Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: A prospective observational study

BACKGROUND: Identifying patients in the immunosuppressive phase of sepsis is essential for development of immunomodulatory therapies. Little data exists comparing the ability of the two most well-studied markers of sepsis-induced immunosuppression, human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-ɑ) production, to predict mortality and morbidity. The purpose of this study was to compare HLA-DR expression and LPS-induced TNF-ɑ production as predictors of 28-day mortality and acquisition of secondary infections in adult septic patients. METHODS: A single-center, prospective observational study of 83 adult septic patients admitted to a medical or surgical intensive care unit. Blood samples were collected at three time points during the septic course (days 1–2, days 3–4, and days 6–8 after sepsis diagnosis) and assayed for HLA-DR expression and LPS-induced TNF-ɑ production. A repeated measures mixed model analysis was used to compare values of these immunological markers among survivors and non-survivors and among those who did and did not develop a secondary infection. RESULTS: Twenty-five patients (30.1 %) died within 28 days of sepsis diagnosis. HLA-DR expression was significantly lower in non-survivors as compared to survivors on days 3–4 (p = 0.04) and days 6–8 (p = 0.002). The change in HLA-DR from days 1–2 to days 6–8 was also lower in non-survivors (p = 0.04). Median HLA-DR expression decreased from days 1–2 to days 3–4 in patients who developed secondary infections while it increased in those without secondary infections (p = 0.054). TNF-ɑ production did not differ between survivors and non-survivors or between patients who did and did not develop a secondary infection. CONCLUSIONS: Monocyte HLA-DR expression may be a more accurate predictor of mortality and acquisition of secondary infections than LPS-stimulated TNF-ɑ production in adult medical and surgical critically ill patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13054-016-1505-0) contains supplementary material, which is available to authorized users

An international longitudinal registry of patients with atrial fibrillation at risk of stroke (GARFIELD) : the UK protocol

Background Atrial fibrillation (AF) is an independent risk factor for stroke and a significant predictor of mortality. Evidence-based guidelines for stroke prevention in AF recommend antithrombotic therapy corresponding to the risk of stroke. In practice, many patients with AF do not receive the appropriate antithrombotic therapy and are left either unprotected or inadequately protected against stroke. The purpose of the Global Anticoagulant Registry in the FIELD (GARFIELD) is to determine the real-life management and outcomes of patients newly diagnosed with non-valvular AF. Methods/design GARFIELD is an observational, international registry of newly diagnosed AF patients with at least one additional investigator-defined risk factor for stroke. The aim is to enrol 55,000 patients at more than 1000 centres in 50 countries worldwide. Enrolment will take place in five independent, sequential, prospective cohorts; the first cohort includes a retrospective validation cohort. Each cohort will be followed up for 2 years. The UK stands to be a significant contributor to GARFIELD, aiming to enrol 4,582 patients, and reflecting the care environment in which patients with AF are managed. The UK protocol will also focus on better understanding the validity of the two main stroke risk scores (CHADS2 and CHA2DS2VASC) and the HAS-BLED bleeding risk score, in the context of a diverse patient population. Discussion The GARFIELD registry will describe how therapeutic strategies, patient care, and clinical outcomes evolve over time. This study will provide UK-specific comprehensive data that will allow a range of evaluations both at a national level and in relation to global data and contribute to a better understanding of AF management in the UK

First Report of a Novel Hepatozoon sp. in Giant Pandas (Ailuropoda melanoleuca)

The first report of giant pandas (Ailuropoda melanoleuca) infected with a novel Hepatozoon species is presented. An intraleukocytic parasite was detected via routine blood smear from a zoo-housed giant panda at the National Zoological Park. Ribosomal DNA sequences indicated a previously undescribed Hepatozoon species. Phylogenetic and distance analyses of the sequences placed it within its own branch, clustered with Old World species with carnivore (primarily ursid and mustelid) hosts. Retrospective and opportunistic testing of other individuals produced additional positive detections (17/23, 73.9%), demonstrating 100% prevalence (14/14) across five institutions. All animals were asymptomatic at time of sampling, and health implications for giant pandas remain unknown

ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

<b>Objective</b> <i>ABCB1</i> encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC).<p></p> <b>Methods</b> The best candidates from fine-mapping analysis of 21 <i>ABCB1</i> SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either ‘standard’ first-line paclitaxel–carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients.<p></p> <b>Result</b> Fine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77–1.01; p = 0.07). In contrast, <i>ABCB1</i> expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours.<p></p> <b>Conclusion</b> Our study represents the largest analysis of <i>ABCB1</i> SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.<p></p&gt

Colouration in amphibians as a reflection of nutritional status : the case of tree frogs in Costa Rica

