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Sodium chloride (NaCl) 23.4% solution has been shown to reduce intracranial pressure (ICP) and reverse transtentorial herniation. A limitation of 23.4% NaCl is its high osmolarity (8008 mOsm/l) and the concern for tissue injury or necrosis following extravasation when administered via peripheral venous access. The use of this agent is therefore often limited to central venous or intraosseous routes of administration. Our objective was to evaluate the safety and efficacy of administration of 23.4% NaCl via peripheral venous access compared with administration via central venous access. We reviewed pharmacy records to identify all administrations of 23.4% NaCl at our institution between December 2017 and February 2020. Medical records were then reviewed to identify complications, such as extravasation, soft tissue injury or necrosis, hypotension (mean arterial pressure less than 65 mm Hg), pulmonary edema, hemolysis, and osmotic demyelination. We also compared the change in physiological variables, such as ICP, mean arterial pressure, cerebral perfusion pressure, and heart rate, as well as laboratory values, such as sodium, chloride, bicarbonate, creatinine, and hemoglobin, following administration of 23.4% NaCl via the peripheral and central venous routes. We identified 299 administrations of 23.4% NaCl (242 central and 57 peripheral) in 141 patients during the study period. There was no documented occurrence of soft tissue injury or necrosis in any patient. One patient developed hypotension following central administration. Among the 38 patients with ICP monitoring at the time of drug administration, there was no significant difference in median ICP reduction (− 13 mm Hg [central] vs. − 24 mm Hg [peripheral], p = 0.21) or cerebral perfusion pressure augmentation (16 mm Hg [central] vs. 15 mm Hg [peripheral], p = 0.87) based on route of administration. Peripheral venous administration of 23.4% NaCl is safe and achieves a reduction in ICP equivalent to that achieved by administration via central venous access.

The overall approach to massive casualty triage has changed little in the past 200 years. As the military and civilian organizations prepare for the possibility of future large-scale combat operations, terrorist attacks and natural disasters, potentially involving hundreds or even thousands of casualties, a modified approach is needed to conduct effective triage, initiate treatment, and save as many lives as possible.Military experience and review of analyses from the Department of Defense Trauma Registry are combined to introduce new concepts in triage and initial casualty management.The classification of the scale of massive casualty (MASCAL) incidents, timeline of life-saving interventions, immediate first pass actions prior to formal triage decisions during the first hour after injury, simplification of triage decisions, and the understanding that ultra-MASCAL will primarily require casualty movement and survival needs with few prehospital life-saving medical interventions are discussed.Self aid, bystander, and first responder interventions are paramount and should be trained and planned extensively. Military and disaster planning should not only train these concepts, but should seek innovations to extend the timelines of effectiveness and to deliver novel capabilities within the timelines to the greatest extent possible.

Initial colonizing bacteria play a critical role in completing the development of the immune system in the gastrointestinal tract of infants. Yet, the interaction of colonizing bacterial organisms with the developing human intestine favors inflammation over immune homeostasis. This characteristic of bacterial-intestinal interaction partially contributes to the pathogenesis of necrotizing enterocolitis (NEC), a devastating premature infant intestinal inflammatory disease. However, paradoxically some unique pioneer bacteria (initial colonizing species) have been shown to have a beneficial effect on the homeostasis of the immature intestine and the prevention of inflammation. We have reported that one such pioneer bacterium, Bacteroides fragilis ( B. fragilis), and its surface component polysaccharide A (PSA) inhibit IL-1β-induced inflammation in a human primary fetal small intestinal cell line (H4 cells). In this study, using transcription profiling of H4 cellular RNA after pretreatment with or without PSA before an inflammatory stimulation of IL-1β, we have begun to further determine the cellular mechanism for anti-inflammation. We show that a developmentally regulated gene, zona pellucida protein 4 ( ZP4), is uniquely elevated after IL-1β stimulation and reduced with PSA exposure. ZP4 was known as a sperm receptor-mediating species-specific binding protein in the initial life of mammals. However, its intestinal epithelial function is unclear. We found that ZP4 is a developmentally regulated gene involved with immune function and regulated by both Toll-like receptor 2 and 4. Knockdown of ZP4-affected PSA inhibited IL-8 mRNA expression in response to IL-1β. This represents an initial study of ZP4 innate immune function in immature enterocytes. This study may lead to new opportunity for efficient treatment of NEC. NEW & NOTEWORTHY This study extends previous observations to define the cellular mechanisms of polysaccharide A-induced anti-inflammation in immature enterocytes using transcription profiling of enterocyte genes after preexposure to polysaccharide A before an inflammatory stimulus with IL-1β.

Significance Phosphohistidine (pHis) is a labile posttranslational modification with two isoforms, 1-pHis and 3-pHis, involved in many cellular processes across the kingdoms of life. Due to its lability, it is difficult to study the pHis modification using standard biochemical tools and techniques. Previously, we developed monoclonal antibodies (mAbs) against the 1-pHis and 3-pHis modifications using stable phosphotriazolylalanine mimetics as immunogens. These antibodies are promising tools to uncover the role of pHis in eukaryotic cells. Here, we report the crystal structures of five of these mAbs bound to their cognate phosphotriazolylalanine peptides, thus providing insight into the structure–function relationships that guide pHis recognition and establishing a foundation for the structure-guided design of improved pHis antibodies., In 2015, monoclonal antibodies (mAbs) that selectively recognize the 1-pHis or 3-pHis isoforms of phosphohistidine were developed by immunizing rabbits with degenerate Ala/Gly peptides containing the nonhydrolyzable phosphohistidine (pHis) analog- phosphotriazolylalanine (pTza). Here, we report structures of five rabbit mAbs bound to cognate pTza peptides: SC1-1 and SC50-3 that recognize 1-pHis, and their 3-pHis–specific counterparts, SC39-4, SC44-8, and SC56-2. These cocrystal structures provide insights into the binding modes of the pTza phosphate group that are distinct for the 1- and 3-pHis mAbs with the selectivity arising from specific contacts with the phosphate group and triazolyl ring. The mode of phosphate recognition in the 3-pHis mAbs recapitulates the Walker A motif, as present in kinases. The complementarity-determining regions (CDRs) of four of the Fabs interact with the peptide backbone rather than peptide side chains, thus conferring sequence independence, whereas SC44-8 shows a proclivity for binding a GpHAGA motif mediated by a sterically complementary CDRL3 loop. Specific hydrogen bonding with the triazolyl ring precludes recognition of pTyr and other phosphoamino acids by these mAbs. Kinetic binding experiments reveal that the affinity of pHis mAbs for pHis and pTza peptides is submicromolar. Bound pHis mAbs also shield the pHis peptides from rapid dephosphorylation. The epitope–paratope interactions illustrate how these anti-pHis antibodies are useful for a wide range of research techniques and this structural information can be utilized to improve the specificity and affinity of these antibodies toward a variety of pHis substrates to understand the role of histidine phosphorylation in healthy and diseased states.

