<100%) necrotic, and performance characteristics and predictive values for the LI-RADS Treatment Response (LR-TR) Viable and Nonviable categories were calculated for each reader. Interreader association was calculated by using the Fleiss κ. Results A total of 45 adults (mean age, 57.1 years ± 8.2; 13 women) with 63 total lesions were included. For predicting incomplete histopathologic tumor necrosis, the accuracy of the LR-TR Viable category for the three readers was 60%-65%, and the positive predictive value was 86%-96%. For predicting complete histopathologic tumor necrosis, the accuracy of the LR-TR Nonviable category was 67%-71%, and the negative predictive value was 81%-87%. By consensus, 17 (27%) of 63 lesions were categorized as LR-TR Equivocal, and 12 of these lesions were incompletely necrotic. Interreader association for the LR-TR category was moderate (κ = 0.55; 95% confidence interval: 0.47, 0.67). Conclusion The Liver Imaging Reporting and Data System 2017 Treatment Response algorithm had high predictive value and moderate interreader association for the histopathologic viability of hepatocellular carcinoma treated with bland arterial embolization when lesions were assessed as Viable or Nonviable. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Gervais in this issue.

Repeat CT Performed Within One Month of CT Conducted in the Emergency Department for Abdominal Pain: A Secondary Analysis of Data From a Prospective Multicenter Study.

OBJECTIVE: The purpose of this study is to determine both the frequency of repeat CT performed within 1 month after a patient visits the emergency department (ED) and undergoes CT evaluation for abdominal pain and the frequency of worsened or new CT-based diagnoses. SUBJECTS AND METHODS: Secondary analysis was performed on data collected during a prospective multicenter study. The parent study included patients who underwent CT in the ED for abdominal pain between 2012 and 2014, and these patients constituted the study group of the present analysis. The proportion of patients who underwent (in any setting) repeat abdominal CT within 1 month of the index CT examination was calculated. For each of these patients, results of the index and repeat CT scans were compared by an independent panel and categorized as follows: no change (group 1); same process, improved (group 2); same process, worse (group 3); or different process (group 4). The proportion of patients in groups 1 and 2 versus groups 3 and 4 was calculated, and patient and ED physician characteristics were compared. RESULTS: The parent study included 544 patients (246 of whom were men [45%]; mean patient age, 49.4 years). Of those 544 patients, 53 (10%; 95% CI, 7.5-13%) underwent repeat abdominal CT. Patients' CT comparisons were categorized as follows: group 1 for 43% of patients (23/53), group 2 for 26% (14/53), group 3 for 15% (8/53), and group 4 for 15% (8/53). New or worse findings were present in 30% of patients (16/53) (95% CI, 19-44%). When patients with findings in groups 1 and 2 were compared to patients with findings in groups 3 and 4, no significant difference was noted in patient age (p = 0.25) or sex (p = 0.76), the number of days between scans (p = 0.98), and the diagnostic confidence of the ED physician after the index CT scan was obtained (p = 0.33). CONCLUSION: Short-term, repeat abdominal CT was performed for 10% of patients who underwent CT in the ED for abdominal pain, and it yielded new or worse findings for 30% of those patients.

Kinase Substrate Profiling Using a Proteome-wide Serine-Oriented Human Peptide Library.

The human proteome encodes >500 protein kinases and hundreds of thousands of potential phosphorylation sites. However, the identification of kinase-substrate pairs remains an active area of research because the relationships between individual kinases and these phosphorylation sites remain largely unknown. Many techniques have been established to discover kinase substrates but are often technically challenging to perform. Moreover, these methods frequently rely on substrate reagent pools that do not reflect human protein sequences or are biased by human cell line protein expression profiles. Here, we describe a new approach called SERIOHL-KILR (serine-oriented human library-kinase library reactions) to profile kinase substrate specificity and to identify candidate substrates for serine kinases. Using a purified library of >100000 serine-oriented human peptides expressed heterologously in Escherichia coli, we perform in vitro kinase reactions to identify phosphorylated human peptide sequences by liquid chromatography and tandem mass spectrometry. We compare our results for protein kinase A to those of a well-established positional scanning peptide library method, certifying that SERIOHL-KILR can identify the same predominant motif elements as traditional techniques. We then interrogate a small panel of cancer-associated PKCß mutants using our profiling protocol and observe a shift in substrate specificity likely attributable to the loss of key polar contacts between the kinase and its substrates. Overall, we demonstrate that SERIOHL-KILR can rapidly identify candidate kinase substrates that can be directly mapped to human sequences for pathway analysis. Because this technique can be adapted for various kinase studies, we believe that SERIOHL-KILR will have many new victims in the future.

Identification of a Substrate-selective Exosite within the Metalloproteinase Anthrax Lethal Factor.

