Journal articles on the topic 'Identification (presque)-faible'

The recurrent laryngeal nerve (RLN) is one of the most frequently injured nerves in head and neck surgery. Routine identification of the RLN during thyroid surgery has reduced the injury rate from 10% to less than 4%. Difficulty in identification of the RLN contributes to this surgical morbidity. Devices previously used for intraoperative identification of the RLN have failed to achieve the simplicity and reliability necessary for clinical use. This animal study uses a simple double-ballooned endotracheal tube and pressure transducer system, which assists intraoperative RLN identification through nerve stimulation and graphic documentation of vocal fold (VF) motion. Iatrogenic injury is demonstrated by a dampened stimulation-pressure tracing. The RLNs of three piglets were injured and examined, and the degree of injury was correlated with perioperative nerve stimulation patterns. The piglet proved to be an adequate model for laryngeal research. An FDA-approved multi-institutional prospective human study using this system of Identification of the RLN is in progress.

A novel modified LuGre friction model is proposed by taking pressure of the cylinders into consideration. And a practical identification method to estimate the parameters associated with the modified friction model is presented. The validity of the modified model is investigated experimentally. It is shown that the modified LuGre model can demonstrate the comprehensive friction behaviors of the forging machine with a fairly good accuracy.

In Connolly and Yagle (1992, 1993) we presented a new model relating cylinder combustion pressure to crankshaft angular velocity in an internal combustion engine, primarily the fluctuations in velocity near the cylinder firing frequency. There are three aspects to this model. First, by changing the independent variable from time to crankshaft angle, a nonlinear differential equation becomes a linear first-order differential equation. Second, a new stochastic model for combustion pressure uses the sum of a deterministic waveform and a raised-cosine window amplitude-modulated by a Bernoulli-Gaussian random sequence, parametrizing the pressure by the sample modulating sequence. This results in a state equation for the square of angular velocity sampled every combustion, with the modulating sequence as input. Third, the inverse problem of reconstructing pressure from noisy angular velocity measurements was formulated as a state-space deconvolution problem, and solved using a Kalman-filter-based deconvolution algorithm. Simulation results in Connolly and Yagle (1992, 1993) show that the parametrized pressure can be deconvolved at low to moderate noise levels, and combustion misfires detected, all in real time. This paper presents and discusses experimental results that confirm this model, at least at the relatively low-speed, low-to-moderate load operating conditions analyzed. They show that cyclic combustion pressure variation is fairly well modeled and may be directly estimated from angular velocity measurements. They also show that the deconvolution algorithm is able to detect misfires and possibly classify their severity. Since the experimental data are taken from an actual V-6 automobile engine, and the algorithms are simple enough to be implemented in real time, these results are directly applicable to real-world combustion pressure identification.

Background. The occurrence of false losses of resistance may be one of the reasons for inadequate or failed epidural block. A CompuFlo® epidural instrument has been introduced to measure the pressure of human tissues in real time at the orifice of a needle and has been used as a tool to identify the epidural space. The aim of this study was to investigate the sensitivity and the specificity of the ability of CompuFlo® to differentiate the false loss of resistance from the true loss of resistance encountered during the epidural space identification procedure. Method. We performed epidural block with the CompuFlo® epidural instrument in 120 healthy women who requested labor epidural analgesia. The epidural needle was considered to have reached the epidural space when an increase in pressure (accompanied by an increase in the pitch of the audible tone) was followed by a sudden and sustained drop in pressure for more than 5 seconds accompanied by a sudden decrease in the pitch of the audible tone, resulting in the formation of a low and stable pressure plateau. We evaluate the sensitivity, specificity, and positive and negative predictive values of the ability of CompuFlo® recordings to correctly identify the true LOR from the false LOR. Results. The drop in pressure associated with the epidural space identification was significantly greater than that recorded after the false loss of resistance (73% vs 33%) (P=0.000001). The sensitivity was 0.83, and the AUC was 0.82. Discussion. We have confirmed the ability of CompuFlo® to differentiate the false loss of resistance from the true loss of resistance and established its specificity and sensitivity. Conclusion. An easier identification of dubious losses of resistance during the epidural procedure is essential to reduce the number of epidural attempts and/or needle reinsertions with the potential of a reduced risk of accidental dural puncture especially in difficult cases or when the procedure is performed by trainees.

The blood pressure patterns obtained from a linearly or stepwise deflating cuff exhibit personalized traits, such as fairly uniform peak patterns and regular beat geometry; it can support the diagnosis and monitoring of hypertensive patients with reduced sensitivity to fluctuations in Blood Pressure (BP) over time. Monitoring of personalized trait in Oscillometric Arterial Blood Pressure Measurements (OABPM) uses the Linear Discriminant Analysis (LDA) algorithm. The representation of personalized traits with features from the oscillometric waveforms using LDA algorithm includes four phases. Data collection consists of blood pressure data using auscultatory measurements and pressure oscillations data obtained from the oscillometric method. Preprocessing involves the normalization of various sized oscillometric waveforms to a uniform size. Feature extraction involves the use of features from oscillometric amplitudes, and trait identification involves the use of the LDA algorithm. In this paper, it presents a novel OABPM-based blood pressure monitoring system that can monitor personalized blood pressure pattern. Our approach can reduce sensitivity to fluctuations in blood pressure with the features extracted from the whole area in oscillometric arterial blood pressure measurement. Therefore this technique offers reliable blood pressure patterns. This study provides a cornerstone for the diagnosis and management of hypertension in the foreseeable future.

For concrete target penetration and/or perforation simulation, the Holmquist–Johnson–Cook (HJC) material model is widely used as concrete material model. However, the strain rate expression of the model has failed to explain the sudden increase in concrete strength at high strain rates. The pressure-volume relationship of the HJC model is complex and requires a large number of material constants. In this study, a modified Holmquist–Johnson–Cook (HJC) model is proposed for concrete material under high velocity impact. The modification involves simplification and improvement of the strain rate expression and pressure-volume relationship. Material parameters identification procedure for the MHJC model is also elaborated. The numerical simulations using the proposed model show a good agreement with experimental observations, especially, on the residual velocities, penetration depths and failure patterns of the target plates. These validate the applicability of the MHJC model for high velocity projectile impact studies for concrete.

AbstractFungal osteomyelitis is an uncommon complication after cardiac surgery and associated with high mortality. A case of Candida albicans and Staphylococcus epidermidis osteomyelitis with device infection after implantation of a left ventricular assist device in a 60-year-old male patient is presented here. After clinical identification and confirmation with microbiological examinations and fluorodeoxyglucose positron emission tomography (FDG-PET) scan, debridement was performed. Surgical specimens grew C. albicans and S. epidermidis. Fluconazole, daptomycin, and negative pressure wound therapy were initiated, but failed to achieve healing. Total sternectomy and pectoralis flap reconstruction were performed. There was no recurrent infection for C. albicans on a prolonged antifungal regime. The combination of antifungal therapy and aggressive surgical debridement may be useful to control fungal osteomyelitis.

This paper presents a flow pattern identifier of the prevailing flow regime during refrigerant condensation inside smooth- and microfin tubes. The power spectral density distribution of the fluctuating condensing pressure signal was used to identify the prevailing flow regime, as opposed to the traditional (and subjective) use of visual-only methods, and/or smooth-tube flow regime maps. The prevailing flow regime was observed by using digital cameras and was validated with the use of the conventional smooth-tube flow regime transition criteria, as well as a new flow regime map for microfin-tube condensation. Experimental work was conducted for condensing refrigerants R-22, R-407C, and R-134a at an average saturation temperature of 40°C with mass fluxes ranging from 300–800 kg/m2 s, and with vapor qualities ranging from 0.05–0.15 at condenser outlet to 0.85–0.95 at condenser inlet. Tests were conducted with one smooth-tube condenser and three microfin-tube condensers (with helix angles of 10°, 18°, and 37° respectively). The power spectral density distributions of the condensing pressure signals distinguish the annular and intermittent (slug and plug) flows. A very low resonant frequency (<40 Hz) and low power spectral density amplitude of the pressure oscillation denoted stratified and wavy flows. As the annular flow regime was approached, the oscillations became larger and their frequencies increased (typically 40–120 Hz). Intermittent flow showed the most distinct character of all flow regimes. Its trace consisted of large amplitude pressure pulses occurring at fairly constant frequencies (approximately 50, 60, 80, 100, and 120 Hz). As the transition from intermittent to annular flow began, the pressure fluctuations became less regular and the amplitude dropped sharply.

To characterize the intramyocardial pressure (IMP) and coronary blood flow distribution in a stenosed coronary circulation, we compared four analog circuits for modeling coronary impedance. The resistor (R)-diode (D) model simulates vascular collapse, and the capacitor (C) simulates compliance effect. Identification of the best model and magnitudes of the endocardial and epicardial IMPs (IMPendo and IMPepi) was done retrospectively using data from studies in 28 anesthetized swine. Performance evaluation was based on comparison of model predicted vs. observed coronary distal pressure (DP) waveforms and endocardial-to-epicardial (endo-epi) flow ratios as determined by radiolabeled microspheres. The R-D-C model gave the best performance at IMPendo = 1.1 times left ventricular pressure (LVP), and IMPepi = 0.1.LVP + 15 mmHg; with good fit to DP (r = 0.98, slope of regression line = 1.0) and estimates of endo-epi flow ratio (r = 0.78, slope = 1.01, P less than 0.02, SEE = 0.21, n = 139). The R-D model gave comparable results even though capacitance was omitted. Although R-C and R models predicted distal coronary pressure well, they failed to predict endo-epi flow ratios (r less than 0.50). The R-D-C and R-D models were applied in seven prospective studies. Both models generated reasonable estimates of endo-epi flow distribution (r = 0.78, n = 50). Thus the R-D-C or R-D models of the stenosed coronary circulation can be used to provide reliable estimates of transmural blood flow distribution.

AbstractObjectives:To investigate the airflow characteristics of respiratory isolation rooms (IRs) and to evaluate the use of visible smoke as a monitoring tool.Methods:Industrial hygienists from the New York State Department of Health evaluated 140 designated IRs in 38 facilities within New York State during 1992 to 1998. The rooms were located in the following settings: hospitals (59%), correctional facilities (40%), and nursing homes (1%). Each room was tested with visible smoke for directional airflow into the patient room (ie, negative air pressure relative to adjacent areas). Information was obtained on each facility's policies and procedures for maintaining and monitoring the operation of the IRs.Results:Inappropriate outward airflow was observed in 38% of the IRs tested. Multiple factors were associated with outward airflow direction, including ventilation systems not balanced (54% of failed rooms), shared anterooms (14%), turbulent airflow patterns (11%), and automated control system inaccuracies (10%). Of the 140 tested rooms, 38 (27%) had either electrical or mechanical devices to monitor air pressurization continuously. The direction of airflow at the door to 50% (19/38) of these rooms was the opposite of that indicated by the continuous monitors at the time of our evaluations. The inability of continuous monitors to indicate the direction of airflow was associated with instrument limitations (74%) and malfunction of the devices (26%). In one facility, daily smoke testing by infection control staff was responsible for identifying the malfunction of a state-of-the-art computerized ventilation monitoring and control system in a room housing a patient infectious with drug-resistant tuberculosis.Conclusion:A substantial percentage of IRs did not meet the negative air pressure criterion. These failures were associated with a variety of characteristics in the design and operation of the IRs. Our findings indicate that a balanced ventilation system does not guarantee inward airflow direction. Devices that continuously monitor and, in some cases, control the pressurization of IRs had poor reliability. This study demonstrates the utility of using visible smoke for testing directional airflow of IRs, whether or not continuous monitors are used. Institutional tuberculosis control programs should include provisions for appropriate monitoring and maintenance of IR systems on a frequent basis, including the use of visible smoke.

Background: Young adults are failed to observe in studies on impact of high blood pressure as they are esteemed to be at a low risk of developing the complication or disease. Study of disease prevalence and their relation with life style habits provide the information required to develop interventional strategies. The objectives were to estimate the prevalence of hypertension among young adults in Jaipur district, Rajasthan and to study the impact of life style habits like tobacco use and alcohol consumption on hypertension.Methods: Data were collected from 390 college students aged 18 years and older in selected degree college by a cross-sectional survey. Blood pressure recordings, anthropometric measurements as well as socio-demographic characteristics were collected.Results: High blood pressure was observed in 152 out of the 390 students (38.97%), of which the 20 (5.13%) are hypertensive, majority were newly diagnosed (65%). Prevalence of high blood pressure among male students was higher (40.29% compared to 37.5% among female students). Out of total 33.85% and 5.12 % of the students were found to pre-hypertensive and hypertensive respectively. Prevalence of hypertension was found higher among those with a history of smoking or alcohol consumption.Conclusions: Majority of students with high blood pressure (hypertensive stage) were previously undiagnosed. A large number of students were in pre-hypertensive stage. Their early identification and right intervention at right time will lessen the impact of high blood pressure in productive age.

A water distribution network (WDN) is a critical infrastructure that must be maintained, ensuring a proper water supply to widespread customers. A WDN consists of various components, such as pipes, valves, pumps, and tanks, and these elements interact with each other to provide adequate system performance. If the elements fail due to internal or external interruptions, this may adversely impact water service to different degrees depending on the failed elements. To determine an appropriate maintenance priority, the critical elements need to be identified and mapped in the network. To identify and prioritize the critical elements (here, we focus on the pipes only) in the WDN, an element-based simulation approach is proposed, in which all the composing pipes of the WDN are reviewed one at a time. The element-based criticality is measured using several criticality indexes that are newly proposed in this study. The proposed criticality indexes are used to quantify the impacts of element failure to water service degradation. Here, four criticality indexes are developed: supply shortage (SS), economic value loss (EVL), pressure decline (PD), and water age degradation (WAD). Each of these indexes measures different aspects of the consequences, specifically social, economic, hydraulic, and water quality, respectively. The separate values of the indexes from all pipes in a network are then combined into a singular criticality value for assessment. For demonstration, the proposed approach is applied to four real WDNs to identify and prioritize the critical pipes. The proposed element-based simulation approach can be used to identify the critical components and setup maintenance scheduling of WDNs for preparedness of failure events.

Two fibrillar collagens, the worm cuticular collagen and the vertebrate Type I fish scale collagen, both organized in a compact tissue, were localized by immunogold electron microscopy in resin sections after freeze-fixation and freeze-substitution. Identification of these two fibrillar collagens failed with the-use of postembedding labeling after conventional electron microscopic processing. Positive labeling of the Type I collagen was observed in sections of fish scales freeze-fixed by either slam-freezing or high-pressure freezing, freeze-substituted in acetone with or without osmium tetroxide, and embedded in LR White. The worm cuticular collagen was detected in sections of cuticle that were freeze-fixed, freeze-substituted (necessarily with osmium tetroxide added to acetone), and embedded in either LR White or Epon. It was also detected in specimens pre-fixed by aldehydes before freeze-fixation. The Type I fish scale collagen appears to be more sensitive than the fibrillar cuticular collagen of worms to the procedures employed for postembedding immunoelectron microcopy. Our results have shown that freeze-fixation and freeze-substitution preserved the antigenicity of the fibrillar collagens organized in a compact three-dimensional network, whereas immunolabeling failed after conventional electron microscopic procedures. These cryostabilization techniques appear to be of value to improve the immunolocalization of collagens.

Background: Complex injury to the esophagus, trachea, and tracheoesophageal fistula in a case of esophageal atresia is rarely reported that requires prompt identification and management. Case Presentation: A very-low-birth-weight preterm with a tracheoesophageal fistula on ventilatory support for respiratory distress syndrome was transferred to our hospital. The baby developed air-leak through the tracheoesophageal fistula into the stomach causing gross distension of the stomach and reduction in oxygen saturation. Repositioning and reintubation failed to reduce the abdominal distension and to improve the saturation. Subsequent intubation with large volume, low pressure cuffed tube, and replacement of Replogle tube resulted in pneumothorax and further deterioration requiring emergency thoracotomy. Complex tracheoesophageal injury to the esophagus, trachea, and fistulous tract was repaired. Conclusion: The baby survived the early repair of the tracheoesophageal fistula and the iatrogenic complex tracheoesophageal injury. Pre-operative tracheo-esophagoscopy with stenting of the fistula with Fogarty catheter helped to carry out a successful repair technically.

Vitamin D deficiency is the most common nutritional deficiency, affecting almost one billion people worldwide. Vitamin D is mostly known for its role in intestinal calcium absorption and bone mineralization. However, the observation of seasonal changes in blood pressure and the subsequent identification of vitamin D receptor (VDR) and 1α-hydroxylase in cardiomyocytes, as well as endothelial and vascular smooth muscle cells, implicated a role of vitamin D in the cardiovascular system. Animal studies provided compelling evidence that vitamin D signaling is essential for cardiovascular integrity, especially for the regulation of vascular tone and as an antifibrotic and antihypertrophic signaling pathway in the heart. In addition, observational studies reported an association between vitamin D deficiency and risk of hypertension, atherosclerosis, and heart failure. However, recent clinical intervention studies failed to prove the causal relationship between vitamin D supplementation and beneficial effects on cardiovascular health. In this review, we aim to highlight our current understanding of the role of vitamin D in the cardiovascular system and to find potential explanations for the large discrepancies between the outcome of experimental studies and clinical intervention trials.