We create and test two novel network-based measures of interconnectedness in the financial industry during 1996 to 2013. A network based on informed trading in financial firms predicts firm-specific risk and performance, while one formed on financial firm returns predicts future macroeconomic risk. The measure of informed trading is robust to variable order arrival rates more common in modern algorithmic trading. A trading strategy based on informed trading network centrality in the financial sector delivers an annualized risk-adjusted return of 7.73%. This risk-adjusted return shows that the network centrality has an economic impact that is relevant beyond the statistical results of the paper.

We create and test two novel network-based measures of interconnectedness in the financial industry during 1996 to 2013. A network based on informed trading in financial firms predicts firm-specific risk and performance, while one formed on financial firm returns predicts future macroeconomic risk. The measure of informed trading is robust to variable order arrival rates more common in modern algorithmic trading. A trading strategy based on informed trading network centrality in the financial sector delivers an annualized risk-adjusted return of 7.73%. This risk-adjusted return shows that the network centrality has an economic impact that is relevant beyond the statistical results of the paper.

Corporate bond investors are compensated for liquidity and counterparty risk in the yield received in excess of the credit premium and risk-free rate. This article shows that the liquidity premium as a hedge against uncertain future states is determined by the ratio of excess coupon payments after paying for credit protection to the capital gain realized after hedging interest rate risk. The liquidity premium increases with the time that investors must wait for compensation. The results suggest that the way in which investors receive compensation for liquidity risk is a more significant determinant of the liquidity premium than turnover.

In this dissertation, I identify the covalent modification of caveolin-3 with small-ubiquitin-like modifier (SUMO) proteins and its interactions with components of the sumoylation machinery. Caveolins are the principal protein components of caveolae membrane microdomains and function as scaffolds that compartmentalize and regulate multiple signaling proteins, their downstream effectors and associated proteins. Caveolin-3 is a muscle-specific caveolin family member that is highly expressed in skeletal muscle and cardiac myocytes. Beta 1- and beta 2- adrenergic receptors ([beta]ARs) use distinct pathways to regulate contraction in cardiac myocytes. Caveolar localization and interaction with caveolin-3 is required for signaling by the [beta]₂AR but not the [beta]₁AR. [beta]₂ARs and [beta]₁ARs also desensitize through distinct pathways in response to agonist stimulation. Evidence presented here suggests that sumoylation of caveolin-3 is involved in the regulation of agonist- induced desensitization of [beta]₂ARs. Sumoylation is a highly dynamic and reversible posttranslational modification that regulates substrates involved in many aspects of cellular function. SUMO E1, E2 and E3 enzymes catalyze the formation of covalent, isopeptide bonds with lysine side chains on target substrates while SUMO- specific proteases (SENPs) remove SUMO proteins from substrates. Experiments in this thesis show that caveolin- 3 is covalently modified by SUMO and poly-SUMO chains in multiple cell types. In vitro and in vivo sumoylation assays demonstrate that modification of caveolin-3 by poly -SUMO-3 chains is enhanced by co-expression of the SUMO E3 ligase PIASy in a dose-dependent manner. Co-expression of SENP1 or SENP2 dramatically reduced modification of caveolin-3 by SUMO-3. Site-directed mutagenesis was used to identify the preferred site of sumoylation and create a sumoylation-deficient mutant to probe the biological function of SUMO modification. Co-expression of caveolin-3 or the sumoylation-deficient mutant with [beta]ARs showed differential effects on the stability of [beta]₂AR, but not [beta]₁AR, expression levels in the presence of prolonged agonist stimulation. This effect on [beta]₂ARs was attenuated by the [beta]AR antagonist (-)-propranolol. Taken together, the data in this dissertation identify sumoylation as a novel mechanism for the regulation of caveolin and its interactions with its signaling partners, including effects on the agonist-induced desensitization of [beta]₂ARs

Histidine phosphorylation is crucial for prokaryotic signal transduction and as an intermediate for several metabolic enzymes, yet its role in mammalian cells remains largely uncharted. This is primarily caused by difficulties in studying histidine phosphorylation because of the relative instability of phosphohistidine (pHis) and lack of specific antibodies and methods to preserve and detect it. The recent synthesis of stable pHis analogs has enabled development of pHis-specific antibodies and their use has started to shed light onto this important, yet enigmatic posttranslational modification. We are beginning to understand that pHis has broader roles in protein and cellular function including; cell cycle regulation, phagocytosis, regulation of ion channel activity and metal ion coordination. Two mammalian histidine kinases (NME1 and NME2), two pHis phosphatases (PHPT1 and LHPP), and a handful of substrates were previously identified. These new tools have already led to the discovery of an additional phosphatase (PGAM5) and hundreds of putative substrates. New methodologies are also being developed to probe the pHis phosphoproteome and determine functional consequences, including negative ion mode mass spectroscopy and unnatural amino acid incorporation. These new tools and strategies have the potential to overcome the unique challenges that have been holding back our understanding of pHis in cell biology.