The metalloproteinase anthrax lethal factor (LF) is secreted by Bacillus anthracis to promote disease virulence through disruption of host signaling pathways. LF is a highly specific protease, exclusively cleaving mitogen-activated protein kinase kinases (MKKs) and rodent NLRP1B (NACHT leucine-rich repeat and pyrin domain-containing protein 1B). How LF achieves such restricted substrate specificity is not understood. Previous studies have suggested the existence of an exosite interaction between LF and MKKs that promotes cleavage efficiency and specificity. Through a combination of in silico prediction and site-directed mutagenesis, we have mapped an exosite to a non-catalytic region of LF. Mutations within this site selectively impair proteolysis of full-length MKKs yet have no impact on cleavage of short peptide substrates. Although this region appears important for cleaving all LF protein substrates, we found that mutation of specific residues within the exosite differentially affects MKK and NLRP1B cleavage in vitro and in cultured cells. One residue in particular, Trp-271, is essential for cleavage of MKK3, MKK4, and MKK6 but dispensable for targeting of MEK1, MEK2, and NLRP1B. Analysis of chimeric substrates suggests that this residue interacts with the MKK catalytic domain. We found that LF-W271A blocked ERK phosphorylation and growth in a melanoma cell line, suggesting that it may provide a highly selective inhibitor of MEK1/2 for use as a cancer therapeutic. These findings provide insight into how a bacterial toxin functions to specifically impair host signaling pathways and suggest a general strategy for mapping protease exosite interactions.

Comparison of Visualization Rates of LI-RADS Version 2014 Major Features With IV Gadobenate Dimeglumine or Gadoxetate Disodium in Patients at Risk for Hepatocellular Carcinoma.

OBJECTIVE: The purpose of this study is to compare visualization rates of the major features covered by Liver Imaging Reporting and Data System (LI-RADS) version 2014 in patients at risk for hepatocellular carcinoma using either gadobenate dimeglumine or gadoxetate disodium IV contrast agent. MATERIALS AND METHODS: This retrospective study included liver MRI examinations performed with either gadobenate dimeglumine or gadoxetate disodium contrast enhancement. Using age, sex, underlying liver disease, and presence of cirrhosis, patients were placed into matched cohorts. All hepatic nodules 1 cm or larger (up to five per subject) were included, resulting in 63 subjects with 130 nodules (median nodule size, 1.9 cm) imaged with gadobenate and 64 subjects with 117 nodules (median nodule size, 2.0 cm) imaged with gadoxetate. Three radiologists reviewed the studies for LI-RADS major features independently. Bootstrap resampling with 10,000 repetitions was used to compare feature detection rates. RESULTS: Arterial phase hyperenhancement was seen in a similar number of nodules with gadobenate dimeglumine (mean, 91.5% [119/130]) and gadoxetate disodium (mean, 88.0% [103/117]) (p = 0.173). Dynamic phase washout was more commonly seen with gadobenate dimeglumine (mean, 60.2% [78.3/130]) than with gadoxetate disodium (mean, 45.3% [53/117]) (p = 0.006). The capsule feature was more often visualized with gadobenate dimeglumine (mean, 50.2% [65.3/130]) than with gadoxetate disodium (mean, 33.3% [39/117]) (p < 0.001). Interreader agreement for arterial phase enhancement and dynamic phase washout was almost perfect for both contrast agents (κ > 0.83). Agreement for the capsule feature was moderate for gadobenate dimeglumine (κ = 0.52) and substantial for gadoxetate disodium (κ = 0.67). CONCLUSION: The rates of visualization of arterial phase hyperenhancement are similar in studies performed with gadobenate dimeglumine and gadoxetate disodium, but dynamic phase washout and capsule appearance are more commonly visualized with gadobenate dimeglumine.

Intravenous Gadoxetate Disodium Administration Reduces Breath-holding Capacity in the Hepatic Arterial Phase: A Multi-Center Randomized Placebo-controlled Trial.

Purpose To determine, in a multicenter double-blinded placebo-controlled trial, whether maximal hepatic arterial phase breath-holding duration is affected by gadoxetate disodium administration. Materials and Methods Institutional review board approval was obtained for this prospective multi-institutional HIPAA-compliant study; written informed consent was obtained from all subjects. At three sites, a total of 44 volunteers underwent a magnetic resonance (MR) imaging examination in which images were acquired before and dynamically after bolus injection of gadoxetate disodium, normal saline, and gadoterate meglumine, administered in random order in a single session. The technologist and volunteer were blinded to the agent. Arterial phase breath-holding duration was timed after each injection, and volunteers reported subjective symptoms. Heart rate (HR) and oxygen saturation were monitored. Images were independently analyzed for motion artifacts by three radiologists. Arterial phase breath-holding duration and motion artifacts after each agent were compared by using the Mann-Whitney U test and the McNemar test. Factors affecting the above outcomes were assessed by using a univariate, multivariable model. Results Arterial phase breath holds were shorter after gadoxetate disodium (mean, 32 seconds ± 19) than after saline (mean, 40 seconds ± 17; P < .001) or gadoterate meglumine (43 seconds ± 21, P < .001) administration. In 80% (35 of 44) of subjects, arterial phase breath holds were shorter after gadoxetate disodium than after both saline and gadoterate meglumine. Three (7%) of 44 volunteers had severe arterial phase motion artifacts after gadoxetate disodium administration, one (2%; P = .62) had them after gadoterate meglumine administration, and none (P = .25) had them after saline administration. HR and oxygen saturation changes were not significantly associated with contrast agent. Conclusion Maximal hepatic arterial phase breath-holding duration is reduced after gadoxetate disodium administration in healthy volunteers, and reduced breath-holding duration is associated with motion artifacts. © RSNA, 2016.

