Predicting the time to death following sepsis in Uganda: a biomarker-based approach

The overall goal of this project was to accurately predict the time to death for patients with sepsis in Uganda using markers involved in the endothelial response to infection. There is substantial evidence from developed countries that endothelial markers measured at the time of hospital admission are associated with increased risk of death within 28 days, and we hypothesized that they would also discriminate between patients who die shortly after admission from those who have slower clinical progression. We first investigated the underlying heterogeneity in sepsis. We hypothesized that patients presenting with severe sepsis represent a mixture of latent processes and subgroups of individuals that can be grouped by their “endothelial response profile”. We characterized the underlying processes and subgroups using latent factor analysis (LFA) and latent profile analysis (LPA), respectively. We then identified biomarkers that accurately predict which patients will die by examining the discriminative value of the candidate predictors. Biomarkers and patient characteristics with the highest predictive accuracy were used to model the relative time to death using a generalized gamma model. The LFA results suggested four latent processes, interpreted as “inflammation”, “vessel stability”, “leukocyte recruitment”, and “vessel instability” based on the known biologic functions of the constituent biomarkers. Using LPA, we identified three subgroups of patients with endothelial response patterns that were homogenous within the group and distinct from the other groups. The patterns were interpreted as “quiescent”, “endothelial dysfunction”, and “endothelial repair”. Death by 28 days was best predicted with a model consisting of endothelial dysfunction, CD4+ T cell count less than 50 cells/mm3, Karnofsky score of 20 or less, and the 5th quintile of sFlt-1 concentration, a soluble receptor involved in vascular leak. The area under the curve (AUC) for the model for 28-day mortality was 0.73 in the derivation set and 0.77 in the validation set. The survival time for patients with endothelial dysfunction was approximately half that of patients with similar CD4+ T cell counts, Karnofsky scores, and sFlt-1 concentrations (relative time = 0.49, 95%CI: 0.32, 0.75). Profiling patients based on their endothelial response may provide a clinically meaningful way to categorize patients into homogenous subgroups and may identify patients at risk of imminent death

Hantavirus Infection in the Republic of Georgia

We describe a laboratory-confirmed case of hantavirus infection in the Republic of Georgia. Limited information is available about hantavirus infections in the Caucasus, although the infection has been reported throughout Europe and Russia. Increasing awareness and active disease surveillance contribute to our improved understanding of the geographic range of this pathogen

Ocean currents help explain population genetic structure

Management and conservation can be greatly informed by considering explicitly how environmental factors influence population genetic structure. Using simulated larval dispersal estimates based on ocean current observations, we demonstrate how explicit consideration of frequency of exchange of larvae among sites via ocean advection can fundamentally change the interpretation of empirical population genetic structuring as compared with conventional spatial genetic analyses. Both frequency of larval exchange and empirical genetic difference were uncorrelated with Euclidean distance between sites. When transformed into relative oceanographic distances and integrated into a genetic isolation-by-distance framework, however, the frequency of larval exchange explained nearly 50 per cent of the variance in empirical genetic differences among sites over scales of tens of kilometres. Explanatory power was strongest when we considered effects of multiple generations of larval dispersal via intermediary locations on the long-term probability of exchange between sites. Our results uncover meaningful spatial patterning to population genetic structuring that corresponds with ocean circulation. This study advances our ability to interpret population structure from complex genetic data characteristic of high gene flow species, validates recent advances in oceanographic approaches for assessing larval dispersal and represents a novel approach to characterize population connectivity at small spatial scales germane to conservation and fisheries management

The changing pattern of human brucellosis: clinical manifestations, epidemiology, and treatment outcomes over three decades in Georgia

<p>Abstract</p> <p>Background</p> <p>Brucellosis is an endemic infection in Georgia. We conducted a review of patient records with a suspected or confirmed diagnosis of brucellosis over three decades at the central referral hospital for brucellosis cases, the Institute of Parasitology and Tropical Medicine (IPTM) in Tbilisi. The purpose was to describe the demographic profile and clinical characteristics as well as diagnostic and treatment strategies in patients with brucellosis.</p> <p>Methods</p> <p>Data were abstracted from randomly selected patient records at the IPTM. In total, 300 records were reviewed from three time periods: 1970-73, 1988-89, and 2004-2008.</p> <p>Results</p> <p>The age distribution of patients shifted from a median age of 40 years in the first time period to 20 years in the third time period. Azeri ethnicity was an increasing proportion of the total number of cases. The frequency of relapsed infection was 14.7% (44 cases). A total of 50 patients received vaccine therapy, and although the vaccine produced immune responses, demonstrated by an increase in agglutination titers, it was not associated with improved outcome.</p> <p>Conclusion</p> <p>The demographics of brucellosis in Georgia fit a profile of persons that tend sheep. Osteoarticular complications were commonly detected, especially in children. The changing pattern of brucellosis in Georgia suggests clinicians should be updated about different trends in brucellosis in their country.</p