Insertional mutagenesis of Magnaporthe oryzae led to the identification of MCK1, a pathogenicity gene predicted to encode mitogen-activated protein kinase kinase kinase (MAPKKK) homologous to BCK1 in Saccharomyces cerevisiae. Targeted disruption of MCK1 resulted in the fungus undergoing autolysis and showing hypersensitivity to cell-wall-degrading enzyme. The mck1 produced significantly reduced numbers of conidia and developed appressoria in a slightly retarded manner compared with the wild type. Appressorium of the mck1 mutant was unable to penetrate into plant tissues, thereby rendering the mutant nonpathogenic. Cytorrhysis assay and monitoring of lipid mobilization suggested that the appressorial wall was altered, presumably affecting the level of turgor pressure within appressorium. Furthermore, the mck1 mutant failed to grow inside plant tissue. Complementation of the mutated gene restored its ability to cause disease symptoms, demonstrating that MCK1 is required for fungal pathogenicity. Taken together, our results suggest that MCK1 is an MAPKKK involved in maintaining cell wall integrity of M. oryzae, and that remodeling of the cell wall in response to host environments is essential for fungal pathogenesis.

ABSTRACT The gene encoding the alternative sigma factor σB in Listeria monocytogenes is induced upon exposure of cells to several stresses. In this study, we investigated the impact of a sigB null mutation on the survival of L. monocytogenes EGD-e at low pH, during high-hydrostatic-pressure treatment, and during freezing. The survival of ΔsigB mutant exponential-phase cells at pH 2.5 was 10,000-fold lower than the survival of EGD-e wild-type cells. Moreover, the ΔsigB mutant failed to show an acid tolerance response. Upon preexposure for 1 h to pH 4.5, the survival at pH 2.5 was 100,000-fold lower for the ΔsigB mutant than for the wild type. The glutamate decarboxylase (GAD) acid resistance system is important in survival and adaptation of L. monocytogenes in acidic conditions. The σB dependence of the gad genes (gadA, gadB, gadC, gadD, and gadE) was analyzed in silico. Putative σB-dependent promoter sites were found upstream of the gadCB operon (encoding a glutamate/γ-aminobutyrate antiporter and a glutamate decarboxylase, respectively) and the lmo2434 gene (gadD, encoding a putative glutamate decarboxylase). Reverse transcriptase PCR revealed that expression of the gadCB operon and expression of gadD are indeed σB dependent. In addition, a proteomics approach was used to analyze the protein expression profiles upon acid exposure. Although the GAD proteins were not recovered, nine proteins accumulated in the wild type but not in the ΔsigB strain. These proteins included Pfk, GalE, ClpP, and Lmo1580. Exposure to pH 4.5, in order to preload cells with active σB and consequently with σ B-dependent general stress proteins, also provided considerable protection against high-hydrostatic-pressure treatment and freezing. The combined data argue that the expression of σB-dependent genes provides L. monocytogenes with nonspecific multiple-stress resistance that may be relevant for survival in the natural environment as well as during food processing.

Renal fibrosis, as the fundamental pathological process of chronic kidney disease (CKD), is a pathologic extension of the normal wound healing process characterized by endothelium injury, myofibroblast activation, macrophage migration, inflammatory signaling stimulation, matrix deposition, and remodelling. Yet, the current method of treating renal fibrosis is fairly limited, including angiotensin-converting enzyme inhibition, angiotensin receptor blockade, optimal blood pressure control, and sodium bicarbonate for metabolic acidosis. MSCs are pluripotent adult stem cells that can differentiate into various types of tissue lineages, such as the cartilage (chondrocytes), bone (osteoblasts), fat (adipocytes), and muscle (myocytes). Because of their many advantages like ubiquitous sources, convenient procurement and collection, low immunogenicity, and low adverse effects, with their special identification markers, mesenchymal stem MSC-based therapy is getting more and more attention. Based on the mechanism of renal fibrosis, MSCs mostly participate throughout the renal fibrotic process. According to the latest and overall literature reviews, we aim to elucidate the antifibrotic mechanisms and effects of diverse sources of MSCs on renal fibrosis, assess their efficacy and safety in preliminarily clinical application, answer the controversial questions, and provide novel ideas into the MSC cellular therapy of renal fibrosis.

The role of the phosphodiesterase type IV isozyme (PDE IV) in the regulation of cerebrovascular tone was investigated in the canine basilar artery in vitro and in vivo. The PDE isozymes extracted from the canine basilar artery were isolated by diethylaminoethanol (DEAE)-Sepharose affinity chromatography and identified based on sensitivity to tsozyme-selective PDE inhibitors. [3H]cAMP hydrolysis was observed in one major and one minor peak of activity. The predominant peak was inhibited by the addition of cGMP (25%), siguazodan (26%), rolipram (39%), and the combination of siguazodan and rolipram (95%). Selective PDE IV inhibitors BRL 61063, rolipram, and denbufylline were equieffective inhibitors of [3H]-ccAMP hydrolysis mediated by PDE IV isolated from the canine basilar artery [concentrations producing 50% inhibition (IC50s) = 0.21 ± 0.05 μM, 0.67 ± 0.23 μM, and 0.73 ±0.16 μM, respectively]. In precontracted isolated ring segments of the canine basilar artery, selective PDE IV inhibitors produced potent and complete relaxation (IC50s <150 nM). In contrast, zaprinast (a selective PDE V inhibitor) and siguazodan (a selective PDE III inhibitor) produced only weak relaxation of the basilar artery (IC50s = 4.5 μM and >10 μM, respectively). Vasorelaxation produced by PDE IV inhibitors was not altered by removing the endothelium, l-NAME, or adenosine receptor antagonism. In a canine model of acute cerebral vasospasm, all three selective PDE IV inhibitors reversed basilar artery spasm produced by autologous blood without altering mean arterial blood pressure. In contrast, prolonged treatment with BRL 61063 failed to alter the development of basilar spasm in the two hemorrhage canine models of chronic cerebral vasospasm. Denbufylline-induced relaxation in vitro was also significantly impaired in basilar arteries obtained from the model of chronic vasospasm. In conclusion, PDE IV appears to be the predominant isozyme regulating vascular tone mediated by cAMP hydrolysis in cerebral vessels. In addition, vasorelaxation modulated by PDE IV is compromised in chronic cerebral vasospasm associated with subarachnoid hemorrhage.

Abstract. It is well known that the storm tracks are a preferred region of stratosphere–troposphere exchange (STE), but a systematic and climatological investigation of the connection between cyclones and STE has not yet been performed. We use two established ERA-Interim climatologies of STE and cyclones for the years 1979–2011 to quantify the amount of STE that occurs during the life cycle of North Atlantic cyclones. A Lagrangian method serves to identify individual STE events, and a sophisticated cyclone identification tool detects cyclones, their shape and size from the sea-level pressure field. Combining the two data sets reveals that roughly half of the total STE in the North Atlantic occurs in the vicinity of cyclones and that both downward and upward fluxes of mass across the tropopause (STT and TST, respectively) are more intense in deeper cyclones (lower minimum pressure) compared to less intense cyclones. In summer, STT and TST in the vicinity of cyclones are almost equal; in the other seasons, STT is larger by 15–45%. Cross-tropopause mass fluxes are enhanced by a factor of about two compared to climatology when a cyclone is present. On average, STE is strongest during the mature phase of cyclones, i.e., in a 24 h time window around the time of maximum intensity. Systematic patterns of exchange locations relative to the cyclone centre are identified via composite analysis and shed light on the different characteristics of STT and TST. During cyclone intensification and in the mature stage, TST is mainly confined to the cyclone centre, whereas STT occurs mainly in a region further southwest. During the decay of the cyclones, both STT and TST are most frequent close the cyclone centre, in a region with a~fairly low tropopause.

SUMMARYThe eggs and oncomiracidia of two species of the capsalid genus Encotyllabe are described. These parasites were identified tentatively as E. caballeroi Velasquez, 1977 and E. caranxi Lebedev, 1967. If these identifications are correct, then E. caballeroi is recorded from two new hosts, Gymnocranius audleyi and the nemipterid Scolopsis monogramma, and E. caranxi from a new host, Pseudocaranx dentex, and a new locality, Heron Island, Queensland, Australia. Encotyllabines have not previously been recorded from fishes of the family Nemipteridae. The eggs of the two parasites failed to hatch spontaneously and did not hatch when exposed to a variety of potential hatching stimuli, but the oncomiracidia within survived for many weeks. Oncomiracidia expelled from eggs by cover-slip pressure are unciliated and possess a saucer-shaped haptor like that of other capsalids with three pairs of median sclerites and 14 marginal hooklets. The paths of tendons associated with the accessory sclerites and the presence of haptoral loculi suggest that encotyllabines are related to the trochopodines. Observations on a single juvenile specimen of E. caballeroi show that the accessory sclerites and the tendons are lost early in development and that one pair of hamuli (probably the posterior pair) ceases to grow early in post-oncomiracidial life. The loculi persist a little longer but also disappear before full sexual maturity is reached.

The aim of the present study was to assess the ability of several echocardiographic and TDI (tissue Doppler imaging) parameters to predict an elevated LVEDP (left ventricular end-diastolic pressure) in patients with abnormal relaxation. Eighty-two consecutive patients presenting with an E/A ratio (ratio of early-to-late diastolic peak transmitral velocity) <0.9 scheduled for left heart catheterization underwent echocardiography, including TDI, and measurement of LVEDP using fluid-filled catheters. The difference in duration between PVR (retrograde peak in the pulmonary veins) and A (ΔPVR-A) was calculated from pulsed Doppler recordings. VP (propagation velocity of the early mitral inflow) was determined by colour M-mode. TDI measurements included E´ (early diastolic peak myocardial velocities near the lateral mitral annulus), MVG (the early diastolic transmyocardial velocity gradient of the posterior basal wall) and the PRT (peak relaxation time), determined as the time interval between aortic valve closure and peak E´. Fifty-six patients presented with LVEDP values <15 mmHg, whereas an LVEDP >15 mmHg was found in 26 patients. The index ΔPVR-A showed a significant linear correlation with LVEDP (r=0.7, P<0.001) and provided the highest predictive accuracy for the identification of LVEDP >15 mmHg [AUC (area under receiver operating characteristic curve)=0.83], followed by PRT (AUC=0.67), whereas other TDI-derived parameters failed to reach significance. In conclusion, ΔPVR-A enabled the most accurate non-invasive estimation of LVEDP. A prolonged peak relaxation time was the only TDI-derived index that differed significantly between patient groups.

Recently much has been done to increase our understanding of workplace bullying including its causes, consequences, and prevalence. Although identification of possible interventions has advanced the field, systematic evidence on the efficacy and effectiveness of specific interventions is lacking. At the same time, organizations are under increasing pressure to prevent and manage workplace bullying more effectively. The aim of this study is to develop and refine a taxonomy of workplace bullying intervention types. Although it does not assess the evidence base of interventions per se, the taxonomy is designed to support the development of research into the future and guide organizations in their decision making when implementing interventions. Using a two-round Delphi process, the expertise of international academics and practitioners ( n = 51 and n = 39) was sought to refine the taxonomy, which classified interventions in terms of mode, focus, agent, specificity, and timecourse. Eleven core intervention types were endorsed as appropriate inclusions in the taxonomy of workplace bullying intervention types. A further six, including mediation, failed to reach consensus among the expert panel. The resulting taxonomy forms a framework to guide workplace bullying intervention efficacy and effectiveness research from a common understanding of the definition, scope, and properties of interventions. Once this occurs, the taxonomy can be used by organizations to audit their existing programs, prioritize new interventions, and consider alternate options. Intervention types that did not reach consensus highlight areas of particular research need, which, when undertaken will add to an evidence base and will be included in future versions of the taxonomy.

Background—The management of major colonic bleeding is problematic. A proportion of patients require emergency surgery which is associated with high morbidity and mortality. Percutaneous embolotherapy, previously considered a high risk procedure in the colon, may provide an alternative treatment in this group of patients.Aims—To assess the safety and efficacy of embolotherapy in the treatment of life threatening colonic haemorrhage.Patients and methods—Thirty eight patients with fresh haemorrhage per rectum were referred for surgery because of failed conservative treatment. All underwent angiography; in 14 a bleeding site or vascular abnormality was detected. A coaxial catheter was directed to the most distal bleeding artery and this was embolised with platinum coils.Results—Detection of a bleeding site correlated with haemodynamic stability at the time of angiography (r=1 for a systolic blood pressure less than 100 mm Hg). Bleeding sites or vascular abnormalities were detected and embolised in 14 patients (37%). In 12/14 there was immediate and sustained haemodynamic improvement; two continued to bleed and required emergency hemicolectomy (14%). Three developed ischaemic complications (21.4%); these were managed conservatively and required no intervention. The 30 day mortality was 7.1% in the embolotherapy group and 10.5% in the overall group of 38 patients.Conclusion—Colonic embolotherapy for life threatening haemorrhage is an effective, relatively safe procedure with a low incidence of major complications. Its use depends on the identification of a focal bleeding point or vascular abnormality, which in turn depends on the haemodynamic stability of the patient at the time of angiography.

ABSTRACT Previously, we identified a Plasmodium yoelii YM 140-kDa merozoite protein, designated PyP140, which formed a complex with apical membrane antigen 1 (AMA1). Furthermore, we produced a nonprotective monoclonal antibody (MAb), 48F8, that immunoprecipitated metabolically labeled PyP140 and localized the protein to the merozoite's apical end and, less frequently, to the merozoite surface, as observed by immunofluorescence assay (IFA). Here, using MAb 48F8, we have identified the pyp140 gene by screening a P. yoelii λ-Zap cDNA expression library. The pyp140 cDNA covers approximately 90% of the putative open reading frame (ORF) of PY02159 from the P. yoelii NL genome sequencing project. Analysis of the complete gene identified the presence of two introns. The ORF encodes a 102,407-Da protein with an amino-terminal signal sequence, a series of three unique types of repeats, and a cysteine-rich region. The binding site of MAb 48F8 was also identified. A BLAST search with the deduced amino acid sequence shows significant similarity with the Toxoplasma gondii RON4 protein and the Plasmodium falciparum RON4 protein, and the sequence is highly conserved in other Plasmodium species. We produced the cysteine-rich domain of PyP140/RON4 by using the Pichia pastoris expression system and characterized the recombinant protein biochemically and biophysically. BALB/c mice immunized with the protein formulated in oil-in-water adjuvants produced antibodies that recognize parasitized erythrocytes by IFA and native PyP140/RON4 by immunoblotting but failed to protect against a lethal P. yoelii YM infection. Our results show that PyP140/RON4 is located within the rhoptries or micronemes. It may associate in part with AMA1, but the conserved cysteine-rich domain does not appear to elicit inhibitory antibodies, a finding that is supported by the marked sequence conservation in this protein within Plasmodium spp., suggesting that it is not under immune pressure.

