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Search Results: 1 - 10 of 119257 matches for " T. Eoin West "
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Fitting a square peg into a round hole: are the current Surviving Sepsis Campaign guidelines feasible for Africa?
Shevin T Jacob, T Eoin West, Patrick Banura
Critical Care , 2011, DOI: 10.1186/cc9981
Abstract: In their article in this issue of Critical Care, Baelani and colleagues [1] attempt to determine whether or not Surviving Sepsis Campaign (SSC) guidelines are implementable in African low- and middle-income countries (LMICs), where hospitals often lack the resources necessary for managing critically ill patients. When the SSC was introduced at the 2002 European Society of Intensive Care Medicine meeting in Barcelona, its main objective was to address the high worldwide mortality from sepsis by compiling a set of guidelines to standardize the management of this condition [2]. While adherence to SSC guidelines has since been associated with improved outcomes in high-income countries (HICs), where adequate resources are readily available [3], the authors highlight the fact that evaluation of the SSC guidelines' feasibility has never been conducted in LMICs, despite a high burden of infection and, consequently, sepsis [4]. Therefore, the authors conducted a survey of anesthesia providers attending the 2009 All Africa Anesthesia Congress, which compared the availability of resources necessary for implementation of SSC guidelines between HICs and African LMICs. The authors describe 307 attendants' responses from 185 hospitals in 24 African countries - low- (LIC) or middle-(MIC) income countries - and 14 HICs.Not surprisingly, the authors report a stark contrast in resources available for sepsis management between African countries and HICs and, to a lesser extent, between LICs and MICs within Africa. These differences occur with respect to the drugs, equipment, and disposable material required to implement SSC guidelines and correspond with an alarmingly low percentage of African hospitals (1.4%) equipped to implement the entirety of SSC guidelines when compared with hospitals in HICs (81.0%). More promising, however, is that the African hospitals could implement 67% of SSC guidelines and 75% of grade 1 recommendations.In reality, this gap in resources is likely to be muc
Strategies to Reduce Mortality from Bacterial Sepsis in Adults in Developing Countries
Allen C Cheng,T. Eoin West,Direk Limmathurotsakul,Sharon J Peacock
PLOS Medicine , 2008, DOI: 10.1371/journal.pmed.0050175
Activation of Toll-like receptors by Burkholderia pseudomallei
T Eoin West, Robert K Ernst, Malinka J Jansson-Hutson, Shawn J Skerrett
BMC Immunology , 2008, DOI: 10.1186/1471-2172-9-46
Abstract: In HEK293 cells transfected with murine or human TLRs, CD14, and MD-2, heat-killed B. pseudomallei activated TLR2 (in combination with TLR1 or TLR6) and TLR4. B. pseudomallei LPS and lipid A activated TLR4 and this TLR4-mediated signaling required MD-2. In TLR2-/- macrophages, stimulation with heat-killed B. pseudomallei augmented TNF-α and MIP-2 production whereas in TLR4-/- cells, TNF-α, MIP-2, and IL-10 production was reduced. Cytokine production by macrophages stimulated with B. pseudomallei LPS or lipid A was entirely dependent on TLR4 but was increased in the absence of TLR2. TLR adaptor molecule MyD88 strongly regulated TNF-α production in response to heat-killed B. pseudomallei.B. pseudomallei activates TLR2 and TLR4. In the presence of MD-2, B. pseudomallei LPS and lipid A are TLR4 ligands. Although the macrophage cytokine response to B. pseudomallei LPS or lipid A is completely dependent on TLR4, in TLR2-/- macrophages stimulated with B. pseudomallei, B. pseudomallei LPS or lipid A, cytokine production is augmented. Other MyD88-dependent signaling pathways may also be important in the host response to B. pseudomallei infection. These findings provide new insights into critical mechanisms of host defense in melioidosis.Melioidosis is an endemic and poorly understood infectious disease in much of the tropical world; it is particularly prevalent in east Asia and northern Australia. The disease accounts for 20% of community-acquired sepsis in parts of northeast Thailand. Despite antibiotic treatment, mortality rates approach 40% [1]. The causative organism, Burkholderia pseudomallei (Bp), is a Gram-negative environmental saprophyte. Aerosol or transcutaneous infection results in an extensive range of disease – from chronic, relapsing illness with abscess formation to fulminant pneumonia and septicemia [2]. The lung is the most commonly affected organ. Concern about the use of Bp as a bioweapon has led to its classification as a CDC Category B pathogen. While t