A topological data analysis approach is taken to the challenging problem of finding and validating the statistical significance of local modes in a data set. As with the SIgnificance of the ZERo (S ...

Four types of phosphate-protein linkage generate nine different phosphoresidues in living organisms. Histidine phosphorylation is a long-time established but largely unexplored post-translational modification, mainly because of the acid-lability of the phosphoramidate bonds. This lability means that standard phosphoproteomic methods used for conventional phosphate esters (phospho-Ser/Thr/Tyr) must be modified to analyze proteins containing the phosphoramidate-amino acids - phospho-His/Arg/Lys. We show that a non-acidic method allows enrichment of non-conventional phosphoresidue-containing peptides from tryptic digests of human cell lines, using hydroxyapatite binding and/or immobilized 1-pHis and 3-pHis monoclonal antibodies for enrichment. 425 unique non-conventional phosphorylation sites (i.e. pHis, pLys and pArg) were detected with a high probability of localization by LC-MS/MS analysis and identified using a customized MaxQuant configuration, contributing to a new era of study in post-translational modification and cell signaling in humans. This is the first fully non-acidic method for phosphopeptide enrichment which uses immunoaffinity purification and remains compatible with mass spectrometry analysis for a wider coverage of potential protein phosphorylation events.

Whereas phosphorylation of serine, threonine, and tyrosine is exceedingly well characterized, the role of histidine phosphorylation in mammalian signaling is largely unexplored. Here we show that phosphoglycerate mutase family 5 (PGAM5) functions as a phosphohistidine phosphatase that specifically associates with and dephosphorylates the catalytic histidine on nucleoside diphosphate kinase B (NDPK-B). By dephosphorylating NDPK-B, PGAM5 negatively regulates CD4(+) T cells by inhibiting NDPK-B-mediated histidine phosphorylation and activation of the K(+) channel KCa3.1, which is required for TCR-stimulated Ca(2+) influx and cytokine production. Using recently developed monoclonal antibodies that specifically recognize phosphorylation of nitrogens at the N1 (1-pHis) or N3 (3-pHis) positions of the imidazole ring, we detect for the first time phosphoisoform-specific regulation of histidine-phosphorylated proteins in vivo, and we link these modifications to TCR signaling. These results represent an important step forward in studying the role of histidine phosphorylation in mammalian biology and disease.

Psychological skills training (PST) is the systematic acquisition and practice of different psychological techniques to improve cognitive and technical performance. This training consists of three phases: education, skills acquisition and practice. Some of the psychological skills developed in this training include relaxation techniques, focusing and concentration skills, positive 'self-suggestion' and visualisation exercises. Since the middle of the 20th century, PST has been successfully applied by athletes, performing artists, business executives, military personnel and other professionals in high-risk occupations. Research in these areas has demonstrated the breadth and depth of the training's effectiveness. Despite the benefits realised in other professions, medicine has only recently begun to explore certain elements of PST. The present paper reviews the history and evidence behind the concept of PST. In addition, it presents some aspects of PST that have already been incorporated into medical training as well as implications for developing more comprehensive programmes to improve delivery of emergency medical care.

MotivationGene expression changes over time in response to perturbations. These changes are coordinated into functional modules via regulatory interactions. The genes within a functional module are expected to be differentially expressed in a manner coherent with their regulatory network. This perspective presents a promising approach to increase power to detect differential signals as well as for describing regulated modules from a mechanistic point of view.ResultsWe present an effective procedure for identifying differentially activated subnetworks in molecular interaction networks. Differential gene expression coherent with the regulatory nature of the network is identified. Sequentially controlling error on genes and links results in more efficient inference. By focusing on local inference, our method is ignorant of the global topology, and as a result equally effective on exponential and scale-free networks. We apply our procedure both to systematically simulated data, comparing its performance to alternative methods, and to the transcription regulatory network in the context of particle-induced pulmonary inflammation, recapitulating and proposing additional candidates to some previously obtained results.Contactstephen.rush@oru.se, dirk.repsilber@oru.se

Histidine phosphorylation, the so-called hidden phosphoproteome, is a poorly characterized post-translational modification of proteins1,2. Here we describe a role of histidine phosphorylation in tumorigenesis. Proteomic analysis of 12 tumours from an mTOR-driven hepatocellular carcinoma mouse model revealed that NME1 and NME2, the only known mammalian histidine kinases, were upregulated. Conversely, expression of the putative histidine phosphatase LHPP was downregulated specifically in the tumours. We demonstrate that LHPP is indeed a protein histidine phosphatase. Consistent with these observations, global histidine phosphorylation was significantly upregulated in the liver tumours. Sustained, hepatic expression of LHPP in the hepatocellular carcinoma mouse model reduced tumour burden and prevented the loss of liver function. Finally, in patients with hepatocellular carcinoma, low expression of LHPP correlated with increased tumour severity and reduced overall survival. Thus, LHPP is a protein histidine phosphatase and tumour suppressor, suggesting that deregulated histidine phosphorylation is oncogenic.

Dose-response relationships for meningioma radiosurgery are poorly characterized. We evaluated determinants of local recurrence for meningiomas treated with Gamma Knife radiosurgery (GKRS), to guide future treatment approaches to optimize tumor control.A total of 101 consecutive patients (108 tumors) who underwent GKRS for benign, atypical, or malignant meningiomas between 1998 and 2011 were studied. Local recurrence was assessed. Cox proportional hazards and logistic regression analyses were used to determine the association of patient-related, tumor-related, and treatment-related characteristics with local recurrence. Acute and late toxicity was evaluated.World Health Organization (2007 classification) tumor grade was I (82%), II (11%), or III (7%). Median dose was 14 Gy (range, 10 to 18 Gy) for grade I tumors and 16 Gy (range, 12 to 20 Gy) for grade II and III tumors. Median follow-up was 25 months (maximum, 17 y). Two- /5-year actuarial local control rates were 100%/98% for grade I tumors and 76%/56% for grade II/III tumors. Higher tumor grade and lower GKRS dose were associated with local failure. In this cohort, there was a 42% relative reduction in local recurrence for each 1 Gy of dose escalation.Treatment was well tolerated with no moderate or severe toxicity. Tumor control was excellent in benign tumors and suboptimal in higher grade tumors. Because the main determinant of local recurrence was GKRS dose, we recommend dose escalation for atypical or malignant tumors to doses between 16 and 20 Gy where critical structures allow.