Summary The Wafra field is located in the partitioned neutral zone between Kuwait and Saudi Arabia. The field produces oil from the Ratawi oolite reservoir, which has been under production since 1956. Barriers to fluid movement have severely restricted aquifer support to the overlying carbonate grainstone reservoir, leading to production-induced pressure depletion and low recovery rates. Creative integration of three-dimensional seismic aspects, well log stratigraphy, and engineering analysis revealed an unexploited reservoir extension that is more open to aquifer pressure support. Wells drilled along this extension are expected to yield higher initial production rates and longer sustained production. The model was used to drill two successful step-out wells that have increased field production by over 12,000 BOPD. Eight of ten additional wells have now been drilled as a follow-up to this success. This paper reviews the case history with a focus on the multidisciplinary integration that led to opportunity identification and exploitation. Introduction The Wafra field, jointly operated by Saudi Arabian Texaco and the Kuwait Oil Company, is located in the partitioned neutral zone (PNZ) between Kuwait and Saudi Arabia (Fig. 1). The field has produced from the Lower Cretaceous Ratawi reservoir since 1956. Liquid withdrawal over the years has depleted reservoir pressures in some parts of the field, leading to a decline in production. Based on prior reservoir characterization and simulation studies in 1995,1 a peripheral water injection and an extension development program have been undertaken in order to arrest the decline and increase the production by over 40,000 BOPD.2 In 1996, a 104 sq mile three-dimensional (3D) seismic survey was acquired to help design and implement these programs. Structural and Stratigraphic Framework The Wafra field is a large anticline approximately 6 by 10 miles in dimension (Fig. 2). The field is composed of a main NW-SE trending structural feature called the Main area, and a lower amplitude extension area east of the Main area called East Wafra. The Ratawi oolite reservoir is found at a depth of 6,135 ft subsea at the structural crest and had an original oil-water contact at about 6,520 ft subsea. Most of the structuring occurred in Middle Cretaceous time as sediment draped over deep-seated horst blocks. Oil migration and accumulation are thought to have occurred primarily in Early Eocene time. The Ratawi formation consists of a marine transgressive sequence of carbonate rocks deposited during Early Cretaceous time. The formation is composed of three distinct intervals: the lower-most Ratawi oolite reservoir, and the overlying Ratawi Limestone and Ratawi Shale cap rocks (Fig. 3). The Ratawi oolite reservoir was formed by a prograding carbonate sand shoaling sequence deposited on a low-angle carbonate ramp or detached platform. The commercially productive reservoir interval is composed primarily of porous grainstones and packstones. Less porous packstone, mudstone, and wackestone facies resulted from a more-restricted lagoonal environment in the central part of the field, and deeper marine shelf facies on the platform boundaries. Stratigraphic analysis of well log data provides an understanding of the depositional framework and serves as a basis for modeling facies distribution within the reservoir. Fig. 4a is a well log cross section traversing the Main area and East Wafra along the path A-B in Fig. 2. The gamma ray (GR) log curves are flattened on the base of the Ratawi limestone (cap rock) and span the interval of the Ratawi oolite reservoir. The GR curves indicate a remarkable character similarity from well to well that is almost exclusively related to the presence of uranium minerals.1 This determination is supported by x-ray analysis of core data that found an absence of clay. Additional evidence is found in comparisons of the GR (uranium, potassium and thorium) with the computed GR (potassium and thorium) from spectrometry gamma ray logs. The computed GR data show a largely diminished log character, implying that the GR log character is largely a function of uranium content. Hence, the correlative nature of the GR curves indicates that the uranium was present at the time of deposition—probably due to regional-scale climatic or environmental influences such as atmospheric fall-out from volcanic activity. This explains the consistent levels of uranium, independent of lithology and porosity, and allows detailed chronostratigraphic correlations to be made. Fig. 4b is an east-west stratigraphic cross section through the reservoir along the same path as in Fig. 4a, showing porosity logs with GR depositional time lines superimposed. The thick solid lines mark lithostratigraphic boundaries between an interval consisting primarily of porous grainstone, which for purposes of this paper will be referred to as the "upper reservoir," a tight interval of predominantly mudstone and packstone, referred to as the "Basal barrier," and a porous grainstone interval called the "lower reservoir." Almost all of the Ratawi oil production is from the upper reservoir grainstones. The chronostratigraphic facies heterogeneity evident in Fig. 4b owes its origin to a transgressive sequence of prograding grain shoals deposited in relatively shallow water.3 During the early stages of transgression, as the shoals prograded over the Wafra paleo-high, muds and finer grain carbonates were deposited in intershoal lagoons. As the sea level rose, carbonate sediment productivity and accumulation surpassed the rise in sea level, resulting in an overall shallowing with time. Evidence of this can be seen in the general coarsening upward character of the porosity logs. With progressively shallower water depths and associated higher depositional energy, the grain shoals became spatially more extensive while the lagoonal areas retreated, ending in fairly expansive grain shoals in the later stages of reservoir development. At the end of Ratawi oolite time, a rapid increase in relative sea level drowned the shoaling sequence, and deposited the deeper marine Ratawi limestone and shale members.

This paper describes a quasi-operational regional air quality forecasting system for the contiguous United States (CONUS) developed at the National Center for Atmospheric Research (NCAR) to support air quality decision-making, field campaign planning, early identification of model errors and biases, and support the atmospheric science community in their research. This system aims to complement the operational air quality forecasts produced by the National Oceanic and Atmospheric Administration (NOAA), not to replace them. A publicly available information dissemination system has been established that displays various air quality products, including a near-real-time evaluation of the model forecasts. Here, we report the performance of our air quality forecasting system in simulating meteorology and fine particulate matter (PM2.5) for the first year after our system started, i.e., 1 June 2019 to 31 May 2020. Our system shows excellent skill in capturing hourly to daily variations in temperature, surface pressure, relative humidity, water vapor mixing ratios, and wind direction but shows relatively larger errors in wind speed. The model also captures the seasonal cycle of surface PM2.5 very well in different regions and for different types of sites (urban, suburban, and rural) in the CONUS with a mean bias smaller than 1 µg m−3. The skill of the air quality forecasts remains fairly stable between the first and second days of the forecasts. Our air quality forecast products are publicly available at a NCAR webpage. We invite the community to use our forecasting products for their research, as input for urban scale (<4 km), air quality forecasts, or the co-development of customized products, just to name a few applications.

Abstrak Penelitian ini bertujuan untuk mengetahui jenis-jenis mikrofungi dan keanekaragaman jenis mikrofungi yang terdapat pada Taman Wisata Alam (TWA) Baumata. Pada penelitian ini mengunakan metode observasi langsung dan Direct metoch . Penelitian dilakukan di TWA Baumata dan proses isolasi dan identifikasi mikrofungi tanah pada laboratorium biologi Program Studi Pendidikan Biologi Universitas Kristen Artha Wacana Kupang dan laboratorium Penyakit Tumbuhan Fakultas Pertanian Universitas Nusa Cendana Kupang dari bulan November 2017 sampai dengan bulan April 2018. Mikrofungi yang teridentifikasi dibedakan jenisnya kemudian di hitung indeks keanekaragamannya. Hasil menunjukkan bahwa ditemukan 5 jenis mikrofungi tanah yang terdapat pada TWA Baumata yakni Mikrofungi Aspergilus terreus, Aspergilus flavus, Aspergilus niger, Penicillium sp., Thamnidium elegans. Tahapan yang dilalui untuk mendapatkan kelima jenis mikrofungi tanah ini adalah melalui tahapan isolasi, pemurnian dan identifikasi. Dengan menggunakan rumus shannon wiener hasil analisis memperlihatkan bahwa tingkat keanekaragam mikrofungi pada TWA Baumata tergolong sedang dengan nilai indeks keanekaragaman (H’) = 1.2691. Hasil Analisis ini menunjukkan bahwa kondisi tanah TWA Baumata memiliki produktivitas cukup, tekanan ekologi sedang dan kondisi ekosistem yang cukup seimbang. Kata kunci: Keanekaragaman, Mikrofungi Tanah, dan Taman Wisata Alam Baumata. Abstract The research to purpose determine the types of microfungi and the diversity of microfungi found in Baumata Natural Tourism Park (TWA). In the reaseaech using direct observation methods and direct metoch. The research was conducted in Baumata TWA and the process of isolation and identification of soil microfungi in the biology laboratory of the Biology Education Study Program at the Arta Wacana Kupang Christian University and the Plant Disease Laboratory of the Faculty of Agriculture, Nusa Cendana Kupang, from November 2017 to April 2018. The identified microfungi are of different types and then count the diversity index The results showed that there were found 5 types of soil microfungi found in Baumata TWA is Microfungi of Aspergilus terreus, Aspergilus flavus, Aspergilus niger, Penicillium sp., Thamnidium elegans. The stages that are passed to get these five types of microfungi are through the stages of isolation, purification and identification. By using the shannon wiener formula the results of the analysis show that the diversity of microfungi in Baumata TWA is classified as moderate with a diversity index (H ') = 1.2691. The results of this analysis indicate that Baumata TWA soil conditions have sufficient productivity, moderate ecological pressure and fairly balanced ecosystem conditions. Keywords: Diversity, Soil Microfungi, and Natural Park Baumata

A great pressure has arisen lately in the business world by movements like occupy Wall Street, or more concerning economic crises started in 2008. Due to this pressure, companies have to be more careful and act more responsibly. In the recent years, Corporate Social Responsibility (CSR) has been seen like a panacea of all stakeholders problems, more and more reports of CSR being published on companies website. However, it has been proven that just to claim actions of social responsibility, does not mean those companies are truly responsible. As expected, this behavior is penalized by a part of stakeholders. In this context, for each firm is important to know which are the most representative stakeholders, and how a certain situation could affect this scale. For explaining this fact, this paper analyzes the case of Brent Spar, pointing how an industrial giant like Shell, using a wrong CSR policy, could lose both money and image capital. In order to do that, in the first part is discussed the CSR from the perspective of stakeholder theory. Although it is present since 1950s in the United States of America and evolved all over the world like an all known concept, CSR does not have yet an universally accepted definition. Therefore, in this article was stated a definition for CSR from the stakeholder theory approach, in order to understand the Brent Spar actions and implications. In the second part of the paper are analyzed the steps taken by both sides, on one hand by Shell and on the other, by some of the stakeholders. The actions have been explained from the CSR paradigm perspective. Finally, it is proved why Brent Spar is a case of CSR failed, and how, by neglecting of some stakeholders categories, a company could pay important costs. Moreover, the paper demonstrates that the image of one company, from a specific area, could affect the all industry field. Therefore, a proper identification of key stakeholders, a good communication with those and flexibility in decision, could be the success factors for companies, and may lead to successful CSR. Correct CSR actions become an imperative in nowadays industrial scenario, being viewed as a change imposed by globalization and by the transnational nature of CSR.

Abstract. It is well known that the storm tracks are a preferred region of stratosphere–troposphere exchange (STE), but a systematic and climatological investigation of the connection between cyclones and STE has not yet been performed. We use two ERA-Interim climatologies of STE and cyclones for the years 1979–2011 to quantify the amount of STE that occurs during the life cycle of North Atlantic cyclones. A Lagrangian method serves to identify individual STE events, and a sophisticated cyclone identification tool detects cyclones, their shape and size from the sea-level pressure (SLP) field and from geopotential height anomalies at 300–700 hPa. Combining the two data sets reveals that roughly 50–60 % of the total STE in the North Atlantic occurs in the vicinity of cyclones and that both downward and upward fluxes of mass across the tropopause (STT and TST, respectively) are more intense in deeper cyclones (lower minimum SLP) compared to less intense cyclones. In summer, STT and TST in the vicinity of cyclones are almost equal; in the other seasons, STT is larger by 25–60 %. Compared to climatology, cross-tropopause mass fluxes are enhanced by a factor of about 1.29 and 1.06 for STT and TST, respectively, when a cyclone is present. On average, STE is strongest during the mature phase of cyclones, i.e., in a 24 h time window around the time of maximum intensity. Systematic patterns of exchange locations relative to the cyclone centre are identified via composite analysis and shed light on the different characteristics of STT and TST. During cyclone intensification and in the mature stage, TST is mainly confined to the cyclone centre, whereas STT occurs mainly in a region further southwest. During the decay of the cyclones, both STT and TST are most frequent close to the cyclone centre, in a region with a fairly low tropopause.

Background: The Symplicity-HTN 3 trial failed to show significant difference in blood pressure (BP) lowering between patients undergoing catheter-based renal denervation (RDN) and the sham-procedure arm of the study. However, there is still optimism about the role of RDN in the treatment of resistant hypertension, because identification of patients with increased sympathetic activity thus being good RDN responders, improvements in the RDN procedure and new technology RDN catheters are all expected to lead to better RDN results. We present our initial experience with RDN for the treatment of resistant hypertension, and the utility of novel anesthetics and cardiac 123I-metaiodobenzylguanidine scintigraphy (123I-MIBG). Methods and Results: Seven patients with resistant hypertension underwent RDN and were followed up for 6 months. MIBG was performed before RDN, in order to estimate sympathetic activity and predict the response to RDN. All patients were sedated with dexmedetomidine and remifentanil during RDN. All patients tolerated the procedure well, were hemodynamically stable and their peri-procedural pain was effectively controlled. A median of 7.6 ± 2.1 and 6 ± 1.4 ablations were delivered in the right and left renal artery respectively, making an average of 6.8 burns per artery. No peri-procedural or late complications - adverse events (local or systematic) occurred. At 6 months, mean reduction in office BP was -26.0/-16.3 mmHg (p=0.004/p=0.02), while mean reduction in ambulatory BP was -12.3/-9.2 mmHg (p=0.118/p=0.045). One patient (14.3%) was a non-responder. None of the cardiac 123I-MIBG imaging indexes(early and late heart-to-mediastinum (H/M) count density ratio, washout rate (WR) of the tracer from the myocardium) were different between responders and non-responders. Conclusion: Patients with resistant hypertension who underwent RDN in our department had a significant reduction in BP 6 months after the intervention. 123I-MIBG was not useful in predicting RDN response. Dexmedetomidine and remifentanil provided sufficient patient comfort during the procedure, allowing an adequate number of ablations per renal artery to be performed, and this could probably lead to improved RDN results.

Abstract Background and aims Conditioned Pain Modulation (CPM) is a well-established phenomenon and several protocols have shown acceptable between-subject reliability [based on intraclass correlation coefficient (ICC) values] in pain-free controls. Recently, it was recommended that future CPM test-retest reliability studies should explicitly report CPM reliability based on CPM responders and non-responders (within-subject reliability) based on measurement error of the test stimulus. Identification of reliable CPM paradigms based on responders and non-responders may be a step towards using CPM as a mechanistic marker in diagnosis and individualized pain management regimes. The primary aim of this paper is to investigate the frequency of CPM responders/non-responders, and to quantify the agreements in the classification of responders/non-responders between 2 different days for 10 different CPM protocols. Methods Data from a previous study investigating reliability of CPM protocols in healthy subjects was used. In 26 healthy men, the test-stimuli used on both days were: Pain thresholds to electrical stimulation, heat stimulation, manual algometry, and computer-controlled cuff algometry as well as pain tolerance to cuff algometry. Two different conditioning stimuli (CS; cold water immersion and a computer-controlled tourniquet) were used in a randomized and counterbalanced order in both sessions. CPM responders were defined as a larger increase in the test stimulus response during the CS than the standard error of measurement (SEM) for the test-stimuli between repeated baseline tests without CS. Results Frequency of responders and non-responders showed large variations across protocols. Across the studied CPM protocols, a large proportion (from 11.5 to 73.1%) of subjects was classified as CPM non-responders when the test stimuli standard error of measurements (SEM) was considered as classifier. The combination of manual pressure algometry and cold water immersion induced a CPM effect in most participants on both days (n=16). However, agreement in the classification of CPM responders versus non-responders between days was only significant when assessed with computer-controlled pressure pain threshold as test-stimulus and tourniquet cuff as CS (κ=0.36 [95% CI, 0.04–0.68], p=0.037). Conclusions and implications Agreements in classification of CPM responders/non-responders using SEM as classifier between days were generally poor suggesting considerable intra-individual variation in CPM. The most reliable paradigm was computer-controlled pressure pain threshold as test-stimulus and tourniquet cuff as conditioning stimulus. However while this CPM protocol had the greatest degree of agreement of classification of CPM responders and non-responders across days, this protocol also failed to induce a CPM response in more than half of the sample. In contrast, the commonly used combination of manual pressure algometry and cold water immersion induced a CPM effect in most participants however it was inconsistent in doing so. Further exploration of the two paradigms and classification of responders and non-responders in a larger heterogeneous sample also including women would further inform the clinical usefulness of these CPM protocols. Future research in this area may be an important step towards using CPM as a mechanistic marker in diagnosis and in developing individualized pain management regimes.

