Identification of early and intermediate biomarkers for ARDS mortality by multi-omic approaches.

The lack of successful clinical trials in acute respiratory distress syndrome (ARDS) has highlighted the unmet need for biomarkers predicting ARDS mortality and for novel therapeutics to reduce ARDS mortality. We utilized a systems biology multi-"omics" approach to identify predictive biomarkers for ARDS mortality. Integrating analyses were designed to differentiate ARDS non-survivors and survivors (568 subjects, 27% overall 28-day mortality) using datasets derived from multiple 'omics' studies in a multi-institution ARDS cohort (54% European descent, 40% African descent). 'Omics' data was available for each subject and included genome-wide association studies (GWAS, n = 297), RNA sequencing (n = 93), DNA methylation data (n = 61), and selective proteomic network analysis (n = 240). Integration of available "omic" data identified a 9-gene set (TNPO1, NUP214, HDAC1, HNRNPA1, GATAD2A, FOSB, DDX17, PHF20, CREBBP) that differentiated ARDS survivors/non-survivors, results that were validated utilizing a longitudinal transcription dataset. Pathway analysis identified TP53-, HDAC1-, TGF-ß-, and IL-6-signaling pathways to be associated with ARDS mortality. Predictive biomarker discovery identified transcription levels of the 9-gene set (AUC-0.83) and Day 7 angiopoietin 2 protein levels as potential candidate predictors of ARDS mortality (AUC-0.70). These results underscore the value of utilizing integrated "multi-omics" approaches in underpowered datasets from racially diverse ARDS subjects.

Factors affecting patient flow in a neurosurgery department.

INTRODUCTION: Patient flow is the process by which movement of patients and clinical productivity is achieved. The objectives of this study were to implement and evaluate the NHS Improvement SAFER patient flow bundle, evaluate the impact of the Red2Green initiative, and assess the impact of frailty on patient flow. MATERIALS AND METHODS: All patients admitted to a neurosurgery unit from 1 September to 30 November 2017 were included. Using guidance set out by NHS, data were prospectively collected from daily ward lists and patient notes, including demographics, admission and discharge details, length of stay, anticipated discharge date, red days with reasons and frailty (Rockwood Clinical Frailty Scale). NHS reference costs were used for cost analyses. RESULTS: A total of 420 patients (55% elective) were included, totalling 3909 bed days. All patients received daily senior reviews before midday, and anticipated discharge dates were set at daily multidisciplinary team meetings. Ten per cent of patients were discharged before midday. There were 21% (837) red days, significantly more (76%) for emergency patients (639 vs 198 elective; P < 0.001); 63% red days were attributed to awaiting a bed in a local hospital; 25% (106) patients were classed as frail (50 elective), which was associated with a significantly longer length of stay (17.3 vs 6; P < 0.01), and more red days (615 vs 222; p<0.01). Considering excess bed charges and lost revenue (with penalties), red days cost over £1 million per year. CONCLUSIONS: SAFER has identified areas for improvement in patient flow, with obvious cost implications. It has created a platform for discussion within the referral network and identified a role for a geriatric liaison service.

Role of Excited States In High-order Harmonic Generation.

We investigate the role of excited states in high-order harmonic generation by studying the spectral, spatial, and temporal characteristics of the radiation produced near the ionization threshold of argon by few-cycle laser pulses. We show that the population of excited states can lead either to direct extreme ultraviolet emission through free induction decay or to the generation of high-order harmonics through ionization from these states and recombination to the ground state. By using the attosecond lighthouse technique, we demonstrate that the high-harmonic emission from excited states is temporally delayed by a few femtoseconds compared to the usual harmonics, leading to a strong nonadiabatic spectral redshift.

The use of ultrasound in intracranial tumor surgery.

BACKGROUND: As an intraoperative imaging modality, ultrasound is a user-friendly and cost-effective real-time imaging technique. Despite this, it is still not routinely employed for brain tumor surgery. This may be due to the poor image quality in inexperienced hands, and the well-documented learning curve. However, with regular use, the operator issues are addressed, and intraoperative ultrasound can provide valuable real-time information. The aim of this review is to provide an understanding for neurosurgeons of the development and use of ultrasound in intracranial tumor surgery, and possible future advances. METHODS: A systematic search of the electronic databases Embase, Medline OvidSP, PubMed, Cochrane, and Google Scholar regarding the use of ultrasound in intracranial tumor surgery was undertaken. RESULTS AND DISCUSSION: Intraoperative ultrasound has been shown to be able to accurately account for brain shift and has potential for regular use in brain tumor surgery. Further developments in probe size, resolution, and image reconstruction techniques will ensure that intraoperative ultrasound is more accessible and attractive to the neuro-oncological surgeon. CONCLUSIONS: This review has summarized the development of ultrasound and its uses with particular reference to brain tumor surgery, detailing the ongoing challenges in this area.

Injuries to the spinal accessory nerve: a lesson to surgeons.

The integrity of the spinal accessory nerve is fundamental to thoracoscapular function and essential for scapulohumeral rhythm. This nerve is vulnerable along its superficial course. This study assessed the delay in diagnosis and referral for management of damage to this nerve, clarified its anatomical course and function, and documented the results of repair. From examination of our records, 111 patients with lesions of the spinal accessory nerve were treated between 1984 and 2007. In 89 patients (80.2%) the damage was iatropathic. Recognition and referral were seldom made by the surgeon responsible for the injury, leading to a marked delay in instituting treatment. Most referrals were made for painful loss of shoulder function. The clinical diagnosis is straightforward. There is a characteristic downward and lateral displacement of the scapula, with narrowing of the inferior scapulohumeral angle and loss of function, with pain commonly present. In all, 80 nerves were explored and 65 were repaired. The course of the spinal accessory nerve in relation to the sternocleidomastoid muscle was constant, with branches from the cervical plexus rarely conveying motor fibres. Damage to the nerve was predominantly posterior to this muscle. Despite the delay, the results of repair were surprising, with early relief of pain, implying a neuropathic source, which preceded generally good recovery of muscle function.