Feasibility of Modified Surviving Sepsis Campaign Guidelines in a Resource-Restricted Setting Based on a Cohort Study of Severe S. Aureus Sepsis
Weera Mahavanakul, Emma K. Nickerson, Pramot Srisomang, Prapit Teparrukkul, Pichet Lorvinitnun, Mingkwan Wongyingsinn, Wirongrong Chierakul, Maliwan Hongsuwan, T. Eoin West, Nicholas P. Day, Direk Limmathurotsakul, Sharon J. Peacock
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0029858
Abstract: Background The Surviving Sepsis Campaign (SSC) guidelines describe best practice for the management of severe sepsis and septic shock in developed countries, but most deaths from sepsis occur where healthcare is not sufficiently resourced to implement them. Our objective was to define the feasibility and basis for modified guidelines in a resource-restricted setting. Methods and Findings We undertook a detailed assessment of sepsis management in a prospective cohort of patients with severe sepsis caused by a single pathogen in a 1,100-bed hospital in lower-middle income Thailand. We compared their management with the SSC guidelines to identify care bundles based on existing capabilities or additional activities that could be undertaken at zero or low cost. We identified 72 patients with severe sepsis or septic shock associated with S. aureus bacteraemia, 38 (53%) of who died within 28 days. One third of patients were treated in intensive care units (ICUs). Numerous interventions described by the SSC guidelines fell within existing capabilities, but their implementation was highly variable. Care available to patients on general wards covered the fundamental principles of sepsis management, including non-invasive patient monitoring, antimicrobial administration and intravenous fluid resuscitation. We described two additive care bundles, one for general wards and the second for ICUs, that if consistently performed would be predicted to improve outcome from severe sepsis. Conclusion It is feasible to implement modified sepsis guidelines that are scaled to resource availability, and that could save lives prior to the publication of international guidelines for developing countries.
Common TLR1 Genetic Variation Is Not Associated with Death from Melioidosis, a Common Cause of Sepsis in Rural Thailand
Narisara Chantratita, Sarunporn Tandhavanant, Nicolle D. Myers, Wirongrong Chierakul, Vanaporn Wuthiekanun, Weera Mahavanakul, Direk Limmathurotsakul, Sharon J. Peacock, T. Eoin West
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0083285
Abstract: Melioidosis, infection caused by the Gram-negative bacterium Burkholderia pseudomallei, is a common cause of sepsis in northeast Thailand. In white North Americans, common functional genetic variation in TLR1 is associated with organ failure and death from sepsis. We hypothesized that TLR1 variants would be associated with outcomes in Thais with melioidosis. We collated the global frequencies of three TLR1 variants that are common in white North American populations: rs5743551 (-7202A/G), rs4833095 (742A/G), and rs5743618 (1804G/T). We noted a reversal of the minor allele from white North American subjects to Asian populations that was particularly pronounced for rs5743618. In the Utah residents of European ancestry, the frequency of the rs5743618 T allele was 17% whereas in Vietnamese subjects the frequency was >99%. We conducted a genetic association study in 427 patients with melioidosis to determine the association of TLR1 variation with organ failure or death. We genotyped rs5743551 and rs4833095. The variants were in high linkage disequilibrium but neither variant was associated with organ failure or in-hospital death. In 300 healthy Thai individuals we further tested the association of TLR1 variation with ex vivo blood responses to Pam3CSK4, a TLR1 agonist. Neither variant was robustly associated with blood cytokine responses induced by Pam3CSK4. We identified additional common variation in TLR1 by searching public databases and the published literature and screened three additional TLR1 variants for associations with Pam3CSK4-induced responses but found none. We conclude that the genetic architecture of TLR1 variation differs substantially in southeast Asians compared to other populations and common variation in TLR1 in Thais is not associated with outcome from melioidosis or with altered blood responses to Pam3CSK4. Our findings highlight the need for additional studies of TLR1 and other innate immune genetic modulators of the inflammatory host response and determinants of sepsis in southeast Asian populations.
