Outcome predictors of uncomplicated sepsis

BACKGROUND: The development of sepsis risk prediction models and treatment guidelines has largely been based on patients presenting in the emergency department (ED) with severe sepsis or septic shock. Therefore, in this study we investigated which patient characteristics might identify patients with an adverse outcome in a heterogeneous group of patients presenting with uncomplicated sepsis to the emergency department (ED). FINDINGS: We performed a retrospective cohort analysis of all ED patients presenting with uncomplicated sepsis in a large teaching hospital during a 3-month period. During this period, 70 patients fulfilled the criteria of uncomplicated sepsis. Eight died in the hospital. Non-survivors were characterized by a higher abbreviated Mortality in Emergency Department Sepsis (MEDS) score (7.2 ± 3.4 vs. 4.8 ± 2.9, p = 0.03) and a lower Hb (6.6 ± 1.2 vs. 7.7 ± 1.4, p = 0.03), and they used beta-blockers more often (75% vs. 19%, p < 0.01). CONCLUSIONS: Non-survivors of uncomplicated sepsis had on average a higher abbreviated MEDS score, a lower hemoglobin (Hb) and more often used β-blockers compared to survivors. Early identification of these factors might contribute to optimization of sepsis treatment for this patient category and thereby prevent disease progression to severe sepsis or septic shock

Low HIV testing rates among tuberculosis patients in Kampala, Uganda

<p>Abstract</p> <p>Background</p> <p>HIV testing among tuberculosis patients is critical in improving morbidity and mortality as those found to be HIV positive will be offered a continuum of care including ART if indicated. We conducted a cross-sectional study in three Kampala City primary care clinics: to assess the level of HIV test uptake among newly diagnosed pulmonary tuberculosis (PTB) patients; to assess patient and health worker factors associated with HIV test uptake; and to determine factors associated with HIV test uptake at the primary care clinics</p> <p>Methods</p> <p>Adult patients who had been diagnosed with smear-positive PTB at a primary care clinic or at the referral hospital and who were being treated at any of the three clinics were interviewed. Associations between having taken the test as the main outcome and explanatory variables were assessed by multivariate logistic regression.</p> <p>Results</p> <p>Between April and October 2007, 112 adults were included in the study. An HIV test had been offered to 74 (66%). Of the 112 patients, 61 (82%) had accepted the test; 45 (74%) had eventually been tested; and 32 (29%) had received their test results.</p> <p>Patients who were <25 yeas old, female or unemployed, or had reported no previous HIV testing, were more likely to have been tested. The strongest predictor of having been tested was if patients had been diagnosed at the referral hospital compared to the city clinic (adjusted OR 24.2; 95% CI 6.7-87.7; p < 0.001). This primarily reflected an "opt-out" (uptake 94%) versus an "opt-in" (uptake 53%) testing policy.</p> <p>Conclusions</p> <p>The overall HIV test uptake was surprisingly low at 40%. The HIV test uptake was significantly higher among TB patients who were identified at hospital, among females and in the unemployed.</p

Systematic monitoring of needs for care and global outcomes in patients with severe mental illness

<p>Abstract</p> <p>Background</p> <p>It was hypothesised that the introduction of tools that allow clinicians to assess patients' needs and to negotiate treatment (Cumulative Needs for Care Monitor; CNCM), would be associated with global outcome improvements in patients diagnosed with severe mental illness.</p> <p>Methods</p> <p>The CNCM was introduced in one region in South Limburg (the Netherlands) in 1998 (REGION-1998) and in the rest of South Limburg in 2004 (REGION-2004). By comparing these two regions, changes after the introduction of the CNCM could be assessed (between-region comparison). In addition, a pre-post within-patient comparison was conducted in both regions.</p> <p>Results</p> <p>The within-patient comparison revealed that global outcomes of psychopathology and impairment improved in the first 3-5 years after the introduction of the CNCM. The between-region comparison revealed an improvement in global psychopathology but not in global impairment in REGION-2004 after 2004, while there was no such improvement in REGION-1998.</p> <p>Conclusion</p> <p>Systematic clinical monitoring of individual severe mental illness patients, in combination with provision of feedback, is associated with global improvement in psychopathology. More research is needed to determine the degree to which this association reflects a causal effect.</p

Human Neural Stem Cells Over-Expressing VEGF Provide Neuroprotection, Angiogenesis and Functional Recovery in Mouse Stroke Model