Sheep Updates 2008 - part 3

This session covers fiveteen papers from different authors: CONTROLLING FLY STRIKE 1. Breeding for Blowfly Resistance - Indicatoe Traits, LJE Karlsson, JC Greeff, L Slocombe, Department of Agriculture & Food, Western Australia 2.A practical method to select for breech strike resistance in non-pedigreed Merino flocks, LJE Karlsson, JC Greeff, L Slocombe, K. Jones, N. Underwood, Department of Agriculture & Food, Western Australia 3. Twice a year shearing - no mulesing, Fred Wilkinson, Producer, Brookton WA BEEF 4. Commercial testing of a new tool for prediction of fatness in beef cattle, WD HoffmanA, WA McKiernanA, VH OddyB, MJ McPheeA, Cooperative Research Centre for Beef Genetic Technologies, A N.S.W. Deptartment of Primary Industries, B University of New England 5. A new tool for the prediction of fatness in beef cattle, W.A. McKiernanA, V.H. OddyB and M.J. McPheeC; Cooperative Research Centre for Beef Genetic Technologies, A N.S.W. Dept of Primary Industries, B University of New England, C N.S.W. Dept of Primary Industries Beef Industry Centre of Excellence. 6. Effect of gene markers for tenderness on eating quality of beef, B.L. McIntyre, CRC for Beef Genetic Technologies, Department of Agriculture and Food WA 7. Accelerating beef industry innovation through Beef Profit Partnerships, Parnell PF1,2, Clark RA1,3, Timms J1,3, Griffith G1,2, Alford A1,2, Mulholland C1 and Hyland P1,4,1Co-operative Research Centre for Beef Genetic Technologies; 2NSW Department of Primary Industries; 3 Qld Department of Primary Industries and Fisheries; 4The University of Queensland. SUSTAINABILITY 8. The WA Sheep Industry - is it ethically and environmentally sustainable? Danielle England, Department of Agriculture and Food Western Australia 9. Overview of ruminant agriculture and greenhouse emissions, Fiona Jones, Department of Agriculture and Food Western Australia 10. Grazing for Nitrogen Efficiency, John Lucey, Martin Staines and Richard Morris, Department of Agriculture and Food Western Australia 11. Investigating potential adaptations to climate change for low rainfall farming system, Megan Abrahams, Caroline Peek, Dennis Van Gool, Daniel Gardiner, Kari-Lee Falconer, Department of Agriculture and Food Western Australia SHEEP 12. Benchmarking ewe productivity through on-farm genetic comparisons, Sandra Prosser, Mario D’Antuono and Johan Greeff; Department of Agriculture and Food Western Australia 13. Increasing profitability by pregnancy scanning ewes, John Young1, Andrew Thompson2 and Chris Oldham2; 1Farming Systems Analysis Service, Kojonup, WA, 2Department of Agriculture and Food Western Australia 14. Targeted treatment of worm-affected sheep - more efficient, more sustainable, Brown Besier, Department of Agriculture and Food Western Australia 15. Improving Weaner Sheep Survival, Angus Campbell and Ralph Behrendt, Cooperative Research Centre for Sheep Industry Innovatio

Trauma Hemorrhagic Shock-Induced Lung Injury Involves a Gut-Lymph-Induced TLR4 Pathway in Mice

Injurious non-microbial factors released from the stressed gut during shocked states contribute to the development of acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS). Since Toll-like receptors (TLR) act as sensors of tissue injury as well as microbial invasion and TLR4 signaling occurs in both sepsis and noninfectious models of ischemia/reperfusion (I/R) injury, we hypothesized that factors in the intestinal mesenteric lymph after trauma hemorrhagic shock (T/HS) mediate gut-induced lung injury via TLR4 activation.The concept that factors in T/HS lymph exiting the gut recreates ALI is evidenced by our findings that the infusion of porcine lymph, collected from animals subjected to global T/HS injury, into naïve wildtype (WT) mice induced lung injury. Using C3H/HeJ mice that harbor a TLR4 mutation, we found that TLR4 activation was necessary for the development of T/HS porcine lymph-induced lung injury as determined by Evan's blue dye (EBD) lung permeability and myeloperoxidase (MPO) levels as well as the induction of the injurious pulmonary iNOS response. TRIF and Myd88 deficiency fully and partially attenuated T/HS lymph-induced increases in lung permeability respectively. Additional studies in TLR2 deficient mice showed that TLR2 activation was not involved in the pathology of T/HS lymph-induced lung injury. Lastly, the lymph samples were devoid of bacteria, endotoxin and bacterial DNA and passage of lymph through an endotoxin removal column did not abrogate the ability of T/HS lymph to cause lung injury in naïve mice.Our findings suggest that non-microbial factors in the intestinal mesenteric lymph after T/HS are capable of recreating T/HS-induced lung injury via TLR4 activation