Little is known about the disease-specific factors that predict responsiveness to CAR-T cell therapy, other the direct presence of the CAR-T target. Clinical outcomes at our center have demonstrated that durable responses to CD19-directed CAR-T therapy in pediatric pre-B-ALL (acute lymphoblastic leukemia) are associated with persistence of CAR-T cells in the peripheral blood, antigenic load (percent CD19-positive cells in marrow prior to CAR-T infusion), and apheresis product T-cell quality (Finney O, et al., 2019). However, in a small number of cases where both antigenic load and T-cell quality predicted a good response, the treatment failed rapidly. This led us to undertake a detailed investigation of the leukemia itself in order to discover potential disease-associated factors that correlate with resistance to CAR-T therapy. We employed advanced exomic, and single-cell genomic and epigenomic analysis techniques to define signatures present in four CD19-CAR-T resistant bone marrow biopsy specimens, in comparison to five specimens from CD19-CAR-T responsive disease, from patients enrolled in a phase I clinical trial at Seattle Children's Hospital (PLAT-02, NCT02028455). Current cytogenic approaches to identify high risks markers (Ph+, Ph-like, MLL) were not informative as to CAR-T susceptibility, as high risk leukemias were CAR-T responsive; while a CAR-T resistant leukemia contained a marker (ETV6-RUNX1 fusion) previously associated with a good prognosis. Thus, we performed bulk whole-exome sequencing and RNAseq, single cell (sc) RNAseq, sc B-cell receptor (BCR)-seq, methylation array, H3K27ac ChIPseq, and ATACseq on these marrow samples. Initial genomic analysis revealed a total of 5 previously described hotspot mutations in ABL1, IKZF1, EP300, and 2 in KRAS. RNAseq analyses identified actionable fusions for ABL1, ETV6, ETV5, and KMT2A. Interestingly, a therapy-sensitive leukemia harbored a KMT2A-AFF1 fusion that was shown to predispose patients to leukemic plasticity and lineage switching when treated with blinatumomab. Importantly, we identified CREBBP-fusions in leukemias that failed to achieve CD19-CAR-T cell induced B cell aplasia. CREBBP perturbations have previously been associated with relapsed and refractory ALL, but not with resistance to CAR-T therapy. Single cell RNAseq and scBCRseq data are being analyzed for the existence of mixed lineage and gene expression-based heterogeneity that may predict clonal selection under CAR-T pressure. RNASeq analysis identified upregulation of JUN and JUND transcripts in CAR-T resistant disease, a finding which is complemented by the hypermethylation of JUND in CAR-T sensitive disease. Similarly, ATACseq and methylation data is being analyzed for lineage specification in CAR-T resistant leukemia. In comparing dysfunctional to functional CAR-T responders by ATACseq, > 10,000 unique open chromatin regions were identified in dysfunctional responders, as opposed to <500 open chromatin regions in the functional responders, indicating that CAR-T resistant disease had more open chromatin. A recent published analysis of cancer cell lines identified EP300 and CREBBP mutations that were proposed to increase substrate acetylation, and which "…may represent the first cancer-associated gain of function mutations for p300 and CBP…" (Ghandi M, et al, 2019). Our study represents one of the most comprehensive approaches to genomic profiling for B-ALL patient samples to date. The immune evasion we have described is not due to overt CD19 antigen loss, or to a long-term process of genetic alteration or drift. We propose that continued analysis of our data may reveal that epigenetic plasticity is a component of CAR-T resistance. The presence of CREBBP fusion genes or mutations, methylation array-based identification of altered JUND/JUN regulation, and ATAC Seq identification of multiple open regions of the genome in leukemias from dysfunctional responders lend support to this hypothesis. Although our analysis is preliminary and the sample number is small, we believe these in-depth analyses will highlight crucial differences in leukemia that predict responsiveness to CAR T therapy Disclosures Gardner: Novartis: Honoraria. Jensen:Bluebird Bio: Research Funding; Juno Therapeutics, a Celgene Company: Research Funding. Orentas:Lentigen Technology Inc., a Miltenyi Biotec Company: Consultancy, Research Funding.

1. Voltage- and ligand-gated currents were recorded from solitary rabbit rod bipolar cells using the whole cell patch-clamp technique. The rod bipolar cell forms a single, stereotypical physiological and morphological class of cells that was easily identified from other neurons and support cells after enzymatic and mechanical dissociation from isolated retina. Protein kinase C immunoreactivity confirmed the validity of using a purely morphological identification of this cell type. 2. Voltage steps in 15-mV increments from a holding potential of -45 mV elicited a large outward current activated near -30 mV. These voltage-gated currents were eliminated by using equimolar substitutions of Cs+ and tetraethylammonium+ for K+ in the pipette, indicating that they represent a mixture of K+ currents. 3. The putative inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and glycine activated inward Cl- currents when pressure-applied from pipettes placed near the axon terminals of rod bipolar cells, which were voltage-clamped at -45 mV. With changes in intracellular or extracellular Cl- concentration, the reversal potential of these ligand-gated currents changed as predicted by the Nernst equation for Cl- activity. The dose-response curves for GABA and glycine were sigmoidal with saturating concentrations of 100 and 300 microM, respectively. 4. GABA-activated currents were 1) reversibly reduced by the allosteric inhibitor picrotoxin and the competitive antagonist bicuculline; 2) potentiated by the benzodiazepine diazepam and the barbiturate barbital sodium; and 3) indistinguishable from muscimol-activated currents. There was no response to the GABAB agonist baclofen. Collectively, these data strongly suggest that the GABA-activated currents in rabbit rod bipolar cells are mediated by the GABAA receptor. This is similar to the GABA-activated currents in other mammalian rod bipolar cells. 5. Application of the conformationally restricted GABA analogue cis-4-aminocrotonic acid (CACA) failed to elicit a response, whereas the conformationally extended GABA analogue trans-4-aminocrotonic acid (TACA) elicited a response similar to that of GABA. Although bicuculline appeared to suppress the GABA-activated current slightly more than the TACA-activated current (not significant using Student's t-distribution), GABA- and TACA-activated currents were equally suppressed by picrotoxin and equally enhanced by diazepam and barbital sodium. These data, coupled with the inefficacy of CACA, argue against the existence of a GABAC-type channel in the rod bipolar cell of the rabbit and suggest that GABA and TACA were activating the same GABAA receptor-channel complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Background: Recent attempts have focused on identifying fewer magnitude of minimal residual disease (MRD) rather than exploring the biological and genetic features of the residual plasma cells (PCs). Interphase fluorescence in situ hybridization (iFISH) analyses in sequential samples provide a simple and reliable method to longitudinal track the dynamic changes in clonal architecture and speculate the possible evolutionary pattern. Here, we report for the first time the incidence and prognostic significance of cytogenetic abnormalities (CA) existed in the PCs of patients achieving at least partial remission. Methods: A cohort of 193 patients with at least one CA at diagnosis were analyzed using data from the prospective, non-randomized clinical trial (BDH 2008/02), and iFISH analyses were performed in patient-paired diagnostic and post-therapy samples. Results: Persistent CA in residual tumor cells were observed for the majority of patients (63%), even detectable in 28/63 (44%) patients with MRD negativity (<10-4). The absence of CA in residual PCs was associated with prolonged survival regardless of MRD status. It was noted that MRD-positive but FISH-negative patients experienced similar survival to MRD-negative patients (m-TTP 4.5 vs. 5.1 years, P=0.983). According to the change of the clonal size of specific CA, patients were clustered into five groups, reflecting five patterns of clone selection under therapy pressure. 1) Pattern A were observed in 36 (19%) patients where a minor subpopulation or undetectable subclone in the pre-treatment sample became dominant after therapy. 2) Pattern B was identified in 29 (15%) patients whose fractions of PCs harboring different CA were decreased with inconsistent extent. 3) Identical CA fraction in residual PCs were found in 22 (11%) patients as Pattern C. 4) Pattern D. The fractions of PCs harboring specific CA in 35 patients (18%) were uniformly declined. 5) 71 patients lost their abnormal cytogenetic clone after therapy (less than cut-off level) were classified as Pattern E. The cytogenetic dynamics of pattern A and B can be interpreted as a therapy-induced selection process with comparable inferior survival (m-TTP 1.2 vs. 1.6 years, respectively). Patients with pattern E experienced the most favorable outcome (m-TTP 5.0 years), following those with pattern D and C (m-TTP 3.5 and 2.5 years). Among the 65 patients with clonal selection, 24 underwent upfront auto-transplantation that experienced significantly improved survival. However, upfront transplant failed to completely reverse the inferior outcome caused by therapy-induced clonal selection. Longitudinal cytogenetic studies at relapse were available in 43 patients. The results suggested that sequential cytogenetic dynamics were observed in most patients, and the cytogenetic architecture of residual cells could to some extent predict the evolutional pattern at relapse. Conclusions: The repeat cytogenetic evaluation in residual cells could not only serves as a good complementary tool for MRD detection, but also provides a better understanding of clinical response and clonal evolution. Therapy-induced clonal selection was associated with inferior outcome regardless of the baseline cytogenetic profiles. The early identification of resistant clone may contribute to guide better tailored therapy strategies based on the feature of the residual tumor cells. Figure Disclosures Munshi: Celgene: Consultancy; Adaptive: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy.

Abstract Various experimental and registered treatments were applied to replicated 12-15 tree plots in a randomized block design primarily to evaluate their activity against the tufted apple bud moth. Each treatment was replicated 4 times. Each plot consisted of alternating trees of ‘Yorking’, and ‘Golden Delicious’. These trees were planted to a spacing of 18 X 25 ft and were 16 yr old. The center ‘Golden Delicious’ and ‘Yorking’ trees in each plot were used as the primary sampling trees. Experimental sprays were applied with a Friend Airmaster ‘309’ calibrated to deliver 100 gpa at 2.4 mph. Applications timings were based on the accumulation of degree days from first adult moth capture in a sex pheromone trap (12 May) in order to predict various percentages of egg hatch for each brood of TABM. Degree day calculations were based on minimum and maximum developmental thresholds of 45°F and 91°F, respectively. Refer to the first table for a listing of application dates and degree day accumulations. All applications were complete sprays, except for one of the RH-5992 and RH-2485 treatments. These treatments were applied using the alternate row middle (ARM) system of spraying. A routine schedule of fungicides (Benlate 50DF, Penncozeb 75DF, Nova 40WP, and Ziram 76WP) was maintained throughout the experiment. One alternate row middle application of Swat 8E at 0.6 lb Al/acre (expressed as amount/acre for a complete spray) for control of the spirea aphid was made on 29 Jun. The effect of the sprays on WALH was evaluated by counting the number of nymphs/25 injured leaves/tree (cv. Yorking). Effectiveness of the treatments on SA was evaluated by counting the number of aphid-infested leaves/ 10 side terminals, and the number of aphids/most infested leaf (cv. Yorking). Effectiveness of the test chemicals on the ERM, TSSM and AF was evaluated by counting the mites several times during the season on samples of 25 random leaves/tree (cv. Yorking), 100 leaves/treatment. The effect of sprays on the predator S. punctum was evaluated by 3-min counts of adults and larvae around the periphery of the same trees. STLM was evaluated by a 5-min count of tissue-feeding mines around the periphery of the trees at the end of each generation. On 5 Jun, only spur leaves were examined, and on 24 Jul and 1 Sep only shoot leaves were examined for tissue-feeding mines (cv. Yorking). Shelters of the various leafrollers were counted in a 5-min examination of each plot tree on 20 Jul (cv. Yorking). All larvae were collected and returned to the laboratory for identification. Effectiveness of the treatments on fruit feeders on ‘Golden Delicious’ was assessed by scoring for injury a harvest sample of 100 fruit per tree from each of two center trees per replicate on 20 Sep and upto 25 dropped fruit per tree. For ‘Yorking’, injury was assessed on 150 picked fruit per tree from the two center trees in each replicate and up to 25 dropped apples per tree. In addition, 50 picked fruit per tree from two outside ‘Yorking’ trees were evaluated for injury. Russet evaluations were made on ‘Golden Delicious’ fruits (30 per replicate) from two replicates. Each apple was rated as 0 (no russet), 1 (raised lenticels), 2 (1-10% russeted surface), 3 (11-25% russeted surface), 4 (26-50% russeted surface), or 5 (&gt;51% russeted surface). Individual ratings were added to calculate a russet rating for each replicate. Possible ranges for the replicate russet ratings (and estimate of range of % of surface russeted) are 0-30 (none to raised lenticels), 31-60 (raised lenticels to 1-10% russeted surface), 61-90 (1-10% to 11-25% russeted surface, 91-120 (11-25% to 26-50% russeted surface), and 121-150 (26-50% to &gt;51% russeted surface). Both rates of Provado (0.50 and 0.075 lb Al/acre), Agri-Mek and Carzol provided excellent control of WALH at 4 and 13 days post-treatment with applications timed at petal fall. Provado at 0.075 lb Al/acre demonstrated the best control of SA followed closely by the high rate of Aphistar (0.25 lb Al/acre). There was a rate response with Aphistar against SA. Seasonal STLM control was obtained with single application of Agri-Mek at petal fall. Also showing excellent control of STLM were treatments of Provado and RH-2485. The single application of Agri-Mek at petal fall maintained seasonal control of ERM. The treatment of Vydate at the pink stage and Carzol at petal fall also provided good early season control, but ERM populations exploded at the end of Jul. Stethorus populations were high across all treatments except the Agri-Mek treatment at petal fall. Leaf shelters containing live TABM larvae were low across all treatments. Surprisingly, only the complete spray of RH-5992, the Penncap M only treatment applied for first brood TABM control, and the one treatment of Compound Z contained relatively high TABM larval populations. Fruit injury from other leafroller species was low and variable during 1995. The complete spray and ARM applications of RH-2485 showed the best control of other leafrollers. All treatments except Dipel 2X reduced fruit injury from first brood TABM below the control. Second brood TABM fruit injury was quite high across all treatments. RH-2485 applied both as complete and alternate row middle applications had the fewest number of fruit injured by second brood TABM. Also showing excellent activity against the second brood were the treatments of RH-5992, Dipel 2X, Xentari, Compound Z and the standard treatment of Penncap plus Lannate. Only the treatment of Penncap alone failed to show a difference from the untreated control. For overall percent clean fruit, all treatments except Penncap M alone were significantly different from the control. No russeting problems were observed. Pest pressure was moderate to high throughout the season depending upon species.

Carotid Intima Media Thickness (IMT) has been widely used to predict cardiovascular events in primary and secondary prevention studies. Yet, the power of IMT to reclassify risk level on top of conventional risk assessment based on classical risk factors remains unsettled. In fact, recent data indicate that the prognostic power of IMT is lower than that provided by the identification of carotid plaques. The role of IMT as surrogate endpoint to assess the efficacy of cardiovascular protective therapies is also still debated. In fact, no studies have ever been designed and powered to show a relationship between changes in carotid IMT during follow-up and cardiovascular events. Recently, two metaanalysis of trials using IMT as surrogate endpoint failed to demonstrate an association between IMT regression and cardiovascular events. The reasons for the lack of predictive role for changes in IMT are uncertain. It has been shown that IMT is not a pure atherosclerotic index, being substantially affected by age and hemodynamic factors including blood pressure and vessel wall shear stress. In addition, the status of carotid vessels does not strictly reflect that of coronary arteries. Finally, intra and inter-observer variability of measurements may further limit the association between IMT changes in individual patients and cardiovascular risk. Thus, IMT represents a valuable risk marker in population studies but its role for tailoring cardiovascular therapy in clinical practice remains currently uncertain.

Background It has been widely recognized that obstructive sleep apnea (OSA) is linked to cardiovascular disease. Yet, randomized controlled studies failed to demonstrate a clear cardiovascular benefit from OSA treatment, mainly because of poor adherence to continuous positive airway pressure (CPAP). To date, no prior study has assessed the effect of CPAP treatment on daytime resting heart rate, a strong predictor of adverse cardiovascular outcomes and mortality. Methods and Results We conducted a randomized controlled study in 39 participants with OSA and prediabetes, who received either in‐laboratory all‐night (ie, optimal) CPAP or an oral placebo for 2 weeks. During daytime, participants continued daily activities outside the laboratory. Resting heart rate was continuously assessed over 19 consecutive days and nights using an ambulatory device consisting of a single‐lead ECG and triaxis accelerometer. Compared with placebo, CPAP reduced daytime resting heart rate (treatment difference, −4.1 beats/min; 95% CI, −6.5 to −1.7 beats/min; P =0.002). The magnitude of reduction in daytime resting heart rate after treatment significantly correlated with the magnitude of decrease in plasma norepinephrine, a marker of sympathetic activity ( r =0.44; P =0.02), and the magnitude of decrease in OSA severity (ie, apnea‐hypopnea index [ r =0.48; P =0.005], oxygen desaturation index [ r =0.50; P =0.003], and microarousal index [ r =0.57; P <0.001]). Conclusions This proof‐of‐concept randomized controlled study demonstrates, for the first time, that CPAP treatment, when optimally used at night, reduces resting heart rate during the day, and therefore has positive cardiovascular carry over effects. These findings suggest that better identification and treatment of OSA may have important clinical implications for cardiovascular disease prevention. Registration URL: https:/// www.clini​caltr​ials.gov ; Unique identifier: NCT01156116.