SummaryHistidine phosphorylation (pHis) is well studied in bacteria; however, its role in mammalian signaling remains largely unexplored due to the lack of pHis-specific antibodies and the lability of the phosphoramidate (P-N) bond. Both imidazole nitrogens can be phosphorylated, forming 1-phosphohistidine (1-pHis) or 3-phosphohistidine (3-pHis). We have developed monoclonal antibodies (mAbs) that specifically recognize 1-pHis or 3-pHis; they do not cross-react with phosphotyrosine or the other pHis isomer. Assays based on the isomer-specific autophosphorylation of NME1 and phosphoglycerate mutase were used with immunoblotting and sequencing IgG variable domains to screen, select, and characterize anti-1-pHis and anti-3-pHis mAbs. Their sequence independence was determined by blotting synthetic peptide arrays, and they have been tested for immunofluorescence staining and immunoaffinity purification, leading to putative identification of pHis-containing proteins. These reagents should be broadly useful for identification of pHis substrates and functional study of pHis using a variety of immunological, proteomic, and biological assays.

In the tactical setting, intraosseous (IO) access has become popular to treat hemorrhagic shock when peripheral intravenous access is difficult or impractical. The traditional sites most commonly used by combat medics, corpsmen, and Pararescuemen (PJs) include the sternum and tibial tuberosity. Recent studies have shown that the humeral head (HH) is an appropriate and effective access site for IO infusion and fluid resuscitation in the clinical setting. In this procedural feasibility study, we assessed the ability of 26 U.S. Air Force PJs to perform HH IO placement on fresh, unfixed human cadavers over two consecutive cadaver lab training sessions. Following a formal didactic session, which highlighted proper patient positioning and technique, the PJs were instructed to attempt to place an IO needle using both a drill and manual driver. Once performed, correct placement was reviewed by a physician and confirmed by aspiration of bone marrow. Rates of success were calculated on first and second pass. First pass success rates were 96% and 90.5% for the drill and driver, respectively. Both devices achieved 100% success by the second pass. Military field personnel would benefit from a HH approach, especially in the care and management of patients of explosive injuries.

Object Parasellar and sellar meningiomas are challenging tumors owing in part to their proximity to important neurovascular and endocrine structures. Complete resection can be associated with significant morbidity, and incomplete resections are common. In this study, the authors evaluated the outcomes of parasellar and sellar meningiomas managed with Gamma Knife radiosurgery (GKRS) both as an adjunct to microsurgical removal or conventional radiation therapy and as a primary treatment modality. Methods A multicenter study of patients with benign sellar and parasellar meningiomas was conducted through the North American Gamma Knife Consortium. For the period spanning 1988 to 2011 at 10 centers, the authors identified all patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were also required to have a minimum of 6 months of imaging and clinical follow-up after GKRS. Factors predictive of new neurological deficits following GKRS were assessed via univariate and multivariate analyses. Kaplan-Meier analysis and Cox multivariate regression analysis were used to assess factors predictive of tumor progression. Results The authors identified 763 patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were assessed clinically and with neuroimaging at routine intervals following GKRS. There were 567 females (74.3%) and 196 males (25.7%) with a median age of 56 years (range 8–90 years). Three hundred fifty-five patients (50.7%) had undergone at least one resection before GKRS, and 3.8% had undergone prior radiation therapy. The median follow-up after GKRS was 66.7 months (range 6–216 months). At the last follow-up, tumor volumes remained stable or decreased in 90.2% of patients. Actuarial progression-free survival rates at 3, 5, 8, and 10 years were 98%, 95%, 88%, and 82%, respectively. More than one prior surgery, prior radiation therapy, or a tumor margin dose < 13 Gy significantly increased the likelihood of tumor progression after GKRS. At the last clinical follow-up, 86.2% of patients demonstrated no change or improvement in their neurological condition, whereas 13.8% of patients experienced symptom progression. New or worsening cranial nerve deficits were seen in 9.6% of patients, with cranial nerve (CN) V being the most adversely affected nerve. Functional improvements in CNs, especially in CNs V and VI, were observed in 34% of patients with preexisting deficits. New or worsened endocrinopathies were demonstrated in 1.6% of patients; hypothyroidism was the most frequent deficiency. Unfavorable outcome with tumor growth and accompanying neurological decline was statistically more likely in patients with larger tumor volumes (p = 0.022) and more than 1 prior surgery (p = 0.021). Conclusions Gamma Knife radiosurgery provides a high rate of tumor control for patients with parasellar or sellar meningiomas, and tumor control is accompanied by neurological preservation or improvement in most patients.

The paper under discussion provides a detailed survey of the important developments in Frechet analysis on manifolds or on stratified sample spaces. As it appears that data is now being realized over non-Euclidean spaces, such a paper is timely as such methods are called for in modern data analysis. In this discussion we explore this in the context of computational biology in general, and in particular for microbiome data which is gaining in popularity both in the scholarly and the popular presses. We will discuss the microbiome and metagenomics as well as outline how data is collected and strategies for data analysis. Finally we tie in how the microbiome data can be analyzed within the context of Frechet analysis.