The lateral approach to intraspinal reimplantation of the brachial plexus: a technical note.

Intraspinal re-implantation after traumatic avulsion of the brachial plexus is a relatively new technique. Three different approaches to the spinal cord have been described to date, namely the posterior scapular, anterolateral interscalenic multilevel oblique corpectomy and the pure lateral. We describe an anatomical study of the pure lateral approach, based on our clinical experience and studies on cadavers.

Synthetic analogs of FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] differentially regulate pulmonary vascular permeability in vivo and in vitro.

Novel therapies are needed to address the vascular endothelial cell (EC) barrier disruption that occurs in inflammatory diseases such as acute lung injury (ALI). We previously demonstrated the potent barrier-enhancing effects of both sphingosine 1-phosphate (S1P) and the structurally similar compound FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] in inflammatory lung injury. In this study, we examined the therapeutic potential of several novel FTY720 analogs to reduce vascular leak. Similar to S1P and FTY720, the (R)- and (S)-enantiomers of FTY720 phosphonate and enephosphonate analogs produce sustained EC barrier enhancement in vitro, as seen by increases in transendothelial electrical resistance (TER). In contrast, the (R)- and (S)-enantiomers of FTY720-regioisomeric analogs disrupt EC barrier integrity in a dose-dependent manner. Barrier-enhancing FTY720 analogs demonstrate a wider protective concentration range in vitro (1-50 microM) and greater potency than either S1P or FTY720. In contrast to FTY720-induced EC barrier enhancement, S1P and the FTY720 analogs dramatically increase TER within minutes in association with cortical actin ring formation. Unlike S1P, these FTY720 analogs exhibit differential phosphorylation effects without altering the intracellular calcium level. Inhibitor studies indicate that barrier enhancement by these analogs involves signaling via G(i)-coupled receptors, tyrosine kinases, and lipid rafts. Consistent with these in vitro responses, the (S)-phosphonate analog of FTY720 significantly reduces multiple indices of alveolar and vascular permeability in a lipopolysaccharide-mediated murine model of ALI (without significant alterations in leukocyte counts). These results demonstrate the capacity for FTY720 analogs to significantly decrease pulmonary vascular leakage and inflammation in vitro and in vivo.

Quality improvement in cardiac critical care.

Our quality improvement program began in 2004 to improve cardiac surgery outcomes. Early tracheal extubation in the cardiovascular intensive unit was utilized as a multidisciplinary driver for the quality improvement program. Continuous improvement in the rate of early extubation to drive multidisciplinary quality improvement in cardiac critical care correlated with decreased mortality, morbidity, and improved operational efficiency. Supportive educational efforts included, but were not limited to, principles of change, trust, competing values, crew resource management, evidence based medicine, and quality improvement.

Can timing of tracheal extubation predict improved outcomes after cardiac surgery?

INTRODUCTION: Early tracheal extubation is a common goal after cardiac surgery. Our study aims to examine whether timing of tracheal extubation predicts improved postoperative outcomes and late survival after cardiac surgery. We also evaluated the optimal timing of extubation and its association with better postoperative outcomes. METHODS: Between 2002 and 2006, 1164 patients underwent early tracheal extubation (<6 hours after surgery) and 1571 had conventional extubation (>6 hours after surgery). Propensity score adjustment and multivariable logistic regression analysis were used to adjust for imbalances in the patients' preoperative characteristics. Receiver operating characteristic curves (ROC) were used to identify the best timing of extubation and improved postoperative outcomes. Cox regression analysis was used to identify whether early extubation is a risk factor for decreased late mortality. RESULTS: Results - Early extubation was associated with lower propensity score-adjusted rate of operative mortality (Odds Ratio =0.55, 95% Confidence Intervals =0.31-0.98, p=0.043). Extubation within 9 hours emerged as the best predictor of improved postoperative morbidity and mortality (sensitivity =85.5%, specificity =52.7%, accuracy =64.5%). Early extubation also predicted decreased late mortality (Hazard Ratio =0.45, 95% Confidence Intervals 0.31-0.67, p<0.001). CONCLUSIONS: Early extubation may predict improved outcomes after cardiac surgery. Extubation within 9 hours after surgery was the best predictor of uncomplicated recovery after cardiac surgery. Those patients intubated longer than 16 hours have a poorer postoperative prognosis. Early extubation predicts prolonged survival up to 16 months after surgery.

Intractable neurostenalgia of the ulnar nerve abolished by neurolysis 18 years after injury.

A 39 year-old farmer sustained a closed rupture of the left brachial artery, which was successfully managed by emergency vein graft repair of the artery. Adjacent nerve trunks were seen to be intact, but stretched. Burning pain in the distribution of the ulnar nerve started at day seven postoperatively, and worsened over the ensuing years. There was no response to membrane stabilising drugs, amitryptiline, nor to regional sympatholytic or local anaesthetic blocks. Neurolysis of the ulnar nerve, which was densely adherent to the dilated vein graft, abolished his pain.