Background: People with addiction do not have control over their behavior, actions or usage. Their addiction may reach to a point that it is harmful. Addiction does not only involve the physical aspects such as drugs or alcohol but also includes abstract things, often described as a behavioral addiction. The causes of addiction differ considerably and are seldom fully understood. They are generally caused by varying degrees of physical, mental, circumstantial and emotional factors. Objectives: To study the electronic devise profile among children and adolescent in modern global cities such as Dubai and to study the prevalence and size of the addiction phenomena. Methodology: This study was carried out in Dubai, United Arab Emirates during the Global School Health Survey in 2015. The sample included 7000 students who were randomly selected (multistage stratified random sample) from 10 private schools in Dubai. Data collection was carried out by standard questionnaire developed by the World Health Organization which includes different health domains (addiction, and addiction to electronic devices). Ethical issues were followed up to standards. The questionnaire and consent forms were given to the participants who met the inclusion criteria. An information sheet was attached to the questionnaire explaining the purpose of the study. The students were assured that the confidentiality and privacy of the answers were maintained. No names, phone numbers, and identification are required. Data coding, data entry and data analysis has been conducted by using SPSS 20 software. Results: The present study revealed that 56% of school children aged 13-15 years old spend three hours or more a day using electronic games, and this percentage rises to nearly 63% with the age group 16-17 years. The study showed that children, who excessively use these games might face social, emotional and behavioral problems such as isolation, anxiety and depression. Pointing out that children may complain of psychological pressure, stress or dehydration and burning eye, due to constant staring with bright light across the screens of devices. Most students (68.7%) said they were on social media between one and five hours daily, while 3.3 per cent said they spend less than an hour. 39.8% of students stayed without food or drink for a long time and 50.5 % tried to quit social media last year but failed. 15% of students spend 4-8 hours on social media and 1.6% spend more than 10 hours. When the students were asked about how they feel of the burden on their daily life and social commitments, 60% of them replied that social media decreases their interaction with the outside environment and family time, 55.6% said it interfered with their homework. The study showed that more than one quarter (26.7%) or almost one out of four reach up to more than 6 hours per day and could sometimes reach up to 10 in browsing and interacting with social media. The study reflected that more than 400 children showed the negative symptoms on the use of tablets. It appeared significantly on children who use them for more than two hours a day compared to their counterparts who do not use it at all or use it less than two hours. They have noticed that those who use it less have great language, motor and mental skills. Parents do not seem to be paying attention on how technology is taking their kids away from them. Children between the ages of 11 and 17 found out what really is keeping them so busy on all these addictive devices. Around 70% of them are most vulnerable to gaming addiction. They belong to the under-five age group, because parents are preoccupied with them. Conclusion: Electronic addiction among children and adolescents is a rapidly growing phenomena in the City of Dubai. It has a significant impact on the social and professional life and functions of this group, which necessitate intervention at many levels.

In recent years, we have witnessed the emergence of a number of concepts and ideas that relate to a new way of understanding the business world.After the historical focus of top management on the concepts of profit, satisfying shareholder interest and a short-term rather than a long-term approach, the new paradigm sees sustainability as the central focus in the strategic formulation of companies. It is no longer about making money or creating value, but about how this is done in a sustainable way, taking a long-term view and considering the interests of the different stakeholders that interact with the company.In this sense, the concept of shared value, developed by Professor Porter, seems to us to be very relevant, which, in summary, concludes by stating that economic value can be created creating social value at the same time.There are many terms, concepts and approaches which, although they may give rise to a certain amount of terminological confusion (acronyms such as CSR, ESG, SRI, for example), are frequently used in the press and in the business world. In terms of concepts, the circular economy, and its growing importance, and the global and cross-cutting nature of the ideas and issues addressed, are also faithfully reflected in the changes that are taking place in the way business is understood.On the other hand, there is a clear and growing interest, not only in the academic world, but also from companies, investors and the various providers of analysis, rankings and opinions, on sustainability that make this issue a hot topic.In Exponential Education we understand, first of all, that when we talk about sustainability, this should be considered from a triple perspective: the economic, environmental and social.The first perspective is usually taken for granted, given that, when talking about companies, their management, investors and asset managers, among others, understand that, without economic and financial sustainability, companies would not be viable.That is why, in our view, the focus when talking about sustainability is on environmental and social sustainability. There are perspectives, increasingly taken up by more and more institutions, and especially by large investment funds and asset managers, that add the governance pillar, proposing an innovative way of analysing and selecting investments based on the ESG concept. Moreover, it seems clear to many experts that the ESG approach enables, as research has shown, superior financial performance, higher revenue growth, improved margins, greater operational efficiency and lower cost of capital. Besides, more and more investment funds and asset managers, as well as individual investors, are demanding greater investment in assets with an ESG approach.From another perspective, the pressure from regulators, both national and transnational, and their concern about non-financial information, has led to a large number of far-reaching legislative changes, for example in the European Union.The European Union, for example, has published the taxonomy related to environmental aspects. The taxonomy related to social aspects and governance is still pending, although the latter aspect is fairly well regulated in the corporate governance regulations of the different countries.We also highlight all the EU initiatives in the field of sustainable finance and their influence, both from the perspective of bond issues, known as green bonds, aimed at financing environmentally friendly projects, as well as companies' own investment projects, with a clear change in the destination of their investments.Another aspect that we underline, from a business management perspective, is the growing importance of the different stakeholders that relate to the company, their identification and prioritisation, the commitments made to them and the fulfilment of these commitments, which will have a significant influence on corporate reputation and the consequent reputational risk.For all these reasons, Exponential Education has developed a research vocation in the field of sustainability and ESG philosophy, which is reflected in the monographic issue that we present with ASEPELT and sponsor with the unconditional support of IASE.It is a publication with a wide thematic variety, eminently transversal and with a great geographical and cultural diversity. The approach is from a scientific perspective subject to blind peer review, as an indexed journal.The monograph covers, among others, issues related to the environment, decarbonisation and environmental sustainability, the circular economy and the transition to it, green bonds, impact investing, renewable energy and the ecological footprint, gender diversity and women's empowerment, the role of venture capital in clean sectors, or the ESG model and financial performance.The monograph, with a clear international vocation, will be distributed on five continents with the support of ASEPELT and IASE.Exponential Education would like to thank all those who have contributed with their articles and opinions to this monograph, and we pledge to continue along the path of quality academic research.

This issue of M/C Journal explores the notion of "impact" and the capacity of contemporary research work to influence not only academia but the direction of current debates in the public sphere surrounding social, political and cultural agendas. The nine papers selected cover a broad range of topics: experimental research methodologies which confront the problem of 'measuring' research impact in the world of work; the creative industries and documentary films; identity politics debates address queer, migrant, racial issues; as well as investigations into the use of storytelling and autoethnography to promote cultural understanding and social inclusion. "Impact" for the vast majority of these contemporary cultural and social researchers is a moot term, especially the idea that the impact of research outcomes is a measurable quantity. However measuring and assessing the affect and applicability of research outcomes is an all too familiar reality, particularly since the majority of funding applications expect such a consideration. Even at the very early stages in a researcher's career, the doctoral Confirmation of Candidature demands a discussion of the proposed study's significance and potential wider cultural and social purpose. The comments of UK-based academic Ananya Kabir support this concern for the "state of research" that resonates far beyond the UK context: Academics cannot afford not to want to be impactful, or their work to be 'applicable'. On every application for funding we make to any Research Council, a 'statement of impact' is not merely desirable; it is very much a demand. This is certainly true of the situation in Australia with the previous government's 2005 planned Research Quality Framework (RQF) which advocated a strong focus on impact and the measuring of it, and the subsequent establishment in 2007 of the Excellence in Research for Australia (ERA) initiative (McDonald). While ERA's main aim is the assessment of research quality with no specific reference to "impact" as such, one of ERA's evaluation indicator categories—research application—requires such a consideration (ERA 2). Moreover, the very recent publication Measuring the Impact of Research by the Group of Eight illustrates the Australian academia's concern with the term, stressing that impact measures would greatly complement ERA's assessment (Rymer 3). However, there is substantial debate and questions raised concerning these government policy developments. Notwithstanding the difficulties of finding reliable measurement methods and differing perspectives on the evaluation of findings (cf. Group of Eight); will a single regime of measurement suit all disciplines equally? As Stefano Harney stresses impact will "subject the humanities to the same pressure as knowledge transfer did engineering and science. And meanwhile the professional schools, business, law, medicine, use their regulative status to prove impact easily, putting yet more pressure on the humanities." Stephen Shapiro paints an even darker picture: "The lesson is clear: 'impact' is the Trojan horse designed to institutionalize entrepreneurial interests that will be the 'invisible hand' policing the British academy." However, does measuring impact really restrict us to a particular definition of the term? It is impact that should be at the heart of these types of discussions not the obsession with measurement. Perhaps the challenge is to encourage high impact research without the constraint of a specific metrics. As Rick Rylance puts it: For me, thinking about impact as a challenge and not as a threat is part of this recognition. This is because impact encourages us to conceive of the disparate kinds of benefit research produces which are of many kinds. Sometimes the outcomes are of direct practical advantage. What is needed then is a greater flexibility with the term and a clearer distinction between impact and impact evaluation or measurement. Although, to some extent, we have to acknowledge the significance of impact evaluation as a necessity in demonstrating that research funding is fairly distributed and spent. Like government funding for the arts for example, it is difficult to demonstrate the value of research aside from the ability to attract financial support. Paula Gilligan observes: "The defence of the Humanities is invariably linked to the defence of the 'Arts'. We are seen to have common cause, united against the scientists, who are 'winning'. We need to start questioning this assumption." In particular, Hadley and Gattenhof's paper in this issue of M/C Journal engages a number of discourses surrounding these concerns, with their response to the Australian Government's "National Cultural Policy Discussion Paper", suggesting an approach for measuring and assessing the impact of the work of artsworkers. Central to their model is the demands of policy requirements for progress to be 'measurable' and therefore the necessity to train arts, cultural and creative workers to conduct such an assessment and to make the impact of this work evident to stakeholders. This investigation also raises questions for scholars, educators and employers about what artsworkers actually do, the worth of their work and how it could be improved upon. Two other papers propose diverse methodologies for addressing the problematic area of measurement and assessment. Humphrey's unique approach to the often neglected area of contemporary work and media, introduces the term "officing" (the daily use of information and communication technology) to explore new ways to approach the identification and measurement of the space, time and technology in everyday work practices. Drawing on the ideas of Anselm Strauss to analyse the office workplace as a "contingent and provisional arrangement or process", the author highlights the benefits of this investigation and its impact on productivity and work-life balance, with the ultimate aim to "contribute to the design of more sustainable work environments". Karlin and Johnson, on the other hand, explore another under-researched area where assessment is required: measuring the impact of films on individual attitudes and cultural narratives and evaluating its importance for documentary film campaigns. The authors argue that though it is increasingly necessary for "issue-based" films to provide information on their social investment returns to justify production costs, of equal importance is that the questions asked and the methods used to answer such queries are "valid and respectful." The paper proposes an "emerging research agenda" for the examination of documentary film which allows investigation of the importance of such evaluations and the key issues relevant to assessing their impact. The power of personal narratives is explored when Hummel investigates the tension between culture and autoethnographic performance. The author questions the "capacity of gender identification to justify the crisis of representation" and the impact of autoethnography with its "resistance to traditional culture and power divisions through its emphasis on shared experience, emotion and subjectivity." This researcher presents a highly personal narrative of her experience as a woman in Bangladesh to highlight the potential of autoethnography to promote alternate ways of understanding and transcend cultural boundaries. Hancox also examines the potential and capacity of storytelling and personal narratives to contribute to cultural research and social inclusion. Through a 2009 digital storytelling project conducted with a group of Forgotten Australians prior to the public apology in the Australian Parliament, the paper explores how the "endemic, institutionalised abuse of a group of people was translated to the broader community and galvanised support through the impact of their personal stories." This approach is advocated as a way of enhancing broader issues, such as public understanding of the needs of marginalized groups, which can result in changes to social inclusion through policy and community based solutions as "personal narratives energise public narratives and shape our ways of thinking and collective understandings" (Harter et al. 4). The effect of Government policy on citizenship and its impact on individuals and communities is examined by two writers: Chisari and Raj. Through a Foucaultian genealogical analysis of Becoming an Australian Citizen, (the resource booklet that prepares a potential new Australian for the citizenship test), Chisari explores Australian identity and how subjects are shaped by the operations of governance and the interrelationship of truth, power and knowledge. In an attempt to move beyond the History Wars, the author problematises the notion of historical "objective truths," endeavouring to influence policy-making surrounding issues of civil education for the Australian migrant. Chisari argues that such an approach has the potential to impact upon historical narratives and promote the inclusion of multiple, alternate stories of Australia and Australian identity. Raj's paper tackles the hot topic of gay marriage in policy and activist debates. With reference to the writings of Judith Butler and Michael Warner, Raj explores neo-liberal political arguments, queer theory and community politics to critique issues such as intimacy, citizenship and equality. Advocating the belief that by "understanding cultural difference(s) rather than conforming to a norm," this paper proposes a critical framework for "intimate citizenship" that provides a platform for further policy and activist dialogues. Another arena of contemporary debate is explored by Malatzky's article which examines representations surrounding what Western women should "look like as mothers," and the importance of cultural research projects for the broader community in terms of their potential to inform and direct discussions. Utilising qualitative feminist methodologies', this researcher investigates the media's role in shaping contemporary expectations surrounding the postnatal body, arguing that such investigations can influence the "creation of alternate mothering discourses, and can direct current debates that have a direct impact on, and relevance for, everyday Australian women and men." Identity is also an issue for our last early career researcher's paper. Al-Natour uses his personal experiences as a researcher investigating the controversy over a proposed Islamic school in Sydney to examine the ways a researcher's identity can affect their participants, and whether this relationship impacts data collection processes. As an outcome of these field work experiences, Al-Natour proposes a series of suggestions for fellow cultural studies researchers in dealing with such dilemmas. An exploration of the impact of cultural and social researchers in this issue of M/C Journal has ranged from the problems of measuring research outcomes to debates surrounding citizenship and identity and the power of narratives to transcend cultural boundaries. A shared belief that emerges from these explorations and proposals is that though the measurement of impact is problematic, by introducing new discourses, perspectives and paradigms which have the capacity to sway policy making, cultural researchers can position themselves as intermediaries to inform societal groups and various communities. The outcomes of these research projects can then address this concern about the affect and applicability of their findings which have the potential to present accessible, transparent and practicable forms of cultural understanding and genuine solutions to social and cultural problems. ReferencesERA. Excellence in Research for Australia – National Report. Canberra: Australian Research Council, 2010.Gilligan, Paula. "'Creative' Functionalism and Continental Philosophy at Middlesex." SocialText - Periscope (Aug. 2010). 12 Dec. 2011 ‹http://www.socialtextjournal.org/periscope/2010/08/impact-innovation-and-creative-functionalism-in-the-uk-the-case-of-the-department-of-philosophy-at-m.php›.Harney, Stefano. "The Real Knowledge Transfer." SocialText - Periscope (Aug. 2010). 12 Dec. 2011 ‹http://www.socialtextjournal.org/periscope/2010/08/the-real-knowledge-transfer.php›.Kabir, Ananya. "The Impact of 'Impact'." SocialText - Periscope (Aug. 2010). 12 Dec. 2011 ‹http://www.socialtextjournal.org/periscope/2010/08/the-impact-of-impact.php›.McDonald, Kate. "New ERA for Research Quality - Science Minister Kim Carr Announces Replacement for Dumped RQF." LifeScientist 27 Feb. 2008. 12 Dec. 2011 ‹http://www.lifescientist.com.au/article/207244/new_era_research_quality/›.Rymer, Les. "Measuring the Impact of Research – The Context for Metric Development." Go8 Backgrounder 23 (2011).RQF. Assessing the Quality and Impact of Research in Australia - Issues Paper. Canberra: Commonwealth of Australia, 2005.Rylance, Rick. "The Impact Effect." SocialText - Periscope (Aug. 2010). 12 Dec. 2011 ‹http://www.socialtextjournal.org/periscope/2010/08/the-impact-effect.php›.Shapiro, Stephen. "Deepwater Impact." SocialText - Periscope (Aug. 2010). 12 Dec. 2011 ‹http://www.socialtextjournal.org/periscope/2010/08/deepwater-impact.php›.