Object Estimating survival time in cancer patients is crucial for clinicians, patients, families, and payers. To provide appropriate and cost-effective care, various data sources are used to provide rational, reliable, and reproducible estimates. The accuracy of such estimates is unknown. Methods The authors prospectively estimated survival in 150 consecutive cancer patients (median age 62 years) with brain metastases undergoing radiosurgery. They recorded cancer type, number of brain metastases, neurological presentation, extracranial disease status, Karnofsky Performance Scale score, Recursive Partitioning Analysis class, prior whole-brain radiotherapy, and synchronous or metachronous presentation. Finally, the authors asked 18 medical, radiation, or surgical oncologists to predict survival from the time of treatment. Results The actual median patient survival was 10.3 months (95% CI 6.4–14). The median physician-predicted survival was 9.7 months (neurosurgeons = 11.8 months, radiation oncologists = 11.0 months, and medical oncologist = 7.2 months). For patients who died before 10 months, both neurosurgeons and radiation oncologists generally predicted survivals that were more optimistic and medical oncologists that were less so, although no group could accurately predict survivors alive at 14 months. All physicians had individual patient survival predictions that were incorrect by as much as 12–18 months, and 14 of 18 physicians had individual predictions that were in error by more than 18 months. Of the 2700 predictions, 1226 (45%) were off by more than 6 months and 488 (18%) were off by more than 12 months. Conclusions Although crucial, predicting the survival of cancer patients is difficult. In this study all physicians were unable to accurately predict longer-term survivors. Despite valuable clinical data and predictive scoring techniques, brain and systemic management often led to patient survivals well beyond estimated survivals.

Let A be a complex unital Banach algebra and let a , b ∈ A . We give regions of the complex plane which contain the spectrum of a + b or ab using von Neumann spectral set theory. These results are a direct generalization of a theorem of Wielandt on the eigenvalues of the sum of two normal matrices.

The US Army pioneered air evacuation of casualties from the battlefield to a forward operating surgical treatment facility after the advent of the helicopter. This rotary-wing capability was initially used for casualty evacuation (CASEVAC) during the Korean War but evolved to the extent that lifesaving resuscitation was initiated en route by the US Army during the Vietnam War. More recently in Iraq and Afghanistan, medical evacuation (MEDEVAC) by platforms operating under a US and UK joint system has matured to the point where advanced medical capabilities are brought forward to the point of injury (POI). Emerging data from the Afghanistan experience however indicate that clinical and doctrinal gaps exist in US forward aeromedical evacuation (FAME) capability. In this review article, we provide a brief history of military MEDEVAC centered on the evolution of FAME, describe the current FAME platforms in Afghanistan, discuss lessons learned from recent studies examining the performance of the current FAME platforms, and propose the way ahead for FAME in future conflicts.

Object Pituitary adenomas are fairly common intracranial neoplasms, and nonfunctioning ones constitute a large subgroup of these adenomas. Complete resection is often difficult and may pose undue risk to neurological and endocrine function. Stereotactic radiosurgery has come to play an important role in the management of patients with nonfunctioning pituitary adenomas. This study examines the outcomes after radiosurgery in a large, multicenter patient population. Methods Under the auspices of the North American Gamma Knife Consortium, 9 Gamma Knife surgery (GKS) centers retrospectively combined their outcome data obtained in 512 patients with nonfunctional pituitary adenomas. Prior resection was performed in 479 patients (93.6%) and prior fractionated external-beam radiotherapy was performed in 34 patients (6.6%). The median age at the time of radiosurgery was 53 years. Fifty-eight percent of patients had some degree of hypopituitarism prior to radiosurgery. Patients received a median dose of 16 Gy to the tumor margin. The median follow-up was 36 months (range 1–223 months). Results Overall tumor control was achieved in 93.4% of patients at last follow-up; actuarial tumor control was 98%, 95%, 91%, and 85% at 3, 5, 8, and 10 years postradiosurgery, respectively. Smaller adenoma volume (OR 1.08 [95% CI 1.02–1.13], p = 0.006) and absence of suprasellar extension (OR 2.10 [95% CI 0.96–4.61], p = 0.064) were associated with progression-free tumor survival. New or worsened hypopituitarism after radiosurgery was noted in 21% of patients, with thyroid and cortisol deficiencies reported as the most common postradiosurgery endocrinopathies. History of prior radiation therapy and greater tumor margin doses were predictive of new or worsening endocrinopathy after GKS. New or progressive cranial nerve deficits were noted in 9% of patients; 6.6% had worsening or new onset optic nerve dysfunction. In multivariate analysis, decreasing age, increasing volume, history of prior radiation therapy, and history of prior pituitary axis deficiency were predictive of new or worsening cranial nerve dysfunction. No patient died as a result of tumor progression. Favorable outcomes of tumor control and neurological preservation were reflected in a 4-point radiosurgical pituitary score. Conclusions Gamma Knife surgery is an effective and well-tolerated management strategy for the vast majority of patients with recurrent or residual nonfunctional pituitary adenomas. Delayed hypopituitarism is the most common complication after radiosurgery. Neurological and cranial nerve function were preserved in more than 90% of patients after radiosurgery. The radiosurgical pituitary score may predict outcomes for future patients who undergo GKS for a nonfunctioning adenoma.

Stress experienced by emergency medical providers during the resuscitation of critically ill or injured patients can cause cognitive and technical performance to deteriorate. Psychological skills training offers a reasonable and easily implemented solution to this problem. In this article, a specific set of 4 performance-enhancing psychological skills is introduced: breathe, talk, see, and focus. These skills comprise breathing techniques, positive self-talk, visualization or mental practice, and implementing a focus "trigger word." The evidence supporting these concepts in various domains is reviewed and specific methods for adapting them to the environment of resuscitation and emergency medicine are provided.