Staphylococcus aureus Bacteraemia in a Tropical Setting: Patient Outcome and Impact of Antibiotic Resistance
Emma K. Nickerson, Maliwan Hongsuwan, Direk Limmathurotsakul, Vanaporn Wuthiekanun, Krupal R. Shah, Pramot Srisomang, Weera Mahavanakul, Therapon Wacharaprechasgul, Vance G. Fowler, T. Eoin West, Nitaya Teerawatanasuk, Harald Becher, Nicholas J. White, Wirongrong Chierakul, Nicholas P. Day, Sharon J. Peacock
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004308
Abstract: Background Most information on invasive Staphylococcus aureus infections comes from temperate countries. There are considerable knowledge gaps in epidemiology, treatment, drug resistance and outcome of invasive S. aureus infection in the tropics. Methods A prospective, observational study of S. aureus bacteraemia was conducted in a 1000-bed regional hospital in northeast Thailand over 1 year. Detailed clinical data were collected and final outcomes determined at 12 weeks, and correlated with antimicrobial susceptibility profiles of infecting isolates. Principal Findings Ninety-eight patients with S. aureus bacteraemia were recruited. The range of clinical manifestations was similar to that reported from temperate countries. The prevalence of endocarditis was 14%. The disease burden was highest at both extremes of age, whilst mortality increased with age. The all-cause mortality rate was 52%, with a mortality attributable to S. aureus of 44%. Methicillin-resistant S. aureus (MRSA) was responsible for 28% of infections, all of which were healthcare-associated. Mortality rates for MRSA and methicillin-susceptible S. aureus (MSSA) were 67% (18/27) and 46% (33/71), respectively (p = 0.11). MRSA isolates were multidrug resistant. Only vancomycin or fusidic acid would be suitable as empirical treatment options for suspected MRSA infection. Conclusions S. aureus is a significant pathogen in northeast Thailand, with comparable clinical manifestations and a similar endocarditis prevalence but higher mortality than industrialised countries. S. aureus bacteraemia is frequently associated with exposure to healthcare settings with MRSA causing a considerable burden of disease. Further studies are required to define setting-specific strategies to reduce mortality from S. aureus bacteraemia, prevent MRSA transmission, and to define the burden of S. aureus disease and emergence of drug resistance throughout the developing world.
Burkholderia Type VI Secretion Systems Have Distinct Roles in Eukaryotic and Bacterial Cell Interactions
Sandra Schwarz,T. Eoin West,Frédéric Boyer,Wen-Chi Chiang,Mike A. Carl,Rachel D. Hood,Laurence Rohmer,Tim Tolker-Nielsen,Shawn J. Skerrett,Joseph D. Mougous
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001068
Abstract: Bacteria that live in the environment have evolved pathways specialized to defend against eukaryotic organisms or other bacteria. In this manuscript, we systematically examined the role of the five type VI secretion systems (T6SSs) of Burkholderia thailandensis (B. thai) in eukaryotic and bacterial cell interactions. Consistent with phylogenetic analyses comparing the distribution of the B. thai T6SSs with well-characterized bacterial and eukaryotic cell-targeting T6SSs, we found that T6SS-5 plays a critical role in the virulence of the organism in a murine melioidosis model, while a strain lacking the other four T6SSs remained as virulent as the wild-type. The function of T6SS-5 appeared to be specialized to the host and not related to an in vivo growth defect, as ΔT6SS-5 was fully virulent in mice lacking MyD88. Next we probed the role of the five systems in interbacterial interactions. From a group of 31 diverse bacteria, we identified several organisms that competed less effectively against wild-type B. thai than a strain lacking T6SS-1 function. Inactivation of T6SS-1 renders B. thai greatly more susceptible to cell contact-induced stasis by Pseudomonas putida, Pseudomonas fluorescens and Serratia proteamaculans—leaving it 100- to 1000-fold less fit than the wild-type in competition experiments with these organisms. Flow cell biofilm assays showed that T6S-dependent interbacterial interactions are likely relevant in the environment. B. thai cells lacking T6SS-1 were rapidly displaced in mixed biofilms with P. putida, whereas wild-type cells persisted and overran the competitor. Our data show that T6SSs within a single organism can have distinct functions in eukaryotic versus bacterial cell interactions. These systems are likely to be a decisive factor in the survival of bacterial cells of one species in intimate association with those of another, such as in polymicrobial communities present both in the environment and in many infections.