Cognitive biases, or systematic errors in cognition, are important contributors to diagnostic error in medicine. In our review, we explore the psychological underpinnings of cognitive bias and highlight several common biases using clinical cases. We conclude by reviewing strategies to improve diagnostic accuracy and by discussing controversies and future research directions.RésuméLes préjugés cognitifs, ou les erreurs systématiques dans la cognition, sont des contributeurs importants à l'erreur diagnostique dans la médecine. Dans notre examen, nous explorons les fondements psychologiques du biais cognitif et soulignons plusieurs préjugés communs en utilisant des cas cliniques. Nous concluons en examinant les stratégies visant à améliorer la précision diagnostique et en discutant des controverses et des futures orientations de recherche.Research in the field of behavioural psychology and its application to medicine has been ongoing for several decades in an effort to better understand clinical decision making.1 Cognitive biases (systematic errors in cognition) are increasingly recognized in behavioural economics2 and more recently have been shown to affect medical decision making.3 Over 100 such cognitive biases have been identified and several dozen are postulated to play a major role in diagnostic error.4 Cognitive errors can take many forms and in one study contributed to as many as 74% of diagnostic errors by internists. 5 Most of these errors were due to “faulty synthesis” of information, including premature diagnostic closure and failed use of heuristics.5 Inadequate medical knowledge, on the other hand, was rare and mostly identified in cases concerning rare conditions. 5 Professional organizations such as the Royal College of Physicians and Surgeons of Canada and the Canadian Medical Protective Association have since been working to raise awareness of cognitive bias in clinical practice.6In our review, we explore the role of cognitive bias in diagnostic error through the use of clinical cases. We also review the literature on de-biasing strategies and comment on limitations and future directions of research.The Dual Process TheoryA prevailing theory to explain the existence of cognitive bias is the dual process theory, which asserts that two cognitive systems are used in decision making, herein called System 1 and System 2 (Table 1). 2,7System 1 can be thought of as our intuitive mode of thinking. It generates hypotheses rapidly, operates beneath our perceptible consciousness and makes judgments that are highly dependent on contextual clues. System 1 is characterized by heuristics (short cuts, or “rules of thumb”) and is an important component of clinical judgment or expertise. In contrast, System 2 is slow, deliberate, analytical and more demanding on cognition. It applies rules that are acquired through learning and it can play a “monitoring role” over System 1, and thus overrides heuristics when their use is inappropriate. The dual process theory implies that errors result when inappropriate judgments generated by System 1 fail to be recognized and corrected by System 2. Maintaining constant vigilance over System 1 would be both impractical and time consuming for routine decisions and would diminish the value of intuition. It follows that a more practical way of improving reasoning is to identify the most common biases of System 1 and to recognize situations when mistakes are most likely to occur.2Alternative Theories of CognitionVariations of dual process theory have further refined our understanding of medical decision making. Fuzzy trace theory, for example, proposes that individuals process information through parallel gist and verbatim representations.8 The “gist” is analogous to System 1 and represents the bottom-line “meaning” of information. This representation is subject to an individual’s worldview, emotions and experiences. In contrast, verbatim representations are precise, literal and analogous to System 2. Fuzzy trace theory is particularly useful in explaining how patients might interpret health information. Proponents of this theory contend that in order for information to lead to meaningful behavioural change, physicians must appeal to both gist and verbatim representations when communicating with patients.8 Other models, such as dynamic graded continuum theory, do away with the dichotomy of System 1 and System 2 and instead represent implicit, automatic and explicit cognitive processes on a continuous scale.9 These single system models are useful to compare against dual process theory but have not replaced it as a well-established framework for understanding and mitigating cognitive bias in clinical decision making.7Case 1: A 55-Year-Old Male with Retrosternal Chest PainA 55year-old non-smoking male was assessed in a busy Emergency Department (ED) for retrosternal chest pain. Past medical history is significant for osteoarthritis for which he takes naproxen. On review of his history, the patient has had multiple visits for retrosternal chest pain in the previous two months. At each encounter, he was discharged home after a negative cardiac workup.Vital signs in the ED were within normal limits except for sinus tachycardia at 112 beats per minute. On exam, the patient was visibly distressed. Cardiac and respiratory exams were normal. There was mild tenderness in the epigastrium. Basic blood-work revealed leukocytosis (16.0 × 109/L), a mildly elevated high sensitivity cardiac troponin, and no other abnormalities. An ECG revealed T wave flattening in leads V3-V4.The patient was referred to the internal medicine service with a diagnosis of non-ST-elevation myocardial infarction and treated with aspirin, clopidogrel, and fondaparinux. Several hours later, the patient became more agitated and complained of worsening retrosternal and epigastric pain. On re-examination, heart rate had increased to 139 beats per minute, blood pressure dropped to 77/60 and he had a rigid abdomen. Abdominal radiography revealed free air under the right hemi-diaphragm and the patient was rushed to the operating room where a perforated gastric ulcer was detected and repaired. The case above illustrates numerous cognitive biases, including:1. Premature diagnostic closure: the tendency to accept a diagnosis before it is fully verified.42. Anchoring: the tendency to over-emphasize features in the patient’s initial presentation and failing to adjust the clinical impression after learning new information.43. Confirmation bias: the tendency to look for confirming evidence to support a diagnosis, rather than to look for (or explain) evidence which puts the diagnosis in question.4In this case, the physician based the diagnosis of myocardial infarction primarily on symptoms of chest pain and an elevated cardiac troponin. However, several other objective findings were present and when taken together, suggested a diagnosis other than myocardial infarction. These included a tender epigastrium, leukocytosis, and resting sinus tachycardia. These symptoms/signs were not explicitly explained or investigated before a treatment decision was made. Premature diagnostic closure is one of the most common cognitive biases underlying medical errors5 and it affects clinicians at all levels of training.10 It is multifactorial in origin5 and is especially common in the face of other cognitive biases such as anchoring and confirmation bias.The physician in this case “anchored” to a diagnosis of cardiac chest pain given the patient’s previous ED visit history and his/her best intentions of ruling out a “worst case scenario.” Anchoring can be especially powerful in the face of abnormal screening investigations that have been reviewed even before the physician has acquired a history or performed a physical examination. If the physician had reviewed the screening investigations before seeing the patient, he/she might have narrowed the differential diagnosis prematurely, failed to gather all the relevant information and failed to adjust the clinical impression based on new information.The physician demonstrated confirmation bias by failing to explain the abnormalities that put the diagnosis of myocardial infarction in question (e.g. tender epigastrium, leukocytosis). Confirmation bias arises from an attempt to avoid cognitive dissonance, a distressing psychological conflict which occurs when inconsistent beliefs or theories are held simultaneously.11 In one study evaluating clinical decision making amongst 75 psychiatrists and 75 medical students,12 13% of psychiatrists and 25% of medical students demonstrated confirmation bias when searching for information after having made a preliminary diagnosis. In this study, confirmation bias resulted in more frequent diagnostic errors and predictably impacted subsequent treatment decisions.An appropriate consideration of all diagnostic possibilities is the first step in avoiding diagnostic error. While acquiring information, physicians should step back and consolidate new data with the working diagnosis, as failure to do so can result in confirmation bias.13 All abnormal findings and tests, especially if considered clinically relevant should be explained by the most probable diagnosis. An alternate diagnosis or the possibility of more than one diagnosis should be considered when an abnormal finding or test cannot reasonably be explained by the working diagnosis.Tschen et al observed a team of physicians working through a simulated scenario which had diagnostic ambiguity.14 Two approaches were found to be effective in reducing the effect of confirmation bias: explicit reasoning and talking to the room. Explicit reasoning involves making causal inferences when interpreting and communicating information. Talking to the room is a process whereby diagnostic reasoning is explained in an unstructured way to a team member or colleague in the room. This allows the clinician the opportunity to elaborate on their thoughts and observers to point out errors or suggest alternate diagnoses in a shared mental model.Case 2: A 30-Yearold Male with Confusion and SeizuresA 30-year-old homeless male is found confused on the street by paramedics and brought to the ED for assessment. Empty bottles of alcohol were noted at the scene. The CIWA (Clinical Institute Withdrawal Assessment for Alcohol) protocol is initiated and he is given several doses of lorazepam to minimal effect. Several hours after the patient is admitted, a resident on-call is paged for elevated CIWA scores on the basis of diaphoresis and agitation. Several additional doses of lorazepam are ordered which fail to completely resolve the symptoms. Gradually, the patient becomes more obtunded. The on-call resident orders a capillary blood glucose and it measures 1.1 mmol/L. Intravenous D50W is promptly administered, the blood glucose normalizes and the patient’s level of consciousness improves.The case above illustrates the following biases:1. Availability bias: the tendency to weigh a diagnosis as being more likely if it comes to mind more readily.42. Diagnostic momentum: the tendency for labels to “stick” to patients and become more definite with time.4Although the symptoms of diaphoresis and agitation are not specific to alcohol withdrawal, this diagnosis was deemed most likely based on how readily it came to mind, the empty alcohol bottles at the scene, and potentially on the patient’s demographics. The unproven diagnosis of alcohol withdrawal “stuck” with the patient despite minimal improvement after a therapeutic trial of benzodiazepines.Availability bias has been shown to affect internal medicine residents. In one single-centre study,15 18 first-year and 18 second-year residents were exposed to case descriptions with associated diagnoses as part of an exercise. They were then asked to diagnose a series of new cases, some of which appeared similar to those they had previously encountered but with pertinent differences that made an alternate diagnosis more likely. Second year residents had lower diagnostic accuracy on these similar-appearing cases; a result consistent with availability bias. First year residents were less prone to this bias because of their limited clinical experience. Most importantly, subsequent reflective diagnostic reasoning countered the bias and improved accuracy.General Strategies to Avoid Cognitive BiasInterventions aimed at mitigating diagnostic error due to cognitive bias take several approaches.1. Improving clinical reasoning2. Reducing cognitive burden3. Improving knowledge and experienceDespite a large number of proposed interventions, there is a lack of empirical evidence supporting the efficacy of many de-biasing strategies. 16 What follows is a brief review of the current evidence.Improving Clinical ReasoningSeveral “de-biasing” strategies have been proposed to improve clinical reasoning. De-biasing strategies assume that System 1 processes are more prone to bias due to their heavy reliance on heuristics and therefore the solution is to activate System 2 at critical points in decision making. De-biasing occurs in several stages: at first an individual is educated about the presence of a cognitive bias, they then employ strategies to eliminate that bias and finally they maintain those strategies in the long term.17Metacognition, or “thinking about thinking,” involves reflecting on one’s own diagnostic reasoning. Internal reflection along with awareness of potential biases should allow the clinician to identify faulty reasoning. However, the evidence underlying reflective practice is mixed.16 Several studies have tried to encourage reflective practice and System 2 processes by instructing participants to proceed slowly through their reasoning18 or by giving participants the opportunity to review their diagnoses.19 These studies have found minimal or no impact on reducing the rate of diagnostic error. On the other hand, some studies have shown improved diagnostic accuracy when physicians are asked to explicitly state their differential diagnoses along with features that are consistent or inconsistent with each diagnosis.20 These results suggest that if reflective practice is to be effective, it must involve a thorough review of the differential diagnosis as opposed to simply taking additional time.Reducing Cognitive BurdenTools that reduce the cognitive burden placed on physicians may reduce the frequency of diagnostic errors. One suggestion has been to incorporate the use of checklists in the diagnostic process. These checklists would be matched to common presenting symptoms and include a list of possible diagnoses. One randomized controlled trial failed to show a statistically significant reduction in the diagnostic error rate with the use of checklists, except in a small subgroup of patients treated in the ED. 21 These findings challenge the results of two other studies that found checklists to be effective in improving scrutiny22 and diagnostic accuracy23 when interpreting electrocardiograms. More advanced forms of clinician decision support systems have also been studied.24 Software programs such as DXplain generate a list of potential diagnoses based on a patient’s chief complaint. In one study, when the software provided physicians a list of possible diagnoses before evaluating patients, diagnoses were 1.31 times more likely to be correct. 25 The use of diagnostic support tools may grow in the future as they are integrated into electronic medical record systems.Improving Knowledge and ExperienceA combination of experience, knowledge and feedback are integral in developing a clinician’s intuition to produce the best hypotheses. Experience without feedback can lead to overconfidence, which itself is a cognitive bias. The evidence supporting feedback is strong. Fridriksson et al showed a significant reduction in diagnostic error when referring doctors were provided feedback on the identification of subarachnoid hemorrhage.26 A systematic review of 118 randomized trials concluded that feedback was effective in improving professional practice.27 The specific characteristics of the best feedback were elusive. In general, however, feedback was thought to be most effective when it was explicit and delivered close to the time of decision making. ConclusionsIn our review, we explore clinical decision making through the lens of dual-process theory. However, multiple different dual-processing models are still being explored and fundamental questions are still under debate. For example, some experts believe that instead of focusing on de-biasing strategies, the key to improving intuitive (System 1) processes is simply to acquire more formal and experiential knowledge.19 Other unanswered questions include: the impact and magnitude of cognitive bias in actual clinical practice, which biases are most prevalent in each medical specialty and which strategies are the most effective in mitigating bias. Further study is also needed to assess the impact of novel educational methods, such as case-based and simulation-based learning, which are promising venues where trainees may identify and correct cognitive biases in a directly observed setting. References 1. Norman G. Research in clinical reasoning: past history and current trends. Med Educ 2005;39:418–27.2. Kahneman D. Thinking, fast and slow. Farrar, Straus and Giroux; 2011.3. Croskerry P. From mindless to mindful practice — cognitive bias and clinical decision making. N Engl J Med 2013;368:2445–8.4. Croskerry P. The importance of cognitive errors in diagnosis and strategies to minimize them. Academic Medicine 2003;78:775–80.5. Graber ML, Franklin N, Gordon R. Diagnostic error in internal medicine. Arch Intern Med 2005;165:1493–9.6. Parush A, Campbell C, Hunter A, et al. Situational awareness and patient safety - a short primer. Ottawa ON: The Royal College of Physicians and Surgeons of Canada; 2011.7. Pelaccia T, Tardif J, Triby E, Charlin B. An analysis of clinical reasoning through a recent and comprehensive approach: the dual-process theory. Med Educ Online 2011;16.8. Reyna VF. A theory of medical decision making and health: fuzzy trace theory. Med Decis 2008;28:850–65.9. Osman M. An evaluation of dual-process theories of reasoning. Psychonom Bull review 2004;11:988–1010.10. Dubeau CE, Voytovich AE, Rippey RM. Premature conclusions in the diagnosis of iron-deficiency anemia: cause and effect. Med Dec Mak 1986;6:169–73.11. Nickerson RS. Confirmation bias: A ubiquitous phenomenon in many guises. Rev Gen Psychol 1998;2:175.12. Mendel R, Traut-Mattausch E, Jonas E, et al. Confirmation bias: why psychiatrists stick to wrong preliminary diagnoses. Psychol Med 2011;41:2651–9.13. Pines JM. Profiles in patient safety: confirmation bias in emergency medicine. Acad Emerg Med 2006;13:90–4.14. Tschan F, Semmer NK, Gurtner A, et al. Explicit reasoning, confirmation bias, and illusory transactive memory: a simulation study of group medical decision making. Small Group Res 2009;40:271–300.15. Mamede S, van Gog T, van den Berge K, et al. Effect of availability bias and reflective reasoning on diagnostic accuracy among internal medicine residents. JAMA 2010;304:1198–203.16. Graber ML, Kissam S, Payne VL, et al. Cognitive interventions to reduce diagnostic error: a narrative review. BMJ Qual Safe 2012;21:535–57.17. Croskerry P, Singhal G, Mamede S. Cognitive debiasing 2: impediments to and strategies for change. BMJ Qual Saf 2013.18. Norman G, Sherbino J, Dore K, et al. The etiology of diagnostic errors: a controlled trial of system 1 versus system 2 reasoning. Acad Med 2014;89:277–84.19. Monteiro SD, Sherbino J, Patel A, Mazzetti I, Norman GR, Howey E. Reflecting on diagnostic errors: taking a second look is not enough. J Gen Intern Med 2015;30:1270–4.20. Bass A, Geddes C, Wright B, Coderre S, Rikers R, McLaughlin K. Experienced physicians benefit from analyzing initial diagnostic hypotheses. Can Med Educ J 2013;4:e7–e15.21. Ely JW, Graber MA. Checklists to prevent diagnostic errors: a pilot randomized controlled trial. Diagnosis 2015;2.22. Sibbald M, de Bruin ABH, Yu E, van Merrienboer JJG. Why verifying diagnostic decisions with a checklist can help: insights from eye tracking. Adv Health Sci Educ Theory Pract 2015;20:1053–60.23. Sibbald M, de Bruin ABH, van Merrienboer JJG. Checklists improve experts' diagnostic decisions. Med Educ 2013;47:301–8.24. Garg AX, Adhikari NKJ, McDonald H, et al. Effects of computerized clinical decision support systems on practitioner performance and patient outcomes: a systematic review. JAMA 2005;293:1223–38.25. Kostopoulou O, Rosen A, Round T, et al. Early diagnostic suggestions improve accuracy of GPs: a randomised controlled trial using computer-simulated patients. Br J Gen Pract 2015;65:e49–54.26. Fridriksson S, Hillman J, Landtblom AM, Boive J. Education of referring doctors about sudden onset headache in subarachnoid hemorrhage. A prospective study. Acta Neurol Scand 2001;103:238–42.27. Jamtvedt G, Young JM, Kristoffersen DT, O'Brien MA, Oxman AD. Does telling people what they have been doing change what they do? A systematic review of the effects of audit and feedback. Qual Saf Health Care 2006;15:433–6.