KCa2.1, KCa2.2, KCa2.3 and KCa3.1 constitute a family of mammalian small- to intermediate-conductance potassium channels that are activated by calcium-calmodulin. KCa3.1 is unique among these four channels in that activation requires, in addition to calcium, phosphorylation of a single histidine residue (His358) in the cytoplasmic region, by nucleoside diphosphate kinase-B (NDPK-B). The mechanism by which KCa3.1 is activated by histidine phosphorylation is unknown. Histidine phosphorylation is well characterized in prokaryotes but poorly understood in eukaryotes. Here, we demonstrate that phosphorylation of His358 activates KCa3.1 by antagonizing copper-mediated inhibition of the channel. Furthermore, we show that activated CD4+ T cells deficient in intracellular copper exhibit increased KCa3.1 histidine phosphorylation and channel activity, leading to increased calcium flux and cytokine production. These findings reveal a novel regulatory mechanism for a mammalian potassium channel and for T-cell activation, and highlight a unique feature of histidine versus serine/threonine and tyrosine as a regulatory phosphorylation site. DOI: http://dx.doi.org/10.7554/eLife.16093.001

Background Stereotactic radiosurgery is an effective treatment modality for small arteriovenous malformations (AVMs) of the brain. For larger AVMs, the treatment dose is often lowered to reduce potential complications, but this decreases the likelihood of cure. One strategy is to divide large AVMs into smaller anatomic volumes and treat each volume separately. Objective To prospectively assess the long-term efficacy and complications associated with staged-volume radiosurgical treatment of large, symptomatic AVMs. Methods Eighteen patients with AVMs larger than 15 mL underwent prospective staged-volume radiosurgery over a 13-year period. The median AVM volume was 22.9 mL (range, 15.7-50 mL). Separate anatomic volumes were irradiated at 3- to 9-month intervals (median volume, 10.9 mL; range, 5.3-13.4 mL; median marginal dose, 15 Gy; range, 15-17 Gy). The AVM was divided into 2 volumes in 10 patients, 3 volumes in 5 patients, and 4 volumes in 3 patients. Seven patients underwent retreatment for residual disease. Results Actuarial rates of complete angiographic occlusion were 29% and 89% at 5 and 10 years. Five patients (27.8%) had a hemorrhage after radiosurgery. Kaplan-Meier analysis of cumulative hemorrhage rates after treatment were 12%, 18%, 31%, and 31% at 2, 3, 5, and 10 years, respectively. One patient died after a hemorrhage (5.6%). Conclusion Staged-volume radiosurgery for AVMs larger than 15 mL is a viable treatment strategy. The long-term occlusion rate is high, whereas the radiation-related complication rate is low. Hemorrhage during the lag period remains the greatest source of morbidity and mortality.

Background Recurrent Clostridum diffcile infection (rCDI) poses major challenges to healthcare providers and patients. Fecal Microbiota Transplantation (FMT) is an effective therapy for rCDI, but the exact mechanism of its efficacy is unknown. Current metagenomics literature indicates that abundance of Bacteroidetes and Firmicutes may protect against CD proliferation and recurrence. However, this is too broad to be useful for developing refined and targeted microbial-specific therapy for rCDI, because the long-term safety of FMT remains unknown. We examined the phylogeny of bacteria pre- and post- FMT to determine the key organisms associated with successful FMT to the genera level. Methods A subset of patient stool samples (n = 35) from a phase 2 study comparing fresh vs. frozen FMT for rCDI was sequenced at four time points: pre-FMT; at day 10; at week 5; and at week 13, following the last FMT. The matching donor stool was sequenced simultaneously with the corresponding patients’ pre- and post-FMT samples. Using the binary outcome to a single FMT as the response, we have developed an in-house machine learning algorithm, Φ-LASSO, to isolate key genera using the bacterial phylogenetic structure. Engraftment was defined as: newly detected operational taxonomic unit (OTUs) in the patient post-FMT, which were present in the donor but undetected in the patient pre-FMT. Augmentation was defined as: non-donor OTUs whose levels substantially increased post-FMT. Figure 1 (below) displays the distribution of engrafted and augmented OTUs at varying thresholds. We observed increases over time points within each threshold level. Results Akkermansia, Blautia and Roseburiaappear to be key genera for successful FMT. The Φ-LASSO fits with consistently positive coefficients, see Figure 2. Conclusion In this preliminary study, using Φ-LASSO, we have shown that specific microbes to the genera level are uniformly present in successful FMT. This information may lead to developing refined and targeted microbial-therapy for rCDI. Figure 1 Observed (a) engraftment of distinct donor OTUs on patients and (b) augmentation of distinct OTUs in patients for day 10 (D10), week 5 (W5), and week 13 (W13) post-treatment. Figure 2 Fitted coefficients for donor OTUs selected by Φ-LASSO. Disclosures All authors: No reported disclosures.

Object In this paper, the authors' goal was to analyze the incidence, timing, and treatment of new metastases following initial treatment with 20-Gy Gamma Knife surgery (GKS) alone in patients with limited brain metastases without whole-brain radiation therapy (WBRT). Methods A retrospective analysis of 114 consecutive adults (75 women and 34 men; median age 61 years) with KPS scores of 60 or higher who received GKS for 1–3 brain metastases ≤ 2 cm was performed (median lesion volume 0.35 cm3). Five patients lacking follow-up data were excluded from analysis. After treatment, patients underwent MR imaging at 6 weeks and every 3 months thereafter. New metastases were preferentially treated with additional GKS. Indications for WBRT included development of numerous metastases, leptomeningeal disease, or diffuse surgical-site recurrence. Results The median overall survival from GKS was 13.8 months. Excluding the 3 patients who died before follow-up imaging, 12 patients (11.3%) experienced local failure at a median of 7.4 months. Fifty-three patients (50%) developed new metastases at a median of 5 months. Six (7%) of 86 instances of new lesions were symptomatic. Most patients (67%) with distant failures were successfully treated using salvage GKS alone. Whole-brain radiotherapy was indicated in 20 patients (18.3%). Thirteen patients (11.9%) died of neurological disease. Conclusions For patients with limited brain metastases and functional independence, 20-Gy GKS provides excellent disease control and high-functioning survival with minimal morbidity. New metastases developed in almost 50% of patients, but additional GKS was extremely effective in controlling disease. Using our algorithm, fewer than 20% of patients required WBRT, and only 12% died of progressive intracranial disease.