Survey of Innate Immune Responses to Burkholderia pseudomallei in Human Blood Identifies a Central Role for Lipopolysaccharide
Narisara Chantratita, Sarunporn Tandhavanant, Nicolle D. Myers, Sudeshna Seal, Arkhom Arayawichanont, Aroonsri Kliangsa-ad, Lauren E. Hittle, Robert K. Ernst, Mary J. Emond, Mark M. Wurfel, Nicholas P. J. Day, Sharon J. Peacock, T. Eoin West
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081617
Abstract: B. pseudomallei is a gram-negative bacterium that causes the tropical infection melioidosis. In northeast Thailand, mortality from melioidosis approaches 40%. As exemplified by the lipopolysaccharide-Toll-like receptor 4 interaction, innate immune responses to invading bacteria are precipitated by activation of host pathogen recognition receptors by pathogen associated molecular patterns. Human melioidosis is characterized by up-regulation of pathogen recognition receptors and pro-inflammatory cytokine release. In contrast to many gram-negative pathogens, however, the lipopolysaccharide of B. pseudomallei is considered only weakly inflammatory. We conducted a study in 300 healthy Thai subjects to investigate the ex vivo human blood response to various bacterial pathogen associated molecular patterns, including lipopolysaccharide from several bacteria, and to two heat-killed B. pseudomallei isolates. We measured cytokine levels after stimulation of fresh whole blood with a panel of stimuli. We found that age, sex, and white blood cell count modulate the innate immune response to B. pseudomallei. We further observed that, in comparison to other stimuli, the innate immune response to B. pseudomallei is most highly correlated with the response to lipopolysaccharide. The magnitude of cytokine responses induced by B. pseudomallei lipopolysaccharide was significantly greater than those induced by lipopolysaccharide from Escherichia coli and comparable to many responses induced by lipopolysaccharide from Salmonella minnesota despite lower amounts of lipid A in the B. pseudomallei lipopolysaccharide preparation. In human monocytes stimulated with B. pseudomallei, addition of polymyxin B or a TLR4/MD-2 neutralizing antibody inhibited the majority of TNF-α production. Challenging existing views, our data indicate that the innate immune response to B. pseudomallei in human blood is largely driven by lipopolysaccharide, and that the response to B. pseudomallei lipopolysaccharide in blood is greater than the response to other lipopolysaccharide expressing isolates. Our findings suggest that B. pseudomallei lipopolysaccharide may play a central role in stimulating the host response in melioidosis.
NLRC4 and TLR5 Each Contribute to Host Defense in Respiratory Melioidosis
T. Eoin West ,Nicolle D. Myers,Narisara Chantratita,Wirongrong Chierakul,Direk Limmathurotsakul,Vanaporn Wuthiekanun,Edward A. Miao,Adeline M. Hajjar,Sharon J. Peacock,H. Denny Liggitt,Shawn J. Skerrett
PLOS Neglected Tropical Diseases , 2014, DOI: 10.1371/journal.pntd.0003178
Abstract: Burkholderia pseudomallei causes the tropical infection melioidosis. Pneumonia is a common manifestation of melioidosis and is associated with high mortality. Understanding the key elements of host defense is essential to developing new therapeutics for melioidosis. As a flagellated bacterium encoding type III secretion systems, B. pseudomallei may trigger numerous host pathogen recognition receptors. TLR5 is a flagellin sensor located on the plasma membrane. NLRC4, along with NAIP proteins, assembles a canonical caspase-1-dependent inflammasome in the cytoplasm that responds to flagellin (in mice) and type III secretion system components (in mice and humans). In a murine model of respiratory melioidosis, Tlr5 and Nlrc4 each contributed to survival. Mice deficient in both Tlr5 and Nlrc4 were not more susceptible than single knockout animals. Deficiency of Casp1/Casp11 resulted in impaired bacterial control in the lung and spleen; in the lung much of this effect was attributable to Nlrc4, despite relative preservation of pulmonary IL-1β production in Nlrc4?/? mice. Histologically, deficiency of Casp1/Casp11 imparted more severe pulmonary inflammation than deficiency of Nlrc4. The human NLRC4 region polymorphism rs6757121 was associated with survival in melioidosis patients with pulmonary involvement. Co-inheritance of rs6757121 and a functional TLR5 polymorphism had an additive effect on survival. Our results show that NLRC4 and TLR5, key components of two flagellin sensing pathways, each contribute to host defense in respiratory melioidosis.
Z(3) Interfaces in Lattice Gauge Theory
S. T. West
Physics , 1997,
Abstract: A study is made of properties of the Z(3) interface which forms between the different ordered phases of pure SU(3) gauge theory above a critical temperature. The theory is simulated on a (2+1)-D lattice at various temperatures above this critical point. At high temperatures, the interface tension is shown to agree well with the prediction of perturbation theory. Near the critical temperature, the interface behaviour is characterised by various displacement moments, and modelled by an interacting scalar field theory. This thesis is provided for reference, as it gives full details of the computational and statistical methods outlined only briefly in preprints hep-lat/9605040 and hep-lat/9607005.
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