I love Darwin, I love it up here, I love the north, I love the swamp. It’s the energy; it’s unpredictable, totally unpredictable. Whether that’s because people are coming and going… It’s probably because of the changeability of the weather; I love the wet season, it’s a dynamic place. I am eventually planning to move down south for a while, I have to, I’ve got family commitments and so on and the thing that worries me most is that it’s all so predictable down there. So Darwin has an energy, it’s alive, I absolutely love it, I absolutely love it. The people that come up here come here because they read that energy I believe; it’s a dynamic place, a very exciting place. Enthusiasm drives all people to make decisions and act, often without thorough thought. It is an important aspect of human life and is needed for development and risk-taking. Much has been written about the key driving role played by enthusiasm in the creative industries in enabling them to thrive (Hesmondhalgh; Leadbeater and Miller). Indeed, much of the focus around enthusiasm and the creative industries has concerned itself with the degree to which exploitation of labour is made possible by the eagerness of creatives to ‘get a foot in the door’, or simply to do the work they love; this is most often discussed in terms of ‘precarious labour’ (Kucklich; Luckman; Neilson and Rossiter; Ross; Terranova). Precarious labour practices , as explained by Neilson and Rossiter, “generate new forms of subjectivity and connection, organised about networks of communication, cognition, and affect”. However there are also other ways in which enthusiasm can be apparent in the work of creative practitioners; for example, not only in relation to their work, but how this relates to, and is inspired by, the spaces and communities within which it is undertaken. As Drake recently argued, the relationship to locality is an important part of creative practice and can, in and of itself, be “a source of aesthetic inspiration” (Drake 512). This article will explore the relationship between enthusiasm, creative industries and place, using interview transcript data generated as part of the ARC funded Linkage project ‘Creative Tropical City: Mapping Darwin’s Creative Industries’. In keeping with the migration statistics which point to Darwin as a city with considerable population turn-over, many of the people who were interviewed discussed moving to Darwin and the reasons they have stayed. This poses important questions, for example: what has enthused people to move to Darwin to practice within their creative industries, and what has motivated them to stay?The Relationship between ‘Enthusiasm’ and ‘Motivation’ Enthusiasm, defined here as “the dynamic motivator that keeps one persistently working toward his goal” (Peale 4) can be manifested in a number of ways. It can enhance creative activities, enable a move, and it can be a motivating factor in creating change. As Kant explains of enthusiasm: “The idea of the good to which affection is superadded is enthusiasm. This state of mind appears to be sublime: so much so that there is a common saying that nothing great can be achieved without it” (90). For enthusiasm to take hold there must first be a passion from which leads to an excitement that appears to be ‘sublime’ (Kant 90). It could be argued that this leads to decisions being made that may be regrettable, however the question remains, what enthuses us to make decisions that will greatly impact our life? There are many decisions that require enthusiasm for a final answer to be produced. Excitement must be present and well established for an enthused decision to be made. Cultural enthusiasm can be produced through mass motivation. As we will see here, the people of Darwin drawn upon here demonstrate such enthusiasm in regards to their creative community, especially when this has involved moving to (distant) Darwin, and leaving family, friends and existing networks. It is arguable that enthusiasm cannot exist without motivation, while motivation can exist without enthusiasm (Maslow, Toward). Motivation drives us to begin and carry through certain acts. Enthusiasm allows us the excitement and passion to create a change but motivation is needed to carry it through. Motivation is another step in the process of decision making from enthusiasm. A person can be enthused to take action, but there needs to be motivation to follow through on the decision. Max Weber argues that there is a “rational understanding of motivation, which consists in placing the act in an intelligible and more inclusive context of meaning” (Weber, Henderson & Parsons, 95). There are rational motivational factors that enable a person to participate in an activity, such as payment or reward. Motivation can be found through both paid and unpaid work, as Weber discusses “elements of the motivation of economic activity under the conditions of a market economy: … the fact that they fun the risk of going entirely without provisions, both for themselves and for those personal dependents, such as children, wives, sometimes parents” (110). Within contemporary capitalist culture there is a requirement to work to be able to provide for oneself as well as family. These opportunities require employment and/or an income. However, as the literature on precarious labour in the creative industries all too readily attests to, volunteer and unpaid work too, require forms of motivation, such a love of one’s work or the possibility of making more lucrative opportunities arise. ‘Enthusiasm’ for Darwin as a Creative Place Enthusiasm can be achieved in many ways, however, in the case of the Darwin creative industry interviewees, what enthuses them to move to, or back to, Darwin? What is attracting them to stay? While leaving one’s home and/or established place of residence is always a big move, the choice to move to and stay in a small, extremely isolated city such as Darwin is almost always circumscribed by a strong emotional connection to the place. It is in this emotional relationship to place that a sense of the sublime can start to become evident, often expressed in terms of the city’s tropical savannah climate or unique remoteness from Australia, but proximity to Asia: It’s just a marvellous place, in terms of the natural environment, I am mesmerised by it and feel a real connection to it, because it is just so marvellous. The other positives are you can't beat the lifestyle, living in shorts and t-shirts and literally outside all the time. And the other thing I love about it is, in terms of the demography of the place, there really is no such thing as the best suburb, or the best street, it is incredible mix, so you can have million dollar mansions with a housing commission block of flats right next door, that you do have black and white and all the shades in between, living in the one street. My entire professional career, has been about promoting understanding and fostering tolerance and appreciation of other cultures. … The community here consider that Asian expanse just to our north as a connecting space.So there are a number of factors connecting creative people to Darwin. On top of the more basic, yet nonetheless motivated reasons for working, there is an enthusiasm evident in peoples’ productive-creative lives. It is a remote area that allows people the time and space to be able to practice their creative activities, including architecture, painting, dance and music as well as the time to think. There are a number of locations that the 61 people who have acknowledged having moved to Darwin from. Some were born in Darwin and moved away for education only to return to practice their creative activities. For example, one acknowledged bringing her skills back with her: Originally from here, I was born in Darwin, so – and I left here when I was 21, and went to live in London, and then I lived in New Zealand for a while. I lived in Sydney … as well, and then came back again. So, bringing those skills, obviously, with me and to try and set up something that you’d find interstate. Inspiration is a vital aspect of enthusiasm. Wordsworth speaks of inspiration in relation to the bible suggesting, “it has an ever-growing adaptation to the future, as the future rises into the present” (420). This idea of inspiration can be carried through to the people of Darwin, as they are inspired to complete works and to stay in Darwin their future ideas meld with the present and are acted out. As one interviewee discusses Darwin is full of inspiration: “The whole of Darwin inspires us because of what Darwin is, because of the natural environment, because of those special characteristics that Darwin has as a city, its different to the other cities in Australia.” In the context of what motivated people to come to Darwin, for some the enthusiasm lies in the people and the situations that Darwin can offer: “One of the reasons I moved here and what I’ve discovered is …It’s less competitive …[there is a] welcoming nature [to] the arts community.” While there may be momentary excitement for an idea following an initial bout of enthusiasm, motivation is required for the idea to progress and manifest into a long-term situation. For a significant proportion of the Darwin-based creative practitioners interviewed as part of this study, this enthusiasm is sustained by the nature and environment of the city which, they believe, encourages and motivates them to stay. As one interviewee suggests: “Absolutely, I think everyone, you'd be hard-pressed to find anyone that doesn’t appreciate the beauty of living here.” There are numerous factors about Darwin that have enthused people to relocate to the area. The main themes discussed were nature, the weather and family and the opportunities that were available. Interestingly, the isolation provided by Darwin is a factor that enthused people to move to the city: I mean that’s why I came up here, not to Darwin initially; I went out bush for 5 years because isolation, I love it. Darwin’s not truly isolated but it is a long way away from the supposed centres. Darwin is in fact a centre itself but it’s just far away from the other centres. Such enthusing factors are prominent throughout the interviews. Darwin gives the creative community an opportunity to slow down and have the time and space to think, which is not offered by cities such as Melbourne or Sydney. Although some did not specify, six people moved to Darwin from Melbourne, five from Sydney and five from Adelaide. There are opportunities that are offered by Darwin that cannot be matched by such large and tightly packed cities. As will be discussed more shortly, such concepts relate to Abraham Maslow’s theories of Self-Actualisation: the need for privacy, “Independence of culture and environment; resisting enculturation” can lead to people moving to areas such as Darwin that allow for isolation and time (Monte 658). These elements allows the realisation of an individual which relies “on own judgement; trusts in self; resists pressure from others and social norms; able to ‘weather hard knocks’ with calm; resists identification with cultural stereotypes; has autonomous values carefully considered” (Monte 658). By fulfilling their ego, people are able to reach a stage of enthusiastic sublime, where enthusiasm is “an affect, the imagination unbridled” (136). Darwin has the space to allow such functions as resisting the social norms; this is not a function that towns such as Sydney or Melbourne are able to provide. The motivation to slow down and reinspire and re-energise as another interviewee discusses is an important factor that enthused some to move to Darwin: “Darwin produces the most amazing artists, you know, like it's such a wonderful place where you can feel inspired all the time. It's got that lovely country town feeling, but still being big enough to be a city, which makes it really unique.” It is important for Darwin to create enthusiasm such as this regarding the creative roles and opportunities available as for Darwin “creativity is the driving force of economic growth” (Florida xv). This is not the case for all economic growth, however, Darwin requires these creative people. As is explained by Luckman et al.: These sorts of aims (cultural flow, artistic influence, networking) appear to us more fitting reasons for seeking greater numbers of creative class professionals from southern states as ‘desirable residents’, rather than the usual emphasis on their bringing with them entrepreneurial skills, investment and cultural capital (especially given the need to find ways of accepting racial alterity). (6) Darwin’s economy depends on tourism and the creative community. Darwin’s strengths arise from the isolation and the seclusion that is available to artists of all kinds, as is discussed by one person: “I think that its strength lies in its isolation from the rest of the country and the fact that it’s a tropical city.” In regards to the weather of Darwin as an integral part of the charm the interviewee continues, “I think that’s a great selling point in that during the bleak weeks of winter down south you can actually come to a city and be part of an outdoor festival, which you’re not going to freeze, and it actually has a different feel than anywhere else in the country.” Many people have found the extreme weather conditions to be have a positive impact on their work. While some move away for the wet season others use it as time to be the most creative as it gives them time to think. For some it was the weather that enthused them to move to Darwin over any other Australian state, “I just came up for the warm weather really.” For others the wet season allows them time to be creative within different areas: “I like the wet season, I’d prefer it to the dry. It’s too dry for me at this time of the year, I like the rain and I like the humidity and all of that, that’s why I’m here.” Enthusiasm, Creativity and Maslow’s Hierarchy of Needs As in the case of one interviewee there were motivating factors that caused them to move back to Darwin, but there was not necessarily any enthusiasm involved. “I came back to Darwin actually to look after my grandmother and I’ve been back in Darwin and that’s when I’ve just been in the process of just continuing on with my choreography.” It is not to suggest that there is not enthusiasm involved in the process; however the motivating factors far outweigh the enthusing factors. Not all of the participants who have moved to Darwin have remained enthused about the decision and have very little motivation to stay. As one participant discussed, “I’m here because I’ve got my business here. That’s the only reason now.” Although some have lost their passion for the city, there is a wealth of enthusiasm amongst the majority of interviewees in regards to moving to Darwin to practice their creativity. Maslow establishes motivation as a vital factor in the human condition. There is a certain hierarchy of needs that have to be met for a person to survive and to thrive. “Freedom, love, community feeling, respect, philosophy, may all be waved aside as fripperies that are useless, since they fail to fill the stomach. Such a man may fairly be said to live by bread alone” (Maslow 37). There are many needs that have to be met for a person to be happy and satisfied beyond instinctual gratifications, such as sustenance, habitation and sex. Motivation allows a person to strive for certain needs and standards. For the people of Darwin, creativity, space, isolation, weather and community can be motivating factors to stay within the city. Once one need has been met, others will emerge and motivations will shift. As Maslow explains: The physiological needs, along with their partial goals, when chronically gratified cease to exist as active determinants or organizers of behaviour. They now exist only in a potential fashion in the sense that they may emerge again to dominate the organism if they are thwarted. But a want that is satisfied is no longer a want. (38) Although somewhat simplistic, Maslow’s hierachical schema is useful to deploy amongst the complexity of contradictory gratifications of interviewees. There needs to be both long term and short enthusiasm for a new want and motivation to achieve goals. Motivation needs to be upheld in order for enthusiasm for the practices to be maintained. Within the creative industries there is a constant need for goals to be met, such as sales or delivering quality goals, and there has to be enthusiasm to do so, especially in the face of unsure or no financial return on work or it will not be achieved. Motivations in life will shift and change with the change of lifestyle, job or situation. Darwin needs to be able to motivate the Creative Industry in order to sustain enthusiasm in the long term. There are certain standards and hierarchies that are present in every person’s life. Once the basic needs of life have been met, motivation can lead to self-actualisation. By moving to Darwin, Creative Industry people are allowing for opportunities for the fulfilment of self-actualisation. As Maslow argues: So far as motivational status is concerned, healthy people have sufficiently gratified their basic needs for safety, belongingness, love, respect and self-esteem so that they are motivated primarily by trends to self-actualisation (defined as ongoing actualisation of potentials, capacities and talents, as fulfilment of mission (or call, fate, destiny, vocation), as a fuller knowledge of, and acceptance of, the person’s own intrinsic nature, as an unceasing trend toward unity, integration or synergy within the person. (25) The people who are practicing within the industry have goals and potentials that need to be met and which motivate them into action; for many of the interviewees in this project, a key action undertaken to enable this was moving to or staying in Darwin. As such Darwin is able to absorb the surplus labour of other cities and use it to enhance local industry on its own terms. Here there is an enthusiasm and passion for creative work that operates on a different level to that present in larger, more built-up cities, which cannot be matched by them. Creative work is inherently motivating through the self-actualisation it allows the creative practitioner. While Darwin allows for these aspects of the creative industries, its relatively small size, and slower pace than bigger cities works to enthuse a unique local creative community, which on a national level punches above its weight. AcknowledgementsThis research was supported under the Australian Research Council’s Linkage Project funding scheme (project number LP0667445). ReferencesDrake, Graham. “‘This Place Gives Me Space’: Place and Creativity in the Creative Industries.” Geoforum 34.4 (2003): 511-524.Florida, Richard. The Rise of the Creative Class. USA: Pluto Press, 2003.Hesmondhalgh, David. Cultural Industries. London: Sage, 2002.Leadbeater, Charles, and Paul Miller. The Pro-Am Revolution: How Enthusiasts Are Changing Our Economy and Society. London: Demos, 2004.Kant, Immanuel, Werner S. Pluhar, and Mary J. Gregor. Critique of Judgement, USA: Hackett Publishing, 1987.Kucklich, Julian. "Precarious Playbour: Modders and the Digital Games Industry." Fibreculture Journal 5 (Sep. 2005). ‹http://journal.fibreculture.org/issue5›.Luckman, Susan. “‘Unalienated Labour’ and Creative Industries: Situating Micro-Entrepreneurial Dance Music Subcultures in the New Economy.” Sonic Synergies: Music, Identity, Technology and Community. Eds. Gerry Bloustien, Margaret Peters, and Susan Luckman. Hampshire: Ashgate, 2008. 185-194.———, Chris Gibson, Tess Lea, and Chris Brennan-Horley. “Darwin as ‘Creative Tropical City’: Just How Transferable Is Creative City Thinking?” University of South Australia. ‹http://www.unisa.edu.au/soac2007/program/papers/0045.PDF›.Maslow, Abraham. Motivation and Personality. USA: Harper and Row Publishers, 1970.———. Self-Actualization. Big Sur Recordings, 1971.———. Toward a Psychology of Being. USA: Van Nostrand Reinhold, 1968.Moran, Dermot. Introduction to Phenemology. London: Routledge, 2000.Neilson, Brett, and Ned Rossiter. "From Precarity to Precariousness and Back Again: Labour, Life and Unstable Networks." Fibreculture Journal 5 (Sep. 2005). ‹http://journal.fibreculture.org/issue5›.Peale, Norman Vincent. Enthusiasm Makes the Difference. USA: Simon and Schuster, 2003.Ross, Andrew. "The Mental Labour Problem." Social Text 18.2 (2000): 1-31.Terranova, Tiziana. "Free Labour: Producing Culture for the Digital Economy." Social Text 18.2 (2000): 33-58.Walker, Ralph C.S. The Arguments and Philosophies of Kant. London: Routledge and Kegan Paul, 1978.Weber, Max, Alexander Morell Henderson, and Talcott Parsons. The Theory of Social and Economic Organization. USA: Free Press, 1997.———, Guenther Roth, and Claus Wittich. Economy and Society, USA: U of California P, 1978.Wordsworth, Christopher. Lectures on the Apocalypse; Critical, Expository, and Practical Hulsean Lects., 1848. Oxford University, 1852.