Objective To review the authors' experience with Gamma Knife radiosurgery (GKR) for small recurrent high-grade gliomas (HGGs) following prior radical resection, external-beam radiation therapy (EBRT), and chemotherapy with temozolomide (TMZ). Methods The authors retrospectively analyzed 26 consecutive adults (9 women and 17 men; median age 60.4 years; Karnofsky Performance Status [KPS] ≥70) who underwent GKR for recurrent HGGs from 2004–2009. Median lesion volume was 1.22 cc, and median treatment dose was 15 Gy. Pathology included glioblastoma multiforme (GBM; n = 16), anaplastic astrocytoma (AA; n = 5), and anaplastic mixed oligoastrocytoma (AMOA; n = 5). Two patients lost to follow-up were excluded from radiographic outcome analyses. Results Median overall survival (OS) for the entire cohort from the time of GKR was 13.5 months. Values for 12-month actuarial survival from time of GKR for GBM, AMOA, and AA were 37%, 20% and 80%. Local failure occurred in 9 patients (37.5%) at a median time of 5.8 months, and 18 patients (75%) experienced distant progression at a median of 4.8 months. Complications included radiation necrosis in two patients and transient worsening of hemiparesis in one patient. Multivariate hazard ratio (HR) analysis showed KPS 90 or greater, smaller tumor volumes, and increased time to recurrence after resection to be associated with longer OS following GKR. Conclusions GKR provided good local tumor control in this group of clinically stable and predominantly high-functioning patients with small recurrent HGGs after radical resection. Meaningful survival times after GKR were seen. GKR can be considered for selected patients with recurrent HGGs.

Object Reports on resection of tumors in or near eloquent cortices have noted neurological complications in up to 30% of patients. This paper contains an analysis of symptom resolution and neurological morbidity following 20-Gy Gamma Knife surgery (GKS) for supratentorial brain metastases ≤ 2 cm in greatest diameter. Methods The authors performed a retrospective analysis of 98 consecutively treated adults (33 men and 65 women with a median age of 61.4 years at the time of GKS) with Karnofsky Performance Scale score ≥ 60, who underwent GKS for supratentorial brain metastases ≤ 2 cm in diameter. Lesion location was classified as noneloquent (Grade I), near eloquent (Grade II), or eloquent (Grade III), in accordance with the grading system developed by the group at M. D. Anderson Cancer Center. Following treatment, the patients underwent MR imaging and clinical examinations at 6 weeks and every 3 months thereafter. Results Ninety-eight patients underwent 20-Gy GKS for 131 metastases at initial presentation and 31 patients underwent salvage 20-Gy GKS for 76 new lesions, for a total of 207 lesions (mean lesion volume 0.44 cm3). Lesions were classified as follows: Grade I, 96 (46.4%); Grade II, 51 (24.6%); and Grade III, 60 (29%). Fifteen patients (2 with Grade II and 13 with Grade III lesions) presented with deficits referable to their lesions, yielding pre-GKS deficit rates of 7.2% per lesion and 15.3% per patient. The pre-GKS deficits improved or resolved in 10 patients (66.7%) at a median time of 2.8 months and remained stable in 3 patients (20%). Two patients (13.3%) experienced worsened neurological deficits. One patient who was neurologically intact prior to treatment developed a new hemiparesis (1 of 83 patients [1.2%]). The rates of permanent neurological deterioration following GKS for Grades I, II, and III lesions were 0% (0 of 96 tumors), 2% (1 of 51), and 3.3% (2 of 60), respectively. The pre-GKS neurological deficits and larger lesions were the most significant risk factors for post-GKS neurological deterioration. Conclusions Gamma Knife surgery performed using a 20-Gy dose provides amelioration of neurological deficits from brain metastases that are ≤ 2 cm in diameter and located in or near eloquent cortices in nearly two-thirds of patients with a low incidence of morbidity. Consistent with the surgical literature, higher rates of neurological complications were observed as proximity to eloquent regions and lesion size increased. There was no neurological deterioration in patients harboring metastases in noneloquent areas.

To determine the long-term complication rates and cosmetic results for patients undergoing postmastectomy radiation therapy (PMRT) after immediate reconstruction (IR).Between January 1998 and December 2005, 92 patients underwent modified radical mastectomy, IR, and PMRT in our practice. A total of 69 patients underwent tissue expander and implant reconstruction (TE/I), and 23 underwent autologous tissue reconstruction (ATR). Follow-up regarding complications and cosmesis was obtained for all 92 patients. Complications were scored as follows: Grade 1, no discomfort; Grade 2, discomfort affecting activities of daily living; Grade 3, surgical intervention or intravenous antibiotics required; and Grade 4, removal or replacement of the reconstruction. Cosmesis was rated as either acceptable or unacceptable to the patient. Both complications and cosmesis were correlated with treatment- and patient-related factors.Median follow-up for all patients was 38 months. The overall rate of severe complications (Grade 3-4) was 25%. The overall rate of poor functional results (Grade 2-4) was 43.4%. When analyzed as a function of type of reconstruction, the rate of Grade 3 to 4 complications was 33.3% for TE/I vs. 0% for ATR (p = 0.001). The rate of Grade 2 to 4 complications was 55% for TE/I vs. 8.7% for ATR (p0.001). Acceptable cosmesis was reported in 51% of TE/I patients vs. 82.6% of ATR patients (p = 0.007). No other treatment or patient-related factors had a significant impact on either complications or cosmesis.In patients undergoing PMRT after IR, ATR is associated with fewer long-term complications and better cosmetic results than TE/I.