BACKGROUND: Intracerebral hemorrhage (ICH) is a lethal stroke type. As mortality approaches 50%, and current medical therapy against ICH shows only limited effectiveness, an alternative approach is required, such as stem cell-based cell therapy. Previously we have shown that intravenously transplanted human neural stem cells (NSCs) selectively migrate to the brain and induce behavioral recovery in rat ICH model, and that combined administration of NSCs and vascular endothelial growth factor (VEGF) results in improved structural and functional outcome from cerebral ischemia. METHODS AND FINDINGS: We postulated that human NSCs overexpressing VEGF transplanted into cerebral cortex overlying ICH lesion could provide improved survival of grafted NSCs, increased angiogenesis and behavioral recovery in mouse ICH model. ICH was induced in adult mice by unilateral injection of bacterial collagenase into striatum. HB1.F3.VEGF human NSC line produced an amount of VEGF four times higher than parental F3 cell line in vitro, and induced behavioral improvement and 2–3 fold increase in cell survival at two weeks and eight weeks post-transplantation. CONCLUSIONS: Brain transplantation of F3 human NSCs over-expressing VEGF near ICH lesion sites provided differentiation and survival of grafted human NSCs and renewed angiogenesis of host brain and functional recovery of ICH animals. These results suggest a possible application of the human neural stem cell line, which is genetically modified to over-express VEGF, as a therapeutic agent for ICH-stroke

Three-dimensional mapping of mechanical activation patterns, contractile dyssynchrony and dyscoordination by two-dimensional strain echocardiography: Rationale and design of a novel software toolbox

<p>Abstract</p> <p>Background</p> <p>Dyssynchrony of myocardial deformation is usually described in terms of variability only (e.g. standard deviations SD's). A description in terms of the spatio-temporal distribution pattern (vector-analysis) of dyssynchrony or by indices estimating its impact by expressing dyscoordination of shortening in relation to the global ventricular shortening may be preferential. Strain echocardiography by speckle tracking is a new non-invasive, albeit 2-D imaging modality to study myocardial deformation.</p> <p>Methods</p> <p>A post-processing toolbox was designed to incorporate local, speckle tracking-derived deformation data into a 36 segment 3-D model of the left ventricle. Global left ventricular shortening, standard deviations and vectors of timing of shortening were calculated. The impact of dyssynchrony was estimated by comparing the end-systolic values with either early peak values only (early shortening reserve ESR) or with all peak values (virtual shortening reserve VSR), and by the internal strain fraction (ISF) expressing dyscoordination as the fraction of deformation lost internally due to simultaneous shortening and stretching. These dyssynchrony parameters were compared in 8 volunteers (NL), 8 patients with Wolff-Parkinson-White syndrome (WPW), and 7 patients before (LBBB) and after cardiac resynchronization therapy (CRT).</p> <p>Results</p> <p>Dyssynchrony indices merely based on variability failed to detect differences between WPW and NL and failed to demonstrate the effect of CRT. Only the 3-D vector of onset of shortening could distinguish WPW from NL, while at peak shortening and by VSR, ESR and ISF no differences were found. All tested dyssynchrony parameters yielded higher values in LBBB compared to both NL and WPW. CRT reduced the spatial divergence of shortening (both vector magnitude and direction), and improved global ventricular shortening along with reductions in ESR and dyscoordination of shortening expressed by ISF.</p> <p>Conclusion</p> <p>Incorporation of local 2-D echocardiographic deformation data into a 3-D model by dedicated software allows a comprehensive analysis of spatio-temporal distribution patterns of myocardial dyssynchrony, of the global left ventricular deformation and of newer indices that may better reflect myocardial dyscoordination and/or impaired ventricular contractile efficiency. The potential value of such an analysis is highlighted in two dyssynchronous pathologies that impose particular challenges to deformation imaging.</p

Genetic Diversity and Ecological Niche Modelling of Wild Barley:Refugia, Large-Scale Post-LGM Range Expansion and Limited Mid-Future Climate Threats?

Describing genetic diversity in wild barley (Hordeum vulgare ssp. spontaneum) in geographic and environmental space in the context of current, past and potential future climates is important for conservation and for breeding the domesticated crop (Hordeum vulgare ssp. vulgare). Spatial genetic diversity in wild barley was revealed by both nuclear- (2,505 SNP, 24 nSSR) and chloroplast-derived (5 cpSSR) markers in 256 widely-sampled geo-referenced accessions. Results were compared with MaxEnt-modelled geographic distributions under current, past (Last Glacial Maximum, LGM) and mid-term future (anthropogenic scenario A2, the 2080s) climates. Comparisons suggest large-scale post-LGM range expansion in Central Asia and relatively small, but statistically significant, reductions in range-wide genetic diversity under future climate. Our analyses support the utility of ecological niche modelling for locating genetic diversity hotspots and determine priority geographic areas for wild barley conservation under anthropogenic climate change. Similar research on other cereal crop progenitors could play an important role in tailoring conservation and crop improvement strategies to support future human food security