In Victorian times, when female travel narratives were read as excursions rather than expeditions, it was common for women authors to preface their travels with an apology. “What this book wants,” begins Mary Kingsley’s Travels in West Africa, “is not a simple preface but an apology, and a very brilliant and convincing one at that” (4). This tendency of the woman writer to depreciate her travel with an acknowledgment of its presumptuousness crafted her apology essentially as an admission of guilt. “Where I have offered my opinions,” Isabella Bird writes in The Englishwoman in America, “I have done so with extreme diffidence, giving impressions rather than conclusions” (2). While Elizabeth Howells has since argued the apologetic preface was in fact an opposing strategy that allowed women writers to assert their authority by averting it, it is certainly telling of the time and genre that a female writer could only defend her work by first excusing it. The personal apology may have emerged as the natural response to social restrictions but it has not been without consequence for female travel. The female position, often constructed as communal, is still problematised in contemporary travel texts. While there has been a traceable shift from apology to affirmation since the first women travellers abandoned their embroidery, it seems some sense of lingering culpability still remains. In many ways, the modern female traveller, like the early lady traveller, is still a displaced woman. She still sets out cautiously, guide book in hand. Often she writes, like the female confessant, in an attempt to recover what Virginia Woolf calls “the lives of the obscure”: those found locked in old diaries, stuffed away in old drawers or simply unrecorded (44). Often she speaks insistently of the abstract things which Kingsley, ironically, wrote so easily and extensively about. She is, however, even when writing from within the confines of her own home, still writing from abroad. Women’s solitary or “unescorted” travel, even in contemporary times, is considered less common in the Western world, with recurrent travel warnings constantly targeted at female travellers. Travelling women are always made aware of the limits of their body and its vulnerabilities. Mary Morris comments on “the fear of rape, for example, whether crossing the Sahara or just crossing a city street at night” (xvii). While a certain degree of danger always exists in travel for men and women alike and while it is inevitable that some of those risks are gender-specific, travel is frequently viewed as far more hazardous for women. Guide books, travel magazines and online advice columns targeted especially at female readers are cramped with words of concern and caution for women travellers. Often, the implicit message that women are too weak and vulnerable to travel is packaged neatly into “a cache of valuable advice” with shocking anecdotes and officious chapters such as “Dealing with Officials”, “Choosing Companions” or “If You Become a Victim” (Swan and Laufer vii). As these warnings are usually levelled at white, middle to upper class women who have the freedom and financing to travel, the question arises as to what is really at risk when women take to the road. It seems the usual dialogue between issues of mobility and issues of safety can be read more complexly as confusions between questions of mobility and morality. As Kristi Siegel explains, “among the various subtexts embedded in these travel warnings is the long-held fear of ‘women on the loose’” (4). According to Karen Lawrence, travel has always entailed a “risky and rewardingly excessive” terrain for women because of the historical link between wandering and promiscuity (240). Paul Hyland has even suggested that the nature of travel itself is “gloriously” promiscuous: “the shifting destination, arrival again and again, the unknown possessed, the quest for an illusory home” (211). This construction of female travel as a desire to wander connotes straying behaviours that are often cast in sexual terms. The identification of these traits in early criminological research, such as 19th century studies of cacogenic families, is often linked to travel in a broad sense. According to Nicolas Hahn’s study, Too Dumb to Know Better, contributors to the image of the “bad” woman frequently cite three traits as characteristic. “First, they have pictured her as irresolute and all too easily lead. Second, they have usually shown her to be promiscuous and a good deal more lascivious than her virtuous sister. Third, they have often emphasised the bad woman’s responsibility for not only her own sins, but those of her mate and descendents as well” (3). Like Eve, who wanders around the edge of the garden, the promiscuous woman has long been said to have a wandering disposition. Interestingly, however, both male and female travel writers have at different times and for dissimilar reasons assumed hermaphroditic identities while travelling. The female traveller, for example, may assume the figure of “the observer” or “the reporter with historical and political awareness”, while the male traveller may feminise his behaviours to confront inevitabilities of confinement and mortality (Fortunati, Monticelli and Ascari 11). Female travellers such as Alexandra David-Neel and Isabelle Eberhardt who ventured out of the home and cross-dressed for safety or success, deliberately and fully appropriated traditional roles of the male sex. Often, this attempt by female wanderers to fulfil their own intentions in cognito evaded their dismissal as wild and unruly women and asserted their power over those duped by their disguise. Those women who did travel openly into the world were often accused of flaunting the gendered norms of female decorum with their “so-called unnatural and inappropriate behaviour” (Siegel 3). The continued harnessing of this cultural taboo by popular media continues to shape contemporary patterns of female travel. In fact, as a result of perceived connections between wandering and danger, the narrative of the woman traveller often emerges as a self-conscious fiction where “the persona who emerges on the page is as much a character as a woman in a novel” (Bassnett 234). This process of self-fictionalising converts the travel writing into a graph of subliminal fears and desires. In Tracks, for example, which is Robyn Davidson’s account of her solitary journey by camel across the Australian desert, Davidson shares with her readers the single, unvarying warning she received from the locals while preparing for her expedition. That was, if she ventured into the desert alone without a guide or male accompaniment, she would be attacked and raped by an Aboriginal man. In her opening pages, Davidson recounts a conversation in the local pub when one of the “kinder regulars” warns her: “You ought to be more careful, girl, you know you’ve been nominated by some of these blokes as the next town rape case” (19). “I felt really frightened for the first time,” Davidson confesses (20). Perhaps no tale better depicts this gendered troubling than the fairytale of Little Red Riding Hood. In the earliest versions of the story, Little Red outwits the Wolf with her own cunning and escapes without harm. By the time the first printed version emerges, however, the story has dramatically changed. Little Red now falls for the guise of the Wolf, and tricked by her captor, is eaten without rescue or escape. Charles Perrault, who is credited with the original publication, explains the moral at the end of the tale, leaving no doubt to its intended meaning. “From this story one learns that children, especially young lasses, pretty, courteous and well-bred, do very wrong to listen to strangers, and it is not an unheard thing if the Wolf is thereby provided with his dinner” (77). Interestingly, in the Grimm Brothers’ version which emerges two centuries later an explicit warning now appears in the tale, in the shape of the mother’s instruction to “walk nicely and quietly, and not run off the path” (144). This new inclusion sanitises the tale and highlights the slippages between issues of mobility and morality. Where Little Red once set out with no instruction not to wander, she is now told plainly to stay on the path; not for her own safety but for implied matters of virtue. If Little Red strays while travelling alone she risks losing her virginity and, of course, her virtue (Siegel 55). Essentially, this is what is at stake when Little Red wanders; not that she will get lost in the woods and be unable to find her way, but that in straying from the path and purposefully disobeying her mother, she will no longer be “a dear little girl” (Grimm 144). In the Grimms’ version, Red Riding Hood herself critically reflects on her trespassing from the safe space of the village to the dangerous world of the forest and makes a concluding statement that demonstrates she has learnt her lesson. “As long as I live, I will never by myself leave the path, to run into the wood, when my mother has forbidden me to do so” (149). Red’s message to her female readers is representative of the social world’s message to its women travellers. “We are easily distracted and disobedient, we are not safe alone in the woods (travelling off the beaten path); we are fairly stupid; we get ourselves into trouble; and we need to be rescued by a man” (Siegel 56). As Siegel explains, even Angela Carter’s Red Riding Hood, who bursts out laughing when the Wolf says “all the better to eat you with” for “she knew she was nobody’s meat” (219), still shocks readers when she uses her virginity to take power over the voracious Wolf. In Carter’s world “children do not stay young for long,” and Little Red, who has her knife and is “afraid of nothing”, is certainly no exception (215). Yet in the end, when Red seduces the Wolf and falls asleep between his paws, there is still a sense this is a twist ending. As Siegel explains, “even given the background Carter provides in the story’s beginning, the scene startles. We knew the girl was strong, independent, and armed. However, the pattern of woman-alone-travelling-alone-helpless-alone-victim is so embedded in our consciousness we are caught off guard” (57). In Roald Dahl’s revolting rhyme, Little Red is also awarded agency, not through sexual prerogative, but through the enactment of traits often considered synonymous with male bravado: quick thinking, wit and cunning. After the wolf devours Grandmamma, Red pulls a pistol from her underpants and shoots him dead. “The small girl smiles. One eyelid flickers. She whips a pistol from her knickers. She aims it at the creature’s head and bang bang bang, she shoots him dead” (lines 48—51). In the weeks that follow Red’s triumph she even takes a trophy, substituting her red cloak for a “furry wolfskin coat” (line 57). While Dahl subverts female stereotypes through Red’s decisive action and immediacy, there is still a sense, perhaps heightened by the rhyming couplets, that we are not to take the shooting seriously. Instead, Red’s girrrl-power is an imagined celebration; it is something comical to be mused over, but its shock value lies in its impossibility; it is not at all believable. While the sexual overtones of the tale have become more explicit in contemporary film adaptations such as David Slade’s Hard Candy and Catherine Hardwicke’s Red Riding Hood, the question that arises is what is really at threat, or more specifically who is threatened, when women travel off the well-ordered path of duty. As this problematic continues to surface in discussions of the genre, other more nuanced readings have also distorted the purpose and practice of women’s travel. Some psychoanalytical theorists, for example, have adopted Freud’s notion of travel as an escape from the family, particularly the father figure. In his essay A Disturbance of Memory on the Acropolis, Freud explains how his own longing to travel was “a wish to escape from that pressure, like the force which drives so many adolescent children to run away from home” (237). “When one first catches sight of the sea,” Freud writes, “one feels oneself like a hero who has performed deeds of improbable greatness” (237). The inherent gender trouble with such a reading is the suggestion women only move in search of a quixotic male figure, “fleeing from their real or imaginary powerful fathers and searching for an idealised and imaginary ‘loving father’ instead” (Berger 55). This kind of thinking reduces the identities of modern women to fragile, unfinished selves, whose investment in travel is always linked to recovering or resisting a male self. Such readings neglect the unique history of women’s travel writing as they dismiss differences in the male and female practice and forget that “travel itself is a thoroughly gendered category” (Holland and Huggan 111). Freud’s experience of travel, for example, his description of feeling like a “hero” who has achieved “improbable greatness” is problematised by the female context, since the possibility arises that women may travel with different e/motions and, indeed, motives to their male counterparts. For example, often when a female character does leave home it is to escape an unhappy marriage, recover from a broken heart or search for new love. Elizabeth Gilbert’s best selling travelogue, Eat, Pray, Love (which spent 57 weeks at the number one spot of the New York Times), found its success on the premise of a once happily married woman who, reeling from a contentious divorce, takes off around the world “in search of everything” (1). Since its debut, the novel has been accused of being self-absorbed and sexist, and even branded by the New York Post as “narcissistic New Age reading, curated by Winfrey” (Callahan par 13). Perhaps most interesting for discussions of travel morality, however, is Bitch magazine’s recent article Eat, Pray, Spend, which suggests that the positioning of the memoir as “an Everywoman’s guide to whole, empowered living” typifies a new literature of privilege that excludes “all but the most fortunate among us from participating” (Sanders and Barnes-Brown par 7). Without seeking to limit the novel with separatist generalisations, the freedoms of Elizabeth Gilbert (a wealthy, white American novelist) to leave home and to write about her travels afterwards have not always been the freedoms of all women. As a result of this problematic, many contemporary women mark out alternative patterns of movement when travelling, often moving deliberately in a variety of directions and at varying paces, in an attempt to resist their placelessness in the travel genre and in the mappable world. As Heidi Slettedahl Macpherson, speaking of Housekeeping’s Ruthie and Sylvie, explains, “they do not travel ever westward in search of some frontier space, nor do they travel across great spaces. Rather, they circle, they drift, they wander” (199). As a result of this double displacement, women have to work twice as hard to be considered credible travellers, particularly since travel is traditionally a male discursive practice. In this tradition, the male is often constructed as the heroic explorer while the female is mapped as a place on his itinerary. She is a point of conquest, a land to be penetrated, a site to be mapped and plotted, but rarely a travelling equal. Annette Kolodny considers this metaphor of “land-as-woman” (67) in her seminal work, The Lay of the Land, in which she discusses “men’s impulse to alter, penetrate and conquer” unfamiliar space (87). Finally, it often emerges that even when female travel focuses specifically on an individual or collective female experience, it is still read in opposition to the long tradition of travelling men. In their introduction to Amazonian, Dea Birkett and Sara Wheeler maintain the primary difference between male and female travel writers is that “the male species” has not become extinct (vii). The pair, who have theorised widely on New Travel Writing, identify some of the myths and misconceptions of the female genre, often citing their own encounters with androcentrism in the industry. “We have found that even when people are confronted by a real, live woman travel writer, they still get us wrong. In the time allowed for questions after a lecture, we are regularly asked, ‘Was that before you sailed around the world or after?’ even though neither of us has ever done any such thing” (xvii). The obvious bias in such a comment is an archaic view of what qualifies as “good” travel and a preservation of the stereotypes surrounding women’s intentions in leaving home. As Birkett and Wheeler explain, “the inference here is that to qualify as travel writers women must achieve astonishing and record-breaking feats. Either that, or we’re trying to get our hands down some man’s trousers. One of us was once asked by the president of a distinguished geographical institution, ‘What made you go to Chile? Was it a guy?’” (xviii). In light of such comments, there remain traceable difficulties for contemporary female travel. As travel itself is inherently gendered, its practice has often been “defined by men according to the dictates of their experience” (Holland and Huggan 11). As a result, its discourse has traditionally reinforced male prerogatives to wander and female obligations to wait. Even the travel trade itself, an industry that often makes its profits out of preying on fear, continues to shape the way women move through the world. While the female traveller then may no longer preface her work with an explicit apology, there are still signs she is carrying some historical baggage. It is from this site of trouble that new patterns of female travel will continue to emerge, distinguishably and defiantly, towards a much more colourful vista of general misrule. References Bassnett, Susan. “Travel Writing and Gender.” The Cambridge Companion to Travel Writing, eds. Peter Hulme and Tim Youngs, Cambridge: Cambridge UP, 2002. 225-40. Berger, Arthur Asa. Deconstructing Travel: Cultural Perspectives on Tourism. Walnut Creek: AltaMira Press, 2004. Bird, Isabella. The Englishwoman in America. London: John Murray, 1856. Birkett, Dea, and Sara Wheeler, eds. Amazonian: The Penguin Book of New Women’s Travel Writing. London: Penguin, 1998. Callahan, Maureen. “Eat, Pray, Loathe: Latest Self-Help Bestseller Proves Faith is Blind.” New York Post 23 Dec. 2007. Carter, Angela. “The Company of Wolves.” Burning Your Boats: The Collected Short Stories. London: Vintage, 1995. 212-20. Dahl, Roald. Revolting Rhymes. London: Puffin Books, 1982. Davidson, Robyn. Tracks. London: Jonathan Cape, 1980. Fortunati, Vita, Rita Monticelli, and Maurizio Ascari, eds. Travel Writing and the Female Imaginary. Bologna: Patron Editore, 2001. Freud, Sigmund. “A Disturbance of Memory on the Acropolis.” The Standard Edition of the Complete Psychological Works of Sigmund Freud, vol. XXII. New Introductory Lectures on Psycho-Analysis and Other Works, 1936. 237-48. Gilbert, Elizabeth. Eat, Pray, Love: One Woman’s Search for Everything Across Italy, India and Indonesia. New Jersey: Penguin, 2007. Grimm, Jacob, and Wilhelm Grimm. “Little Red Riding Hood.” Grimms’ Fairy Tales, London: Jonathan Cape, 1962. 144-9. Hahn, Nicolas. “Too Dumb to Know Better: Cacogenic Family Studies and the Criminology of Women.” Criminology 18.1 (1980): 3-25. Hard Candy. Dir. David Slade. Lionsgate. 2005. Holland, Patrick, and Graham Huggan. Tourists with Typewriters: Critical Reflections on Contemporary Travel Writing. Ann Arbor: U of Michigan P, 2003. Howells, Elizabeth. “Apologizing for Authority: The Rhetoric of the Prefaces of Eliza Cook, Isabelle Bird, and Hannah More.” Professing Rhetoric: Selected Papers from the 2000 Rhetoric Society of America Conference, eds. F.J. Antczak, C. Coggins, and G.D. Klinger. London: Lawrence Erlbaum Associates, 2002. 131-7. Hyland, Paul. The Black Heart: A Voyage into Central Africa. New York: Paragon House, 1988. Kingsley, Mary. Travels in West Africa. Middlesex: The Echo Library, 2008. Kolodny, Annette. The Lay of the Land: Metaphor as Experience and History in American Life and Letters. USA: U of North Carolina P, 1975. Lawrence, Karen. Penelope Voyages: Women and Travel in the British Literary Tradition. Ithaca: Cornell UP, 1994. Morris, Mary. Maiden Voyages: Writings of Women Travellers. New York: Vintage Books, 1993. Perrault, Charles. Perrault’s Complete Fairytales. Trans. A.E. Johnson and others. London: Constable & Company, 1961. Red Riding Hood. Dir. Catherine Hardwicke. Warner Bros. 2011. Sanders, Joshunda, and Diana Barnes-Brown. “Eat, Pray, Spend: Priv-Lit and the New, Enlightened American Dream” Bitch Magazine 47 (2010). 10 May, 2011 < http://bitchmagazine.org/article/eat-pray-spend >. Siegel, Kristi. Ed. Gender, Genre, and Identity in Women’s Travel Writing. New York: Peter Lang, 2004. Slettedahl Macpherson, Heidi. “Women’s Travel Writing and the Politics of Location: Somewhere In-Between.” Gender, Genre, and Identity in Women’s Travel Writing, ed. Kristi Siegel. New York: Peter Lang, 2004. 194-207. Swan, Sheila, and Peter Laufer. Safety and Security for Women who Travel. 2nd ed. San Francisco: Travelers’ Tales, 2004. Woolf, Virginia. Women and Writing. London: The Women’s Press, 1979.