Hepatocyte growth factor (HGF) influences several components of the angiogenic response, including endothelial cell migration. While recent studies indicate a crucial role of HGF in brain angiogenesis, the signaling pathways that regulate brain endothelial cell migration by HGF remain uncharacterized. Herein, we report that HGF stimulated human brain microvascular endothelial cell (HBMEC) migration in a dose- and time-dependent manner. Challenge of HBMECs with HGF activated the c-jun amino-terminal kinase (JNK), increased phosphorylation of the proline-rich tyrosine kinase 2 (Pyk-2) at Tyr402 and activated c-Src. Inhibition of JNK by SP600125 or expression of a dominant negative JNK1 construct abrogated the migratory response of HBMECs to HGF. Treatment of HBMECs with the Src inhibitor PP2 markedly decreased HGF-stimulated JNK activation and migration to HGF. Moreover, expression of a mutant Pyk-2 construct prevented HGF-induced Pyk-2 phosphorylation at Tyr402 and stimulation of HBMEC migration. Next, we examined activation of the extracellular signal regulated kinase (ERK) pathway. Stimulation of HBMECs by HGF led to rapid activation of ERK1/2, phosphorylation of Raf-1 at Ser338 and Tyr340/341 and MEK1/2 at Ser222. Moreover, inhibition of ERK activation by UO126 and PD98059 markedly decreased HGF-stimulated HBMEC migration. HGF also activated AKT, while inhibition of AKT by LY294002 induced a modest decrease of HGF-induced HBMEC migration. These results highlight a model whereby JNK and ERK play a critical role in regulation of brain endothelial cell migration by HGF.

Psychological skills training (PST) is the systematic acquisition and practice of different psychological techniques to improve cognitive and technical performance. This training consists of three phases: education, skills acquisition and practice. Some of the psychological skills developed in this training include relaxation techniques, focusing and concentration skills, positive 'self-suggestion' and visualisation exercises. Since the middle of the 20th century, PST has been successfully applied by athletes, performing artists, business executives, military personnel and other professionals in high-risk occupations. Research in these areas has demonstrated the breadth and depth of the training's effectiveness. Despite the benefits realised in other professions, medicine has only recently begun to explore certain elements of PST. The present paper reviews the history and evidence behind the concept of PST. In addition, it presents some aspects of PST that have already been incorporated into medical training as well as implications for developing more comprehensive programmes to improve delivery of emergency medical care.

This article highlights recent advances made in U.S. Air Force Pararescue Medical Operations in relation to tactical evacuation procedures. Most of these changes have been adopted and adapted from civilian medicine practice, and some have come from shared experiences with partner nations. Patient assessment includes a more comprehensive evaluation for hemorrhage and indications for hemorrhagic control. Ketamine has replaced morphine and fentanyl as the primary sedative used during rapid sequence intubation and procedural sedation. There has been an increasing use of the bougie to clear an airway or nasal cavity that becomes packed with debris. Video laryngoscopy provides advantages over direct laryngoscopy, especially in situations where there are environmental constraints such as the back of a Pave Hawk helicopter. Intraosseous access has become popular to treat and control hemorrhagic shock when peripheral intravenous access is impractical or impossible. Revisions to patient treatment cards have improved the efficacy and compliance of documentation and have made patient handoff more efficient. These improvements have only been possible because of the concerted efforts of U.S. Air Force and partner platforms operating in Afghanistan.

We perform the first large-sample estimation of the Volume Synchronized Probability of Informed Trading (VPIN) measure on the NYSE TAQ universe, enabling us to test the validity of VPIN with high statistical power and to do traditional asset pricing tests of informed trading. Informed trading measured by VPIN is priced, and is not explained by firm characteristics such as volume, volatility, or liquidity, supporting the validity of the measure. Additionally, we create a novel signed version of VPIN to identify the direction of informed trades. A portfolio long low-VPIN stocks and short high-VPIN ones delivers a monthly five-factor alpha of .18%, which rises to .29% when using signed VPIN. A trading strategy following this signed VPIN factor delivers an annualized five-factor BHAR of 11.45%. We further document a reversal in stock performance in portfolio sorts on signed VPIN, the incorporation of which into a trading strategy improves performance to an annualized BHAR of 17.34%.

Following the recession in the early 2000s, U.S. corporate and public defined benefit (DB) plans faced unprecedented uncertainty with respect to their funding requirements going forward. Just as capital market performance started helping plan sponsors improve the health of their DB plans, the financial crisis of 2007-2009 delivered another serious blow. Consequently, plan sponsors turned their focus on improving their risk management practices and determining whether asset managers with proven track records should be given more broadly defined mandates, specifically designed to allow for more effective navigation in more volatile markets. Tactical asset allocation strategies seek to add value by deviating from a plan’s policy mix based on the manager’s view on the attractiveness of various asset classes, regions and sectors within the investment opportunity set. Although tactical asset allocation can add value to a portfolio, manager skill and risk taking are required to achieve reasonable risk adjusted performance. The timing and magnitude of shifts from the policy mix can have a significant impact on the portfolio outcomes. Therefore, it is essential for investors to assess the appropriate role of tactical asset allocation in their portfolio management process and evaluate the risk-return tradeoff of tactical deviations from policy. Our study uses a sample of historical returns from the global financial markets and simulation methodology to investigate the relationship of tactical band size and rebalancing practices to various measures of portfolio performance. The results show that providing investment managers with limited flexibility in making asset allocation decisions may allow DB plans to weather down markets better. For DB plan sponsors who are considering giving managers less constrained mandates, manager skill in adding value through tactical asset allocation decisions should be considered.

Corporate bond investors are compensated for liquidity and counter-party risk in the yield received in excess of the credit premium and risk-free rate. This paper shows that the liquidity premium as a hedge against uncertain future states is determined by the ratio of excess coupon payments after paying for credit protection to the capital gain realized after hedging interest rate risk. The liquidity premium increases with the time that investors must wait for compensation. The results suggest that the way in which investors receive compensation for liquidity risk is a more significant determinate of the liquidity premium than turnover.