Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis

BACKGROUND: After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. METHODS: We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics. RESULTS: We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. CONCLUSIONS: In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158.

Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications.

Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non-CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele-specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression

Galactic and Extragalactic Samples of Supernova Remnants: How They Are Identified and What They Tell Us

Supernova remnants (SNRs) arise from the interaction between the ejecta of a supernova (SN) explosion and the surrounding circumstellar and interstellar medium. Some SNRs, mostly nearby SNRs, can be studied in great detail. However, to understand SNRs as a whole, large samples of SNRs must be assembled and studied. Here, we describe the radio, optical, and X-ray techniques which have been used to identify and characterize almost 300 Galactic SNRs and more than 1200 extragalactic SNRs. We then discuss which types of SNRs are being found and which are not. We examine the degree to which the luminosity functions, surface-brightness distributions and multi-wavelength comparisons of the samples can be interpreted to determine the class properties of SNRs and describe efforts to establish the type of SN explosion associated with a SNR. We conclude that in order to better understand the class properties of SNRs, it is more important to study (and obtain additional data on) the SNRs in galaxies with extant samples at multiple wavelength bands than it is to obtain samples of SNRs in other galaxiesComment: Final 2016 draft of a chapter in "Handbook of Supernovae" edited by Athem W. Alsabti and Paul Murdin. Final version available at https://doi.org/10.1007/978-3-319-20794-0_90-

Radio emission from Supernova Remnants

The explosion of a supernova releases almost instantaneously about 10^51 ergs of mechanic energy, changing irreversibly the physical and chemical properties of large regions in the galaxies. The stellar ejecta, the nebula resulting from the powerful shock waves, and sometimes a compact stellar remnant, constitute a supernova remnant (SNR). They can radiate their energy across the whole electromagnetic spectrum, but the great majority are radio sources. Almost 70 years after the first detection of radio emission coming from a SNR, great progress has been achieved in the comprehension of their physical characteristics and evolution. We review the present knowledge of different aspects of radio remnants, focusing on sources of the Milky Way and the Magellanic Clouds, where the SNRs can be spatially resolved. We present a brief overview of theoretical background, analyze morphology and polarization properties, and review and critical discuss different methods applied to determine the radio spectrum and distances. The consequences of the interaction between the SNR shocks and the surrounding medium are examined, including the question of whether SNRs can trigger the formation of new stars. Cases of multispectral comparison are presented. A section is devoted to reviewing recent results of radio SNRs in the Magellanic Clouds, with particular emphasis on the radio properties of SN 1987A, an ideal laboratory to investigate dynamical evolution of an SNR in near real time. The review concludes with a summary of issues on radio SNRs that deserve further study, and analyzing the prospects for future research with the latest generation radio telescopes.Comment: Revised version. 48 pages, 15 figure

Attention bias to emotional faces varies by IQ and anxiety in Williams syndrome

Individuals with Williams syndrome (WS) often experience significant anxiety. A promising approach to anxiety intervention has emerged from cognitive studies of attention bias to threat. To investigate the utility of this intervention in WS, this study examined attention bias to happy and angry faces in individuals with WS (N=46). Results showed a significant difference in attention bias patterns as a function of IQ and anxiety. Individuals with higher IQ or higher anxiety showed a significant bias toward angry, but not happy faces, whereas individuals with lower IQ or lower anxiety showed the opposite pattern. These results suggest that attention bias interventions to modify a threat bias may be most effectively targeted to anxious individuals with WS with relatively high IQ

Clinical effectiveness of Enneking appropriate versus Enneking inappropriate procedure in patients with primary osteosarcoma of the spine: a systematic review with meta-analysis