The Growth of Hospitalists and the Future of the Society of General Internal Medicine: Results from the 2014 Membership Survey.

According to the most recent annual membership surveys, hospitalists are a rapidly growing component of the Society of General Internal Medicine (SGIM). Should this trend continue, hospitalists could increase from 22% of SGIM membership in 2014 to nearly 33% by 2020. Only 34% of hospitalists who responded to the survey, however, consider SGIM their academic home, compared to 54% of non-hospitalist respondents. Based on these survey findings, it is clear that the landscape of general internal medicine is changing with the growth of hospitalists, and SGIM will need to strategize to keep these hospitalist members actively engaged in the organization.

Role of CT in the Diagnosis of Nonspecific Abdominal Pain: A Multicenter Analysis.

OBJECTIVE: The objective of our study was to determine whether specific patient and physician factors-known before CT-are associated with a diagnosis of nonspecific abdominal pain (NSAP) after CT in the emergency department (ED). MATERIALS AND METHODS: We analyzed data originally collected in a prospective multicenter study. In the parent study, we identified ED patients referred to CT for evaluation of abdominal pain. We surveyed their physicians before and after CT to identify changes in leading diagnoses, diagnostic confidence, and admission decisions. In the current study, we conducted a multiple regression analysis to identify whether the following were associated with a post-CT diagnosis of NSAP: patient age; patient sex; physicians' years of experience; physicians' pre-CT diagnostic confidence; and physicians' pre-CT admission decision if CT had not been available. We analyzed patients with and those without a pre-CT diagnosis of NSAP separately. For the sensitivity analysis, we excluded patients with different physicians before and after CT. RESULTS: In total, 544 patients were included: 10% (52/544) with a pre-CT diagnosis of NSAP and 90% (492/544) with a pre-CT diagnosis other than NSAP. The leading diagnoses changed after CT in a large proportion of patients with a pre-CT diagnosis of NSAP (38%, 20/52). In regression analysis, we found that physicians' pre-CT diagnostic confidence was inversely associated with a post-CT diagnosis of NSAP in patients with a pre-CT diagnosis other than NSAP (p = 0.0001). No other associations were significant in both primary and sensitivity analyses. CONCLUSION: With the exception of physicians' pre-CT diagnostic confidence, the factors evaluated were not associated with a post-CT diagnosis of NSAP.

Multimodality Monitoring: Toward Improved Outcomes.

Multimodality monitoring provides insights into the critically ill brain-injured patient through the assessment of biochemical, physiological, and electrical data that provides insight into a patient's condition and what strategies may be available to limit further damage and improve the odds for recovery. Modalities utilized include evaluation of intracranial pressure along with cerebral perfusion pressure to determine adequate blood flow; continuous electroencephalography to protect the patient from seizures and to identify early functional manifestations of ischemia and toxicity; transcranial Doppler evaluation for bedside review of circulatory adequacy; tissue oxygen monitoring to establish that brain tissue is receiving adequate oxygen from blood flow; and microdialysis to evaluate the metabolic function of the tissue in areas of concern. These monitors provide insights regarding specific aspects of brain tissue and overall brain function in the critically ill patient. Although recommendations continue to evolve for therapeutic targets for each of these modalities, an effective clinician may use each of these modalities to evaluate patients on an individual basis to improve the outcome of each patient, tailoring management to provide the care needed for any unique clinical presentation.

Emergency Neurological Life Support: Third Edition, Updates in the Approach to Early Management of a Neurological Emergency.

Emergency Neurologic Life Support (ENLS) is an educational program designed to provide users advisory instructions regarding management for the first few hours of a neurologic emergency. The content of the course is divided into 14 modules, each addressing a distinct category of neurological injury. The course is appropriate for practitioners and providers from various backgrounds who work in environments of variable medical complexity. The focus of ENLS is centered on a standardized treatment algorithm, checklists, to guide early patient care, and a structured format for communication of findings and concerns to other healthcare professionals. Certification and training in ENLS is hosted by the Neurocritical Care Society. This document introduces the concept of ENLS and describes revisions that constitute the third version.