Epigenetic Regulation of Histone H3 Serine 10 Phosphorylation Status by HCF-1 Proteins in C. elegans and Mammalian Cells

BACKGROUND: The human herpes simplex virus (HSV) host cell factor HCF-1 is a transcriptional coregulator that associates with both histone methyl- and acetyltransferases, and a histone deacetylase and regulates cell proliferation and division. In HSV-infected cells, HCF-1 associates with the viral protein VP16 to promote formation of a multiprotein-DNA transcriptional activator complex. The ability of HCF proteins to stabilize this VP16-induced complex has been conserved in diverse animal species including Drosophila melanogaster and Caenorhabditis elegans suggesting that VP16 targets a conserved cellular function of HCF-1. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the role of HCF proteins in animal development, we have characterized the effects of loss of the HCF-1 homolog in C. elegans, called Ce HCF-1. Two large hcf-1 deletion mutants (pk924 and ok559) are viable but display reduced fertility. Loss of Ce HCF-1 protein at reduced temperatures (e.g., 12 degrees C), however, leads to a high incidence of embryonic lethality and early embryonic mitotic and cytokinetic defects reminiscent of mammalian cell-division defects upon loss of HCF-1 function. Even when viable, however, at normal temperature, mutant embryos display reduced levels of phospho-histone H3 serine 10 (H3S10P), a modification implicated in both transcriptional and mitotic regulation. Mammalian cells with defective HCF-1 also display defects in mitotic H3S10P status. CONCLUSIONS/SIGNIFICANCE: These results suggest that HCF-1 proteins possess conserved roles in the regulation of cell division and mitotic histone phosphorylation

A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history

Introduction Unclassified variants (UVs) in the BRCA1/BRCA2 genes are a frequent problem in counseling breast cancer and/or ovarian cancer families. Information about cancer family history is usually available, but has rarely been used to evaluate UVs. The aim of the present study was to identify which is the best combination of clinical parameters that can predict whether a UV is deleterious, to be used for the classification of UVs. Methods We developed logistic regression models with the best combination of clinical features that distinguished a positive control of BRCA pathogenic variants (115 families) from a negative control population of BRCA variants initially classified as UVs and later considered neutral (38 families). Results The models included a combination of BRCAPRO scores, Myriad scores, number of ovarian cancers in the family, the age at diagnosis, and the number of persons with ovarian tumors and/ or breast tumors. The areas under the receiver operating characteristic curves were respectively 0.935 and 0.836 for the BRCA1 and BRCA2 models. For each model, the minimum receiver operating characteristic distance (respectively 90% and 78% specificity for BRCA1 and BRCA2) was chosen as the cutoff value to predict which UVs are deleterious from a study population of 12 UVs, present in 59 Dutch families. The p. S1655F, p. R1699W, and p. R1699Q variants in BRCA1 and the p. Y2660D, p. R2784Q, and p. R3052W variants in BRCA2 are classified as deleterious according to our models. The predictions of the p. L246V variant in BRCA1 and of the p. Y42C, p. E462G, p. R2888C, and p. R3052Q variants in BRCA2 are in agreement with published information of them being neutral. The p. R2784W variant in BRCA2 remains uncertain. Conclusions The present study shows that these developed models are useful to classify UVs in clinical genetic practic

Production of ultrasonic vocalizations by Peromyscus mice in the wild

BACKGROUND: There has been considerable research on rodent ultrasound in the laboratory and these sounds have been well quantified and characterized. Despite the value of research on ultrasound produced by mice in the lab, it is unclear if, and when, these sounds are produced in the wild, and how they function in natural habitats. RESULTS: We have made the first recordings of ultrasonic vocalizations produced by two free-living species of mice in the genus Peromyscus (P. californicus and P. boylii) on long term study grids in California. Over 6 nights, we recorded 65 unique ultrasonic vocalization phrases from Peromyscus. The ultrasonic vocalizations we recorded represent 7 different motifs. Within each motif, there was considerable variation in the acoustic characteristics suggesting individual and contextual variation in the production of ultrasound by these species. CONCLUSION: The discovery of the production of ultrasonic vocalizations by Peromyscus in the wild highlights an underappreciated component in the behavior of these model organisms. The ability to examine the production of ultrasonic vocalizations in the wild offers excellent opportunities to test hypotheses regarding the function of ultrasound produced by rodents in a natural context