The Use of Biomaterials in Islet Transplantation

Pancreatic islet transplantation is a therapeutic option to replace destroyed β cells in autoimmune diabetes. Islets are transplanted into the liver via the portal vein; however, inflammation, the required immunosuppression, and lack of vasculature decrease early islet viability and function. Therefore, the use of accessory therapy and biomaterials to protect islets and improve islet function has definite therapeutic potential. Here we review the application of niche accessory cells and factors, as well as the use of biomaterials as carriers or capsules, for pancreatic islet transplantation

Fibrosis Progression Rate in Biopsy-Proven Nonalcoholic Fatty Liver Disease Among People With Diabetes Versus People Without Diabetes: A Multicenter Study

Background &amp; aimsThere are limited data regarding fibrosis progression in biopsy-proven nonalcoholic fatty liver disease (NAFLD) in people with type 2 diabetes mellitus (T2DM) compared with people without T2DM. We assessed the time to fibrosis progression in people with T2DM compared with people without T2DM in a large, multicenter, study of people with NAFLD who had paired liver biopsies.MethodsThis study included 447 adult participants (64% were female) with NAFLD who had paired liver biopsies more than 1 year apart. Liver histology was systematically assessed by a central pathology committee blinded to clinical data. The primary outcome was the cumulative incidence of a ≥1-stage increase in fibrosis in participants with T2DM compared with participants without T2DM.ResultsThe mean (SD) age and body mass index (calculated as weight in kilograms divided by the square of the height in meters) were 50.9 (11.5) years and 34.7 (6.3), respectively. The median time between biopsies was 3.3 years (interquartile range, 1.8-6.1 years). Participants with T2DM had a significantly higher cumulative incidence of fibrosis progression at 4 years (24% vs 20%), 8 years (60% vs 50%), and 12 years (93% vs 76%) (P&nbsp;= .005). Using a multivariable Cox proportional hazards model adjusted for multiple confounders, T2DM remained an independent predictor of fibrosis progression (adjusted hazard ratio, 1.69; 95% CI, 1.17-2.43; P&nbsp;= .005). The cumulative incidence of fibrosis regression by ≥1 stage was similar in participants with T2DM compared with participants without T2DM (P&nbsp;= .24).ConclusionsIn this large, multicenter cohort study of well-characterized participants with NAFLD and paired liver biopsies, we found that fibrosis progressed faster in participants with T2DM compared with participants without T2DM. These data have important implications for clinical practice and trial design

Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesPersistent insomnia is among the most frequent complaints in general practice. To identify genetic factors for insomnia complaints, we performed a genome-wide association study (GWAS) and a genome-wide gene-based association study (GWGAS) in 113,006 individuals. We identify three loci and seven genes associated with insomnia complaints, with the associations for one locus and five genes supported by joint analysis with an independent sample (n = 7,565). Our top association (MEIS1, P < 5 × 10-8) has previously been implicated in restless legs syndrome (RLS). Additional analyses favor the hypothesis that MEIS1 exhibits pleiotropy for insomnia and RLS and show that the observed association with insomnia complaints cannot be explained only by the presence of an RLS subgroup within the cases. Sex-specific analyses suggest that there are different genetic architectures between the sexes in addition to shared genetic factors. We show substantial positive genetic correlation of insomnia complaints with internalizing personality traits and metabolic traits and negative correlation with subjective well-being and educational attainment. These findings provide new insight into the genetic architecture of insomnia.Netherlands Organization for Scientific Research NWO Brain & Cognition 433-09-228 European Research Council ERC-ADG-2014-671084 INSOMNIA Netherlands Scientific Organization (NWO) VU University (Amsterdam, the Netherlands) Dutch Brain Foundation Helmholtz Zentrum Munchen - German Federal Ministry of Education and Research state of Bavaria German Migraine & Headache Society (DMKG) Almirall AstraZeneca Berlin Chemie Boehringer Boots Health Care GlaxoSmithKline Janssen Cilag McNeil Pharma MSD Sharp Dohme Pfizer Institute of Epidemiology and Social Medicine at the University of Munster German Ministry of Education and Research (BMBF) German Restless Legs Patient Organisation (RLS Deutsche Restless Legs Vereinigung) Swiss RLS Patient Association (Schweizerische Restless Legs Selbsthilfegruppe