Purpose Primary osteosarcoma of the spine is a rare osseous tumour. En bloc resection, in contrast to intralesional resection, is the only procedure able to provide Enneking appropriate (EA) margins, which has improved local control and survival of patients with primary osteosarcoma of the spine. The objective of this study is to compare the risk of local recurrence, metastases development and survival in patients with primary osteosarcoma of the spine submitted to Enneking appropriate (EA) and Enneking inappropriate (EI) procedures. Methods A systematic search was performed on EBSCO, PubMed and Web of Science, between 1966 and 2018, to identify studies evaluating patients submitted to resection of primary osteosarcoma of the spine. Two reviewers independently assessed all reports. The outcomes were local recurrence, metastases development and survival at 12, 24 and 60 months. Results Five studies (108 patients) were included for systematic review. These studies support the conclusion that EA procedure has a lower local recurrence rate (RR 0.33, 95% CI 0.17-0.66), a lower metastases development rate (RR 0.39, 95% CI 0.17-0.89) and a higher survival rate at 24 months (RR 1.78, 95% CI 1.24-2.55) and 60 months (RR 1.97, 95% CI 1.14-3.42) of follow-up; however, at 12 months, there is a non-significant difference. Conclusions EA procedure increases the ratio of remission and survival after 24 months of follow-up. Multidisciplinary oncologic groups should weigh the morbidity of an en bloc resection, knowing that in the first year the probability of survival is the same for EA and EI procedures. Graphic abstract These slides can be retrieved under Electronic Supplementary Material

Diagnostic Accuracy of Age and Alarm Symptoms for Upper GI Malignancy in Patients with Dyspepsia in a GI Clinic: A 7-Year Cross-Sectional Study

<div><h3>Objectives</h3><p>We investigated whether using demographic characteristics and alarm symptoms can accurately predict cancer in patients with dyspepsia in Iran, where upper GI cancers and <em>H. pylori</em> infection are common.</p> <h3>Methods</h3><p>All consecutive patients referred to a tertiary gastroenterology clinic in Tehran, Iran, from 2002 to 2009 were invited to participate in this study. Each patient completed a standard questionnaire and underwent upper gastrointestinal endoscopy. Alarm symptoms included in the questionnaire were weight loss, dysphagia, GI bleeding, and persistent vomiting. We used logistic regression models to estimate the diagnostic value of each variable in combination with other ones, and to develop a risk-prediction model.</p> <h3>Results</h3><p>A total of 2,847 patients with dyspepsia participated in this study, of whom 87 (3.1%) had upper GI malignancy. Patients reporting at least one of the alarm symptoms constituted 66.7% of cancer patients compared to 38.9% in patients without cancer (p<0.001). Esophageal or gastric cancers in patients with dyspepsia was associated with older age, being male, and symptoms of weight loss and vomiting. Each single predictor had low sensitivity and specificity. Using a combination of age, alarm symptoms, and smoking, we built a risk-prediction model that distinguished between high-risk and low-risk individuals with an area under the ROC curve of 0.85 and acceptable calibration.</p> <h3>Conclusions</h3><p>None of the predictors demonstrated high diagnostic accuracy. While our risk-prediction model had reasonable accuracy, some cancer cases would have remained undiagnosed. Therefore, where available, low cost endoscopy may be preferable for dyspeptic older patient or those with history of weight loss.</p> </div

Facial expression training optimises viewing strategy in children and adults

This study investigated whether training-related improvements in facial expression categorization are facilitated by spontaneous changes in gaze behaviour in adults and nine-year old children. Four sessions of a self-paced, free-viewing training task required participants to categorize happy, sad and fear expressions with varying intensities. No instructions about eye movements were given. Eye-movements were recorded in the first and fourth training session. New faces were introduced in session four to establish transfer-effects of learning. Adults focused most on the eyes in all sessions and increased expression categorization accuracy after training coincided with a strengthening of this eye-bias in gaze allocation. In children, training-related behavioural improvements coincided with an overall shift in gaze-focus towards the eyes (resulting in more adult-like gaze-distributions) and towards the mouth for happy faces in the second fixation. Gaze-distributions were not influenced by the expression intensity or by the introduction of new faces. It was proposed that training enhanced the use of a uniform, predominantly eyes-biased, gaze strategy in children in order to optimise extraction of relevant cues for discrimination between subtle facial expressions