Colouration has been considered a cue for mating success in many species; ornaments in males often are related to carotenoid mobilization towards feathers and/or skin and can signal general health and nutrition status. However, there are several factors that can also link with status, such as physiological blood parameters and body condition, but there is not substantial evidence which supports the existence of these relationships and interactions in anurans. This study evaluated how body score and blood values interact with colouration in free-range Agalychnis callidryas and Agalychnis annae males. We found significant associations between body condition and plasmatic proteins and haematocrit, as well as between body condition and colour values from the chromaticity diagram. We also demonstrated that there is a significant relation between the glucose and plasmatic protein values that were reflected in the ventral colours of the animals, and haematocrit inversely affected most of those colour values. Significant differences were found between species as well as between populations of A. callidryas, suggesting that despite colour variation, there are also biochemical differences within animals from the same species located in different regions. These data provide information on underlying factors for colouration of male tree frogs in nature, provide insights about the dynamics of several nutrients in the amphibian model and how this could affect the reproductive output of the animals

Clinical Conditions “Suggestive of Progressive Supranuclear Palsy”—Diagnostic Performance

Background: The Movement Disorder Society diagnostic criteria for progressive supranuclear palsy introduced the diagnostic certainty level “suggestive of progressive supranuclear palsy” for clinical conditions with subtle signs, suggestive of the disease. This category aims at the early identification of patients, in whom the diagnosis may be confirmed as the disease evolves. Objective: To assess the diagnostic performance of the defined clinical conditions suggestive of progressive supranuclear palsy in an autopsy-confirmed cohort. Methods: Diagnostic performance of the criteria was analyzed based on retrospective clinical data of 204 autopsy-confirmed patients with progressive supranuclear palsy and 216 patients with other neurological diseases. Results: The conditions suggestive of progressive supranuclear palsy strongly increased the sensitivity compared to the National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy criteria. Within the first year after symptom onset, 40% of patients with definite progressive supranuclear palsy fulfilled criteria for suggestive of progressive supranuclear palsy. Two-thirds of patients suggestive of progressive supranuclear palsy evolved into probable progressive supranuclear palsy after an average of 3.6 years. Application of the criteria for suggestive of progressive supranuclear palsy reduced the average time to diagnosis from 3.8 to 2.2 years. Conclusions: Clinical conditions suggestive of progressive supranuclear palsy allow earlier identification of patients likely to evolve into clinically possible or probable progressive supranuclear and to have underlying progressive supranuclear palsy pathology. Further work needs to establish the specificity and positive predictive value of this category in real-life clinical settings, and to develop specific biomarkers that enhance their diagnostic accuracy in early disease stages

Distribution patterns of tau pathology in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. W

The Impact of Realistic Age Structure in Simple Models of Tuberculosis Transmission

Background : Mathematical models of tuberculosis (TB) transmission have been used to characterize disease dynamics, investigate the potential effects of public health interventions, and prioritize control measures. While previous work has addressed the mathematical description of TB natural history, the impact of demography on the behaviour of TB models has not been assessed. Methods : A simple model of TB transmission, with alternative assumptions about survivorship, is used to explore the effect of age structure on the prevalence of infection, disease, basic reproductive ratio and the projected impact of control interventions. We focus our analytic arguments on the differences between constant and exponentially distributed lifespans and use an individual-based model to investigate the range of behaviour arising from realistic distributions of survivorship. Results : The choice of age structure and natural (non-disease related) mortality strongly affects steady-state dynamics, parameter estimation and predictions about the effectiveness of control interventions. Since most individuals infected with TB develop an asymptomatic latent infection and never progress to active disease, we find that assuming a constant mortality rate results in a larger reproductive ratio and an overestimation of the effort required for disease control in comparison to using more realistic age-specific mortality rates. Conclusions : Demographic modelling assumptions should be considered in the interpretation of models of chronic infectious diseases such as TB. For simple models, we find that assuming constant lifetimes, rather than exponential lifetimes, produces dynamics more representative of models with realistic age structure

Effect of aspirin on cancer incidence and mortality in older adults.

BACKGROUND: ASPirin in Reducing Events in the Elderly (ASPREE), a randomized double-blind placebo-controlled trial (RCT) of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast prior RCTs, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality. METHODS: 19,114 Australian and U.S. community-dwelling participants aged 70+ years (U.S. minorities 65+ years) without cardiovascular disease, dementia or physical disability were randomized and followed for a median of 4.7 years. Fatal and non-fatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records. RESULTS: 981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (HR = 1.04, 95% CI = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64). CONCLUSIONS: In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and thus, suggest caution with its use in this age group

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition