Computerized Clinical Decision Support Systems for the Early Detection of Sepsis Among Adult Inpatients: Scoping Review.

BACKGROUND: Sepsis is a significant cause of morbidity and mortality worldwide. Early detection of sepsis followed promptly by treatment initiation improves patient outcomes and saves lives. Hospitals are increasingly using computerized clinical decision support (CCDS) systems for the rapid identification of adult patients with sepsis. OBJECTIVE: This scoping review aims to systematically describe studies reporting on the use and evaluation of CCDS systems for the early detection of adult inpatients with sepsis. METHODS: The protocol for this scoping review was previously published. A total of 10 electronic databases (MEDLINE, Embase, CINAHL, the Cochrane database, LILACS [Latin American and Caribbean Health Sciences Literature], Scopus, Web of Science, OpenGrey, ClinicalTrials.gov, and PQDT [ProQuest Dissertations and Theses]) were comprehensively searched using terms for sepsis, CCDS, and detection to identify relevant studies. Title, abstract, and full-text screening were performed by 2 independent reviewers using predefined eligibility criteria. Data charting was performed by 1 reviewer with a second reviewer checking a random sample of studies. Any disagreements were discussed with input from a third reviewer. In this review, we present the results for adult inpatients, including studies that do not specify patient age. RESULTS: A search of the electronic databases retrieved 12,139 studies following duplicate removal. We identified 124 studies for inclusion after title, abstract, full-text screening, and hand searching were complete. Nearly all studies (121/124, 97.6%) were published after 2009. Half of the studies were journal articles (65/124, 52.4%), and the remainder were conference abstracts (54/124, 43.5%) and theses (5/124, 4%). Most studies used a single cohort (54/124, 43.5%) or before-after (42/124, 33.9%) approach. Across all 124 included studies, patient outcomes were the most frequently reported outcomes (107/124, 86.3%), followed by sepsis treatment and management (75/124, 60.5%), CCDS usability (14/124, 11.3%), and cost outcomes (9/124, 7.3%). For sepsis identification, the systemic inflammatory response syndrome criteria were the most commonly used, alone (50/124, 40.3%), combined with organ dysfunction (28/124, 22.6%), or combined with other criteria (23/124, 18.5%). Over half of the CCDS systems (68/124, 54.8%) were implemented alongside other sepsis-related interventions. CONCLUSIONS: The current body of literature investigating the implementation of CCDS systems for the early detection of adult inpatients with sepsis is extremely diverse. There is substantial variability in study design, CCDS criteria and characteristics, and outcomes measured across the identified literature. Future research on CCDS system usability, cost, and impact on sepsis morbidity is needed. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/24899.

Evaluation of cross-platform and interlaboratory concordance via consensus modelling of genomic measurements.

MOTIVATION: A synoptic view of the human genome benefits chiefly from the application of nucleic acid sequencing and microarray technologies. These platforms allow interrogation of patterns such as gene expression and DNA methylation at the vast majority of canonical loci, allowing granular insights and opportunities for validation of original findings. However, problems arise when validating against a "gold standard" measurement, since this immediately biases all subsequent measurements towards that particular technology or protocol. Since all genomic measurements are estimates, in the absence of a "gold standard" we instead empirically assess the measurement precision and sensitivity of a large suite of genomic technologies via a consensus modelling method called the row-linear model. This method is an application of the American Society for Testing and Materials Standard E691 for assessing interlaboratory precision and sources of variability across multiple testing sites. Both cross-platform and cross-locus comparisons can be made across all common loci, allowing identification of technology- and locus-specific tendencies. RESULTS: We assess technologies including the Infinium MethylationEPIC BeadChip, whole genome bisulfite sequencing (WGBS), two different RNA-Seq protocols (PolyA+ and Ribo-Zero) and five different gene expression array platforms. Each technology thus is characterised herein, relative to the consensus. We showcase a number of applications of the row-linear model, including correlation with known interfering traits. We demonstrate a clear effect of cross-hybridisation on the sensitivity of Infinium methylation arrays. Additionally, we perform a true interlaboratory test on a set of samples interrogated on the same platform across twenty-one separate testing laboratories. AVAILABILITY AND IMPLEMENTATION: A full implementation of the row-linear model, plus extra functions for visualisation, are found in the R package consensus at https://github.com/timpeters82/consensus. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

LipiD-QuanT: a novel method to quantify lipid accumulation in live cells.

Lipid droplets (LDs) are the main storage organelles for triglycerides. Elucidation of lipid accumulation mechanisms and metabolism are essential to understand obesity and associated diseases. Adipogenesis has been well studied in murine 3T3-L1 and human Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte cell lines. However, most techniques for measuring LD accumulation are either not quantitative or can be destructive to samples. Here, we describe a novel, label-free LD quantification technique (LipiD-QuanT) to monitor lipid dynamics based on automated image analysis of phase contrast microscopy images acquired during in vitro human adipogenesis. We have applied LipiD-QuanT to measure LD accumulation during differentiation of SGBS cells. We demonstrate that LipiD-QuanT is a robust, nondestructive, time- and cost-effective method compared with other triglyceride accumulation assays based on enzymatic digest or lipophilic staining. Further, we applied LipiD-QuanT to measure the effect of four potential pro- or antiobesogenic substances: DHA, rosiglitazone, elevated levels of D-glucose, and zinc oxide nanoparticles. Our results revealed that 2 µmol/l rosiglitazone treatment during adipogenesis reduced lipid production and caused a negative shift in LD diameter size distribution, but the other treatments showed no effect under the conditions used here.

Methylome and transcriptome maps of human visceral and subcutaneous adipocytes reveal key epigenetic differences at developmental genes.

Adipocytes support key metabolic and endocrine functions of adipose tissue. Lipid is stored in two major classes of depots, namely visceral adipose (VA) and subcutaneous adipose (SA) depots. Increased visceral adiposity is associated with adverse health outcomes, whereas the impact of SA tissue is relatively metabolically benign. The precise molecular features associated with the functional differences between the adipose depots are still not well understood. Here, we characterised transcriptomes and methylomes of isolated adipocytes from matched SA and VA tissues of individuals with normal BMI to identify epigenetic differences and their contribution to cell type and depot-specific function. We found that DNA methylomes were notably distinct between different adipocyte depots and were associated with differential gene expression within pathways fundamental to adipocyte function. Most striking differential methylation was found at transcription factor and developmental genes. Our findings highlight the importance of developmental origins in the function of different fat depots.

COBRA-Seq: Sensitive and Quantitative Methylome Profiling.

Combined Bisulfite Restriction Analysis (COBRA) quantifies DNA methylation at a specific locus. It does so via digestion of PCR amplicons produced from bisulfite-treated DNA, using a restriction enzyme that contains a cytosine within its recognition sequence, such as TaqI. Here, we introduce COBRA-seq, a genome wide reduced methylome method that requires minimal DNA input (0.1-1.0 mg) and can either use PCR or linear amplification to amplify the sequencing library. Variants of COBRA-seq can be used to explore CpG-depleted as well as CpG-rich regions in vertebrate DNA. The choice of enzyme influences enrichment for specific genomic features, such as CpG-rich promoters and CpG islands, or enrichment for less CpG dense regions such as enhancers. COBRA-seq coupled with linear amplification has the additional advantage of reduced PCR bias by producing full length fragments at high abundance. Unlike other reduced representative methylome methods, COBRA-seq has great flexibility in the choice of enzyme and can be multiplexed and tuned, to reduce sequencing costs and to interrogate different numbers of sites. Moreover, COBRA-seq is applicable to non-model organisms without the reference genome and compatible with the investigation of non-CpG methylation by using restriction enzymes containing CpA, CpT, and CpC in their recognition site.

Atmospheric gas plasma-induced ROS production activates TNF-ASK1 pathway for the induction of melanoma cancer cell apoptosis.

Atmospheric gas plasmas (AGPs) are able to selectively induce apoptosis in cancer cells, offering a promising alternative to conventional therapies that have unwanted side effects such as drug resistance and toxicity. However, the mechanism of AGP-induced cancer cell death is unknown. In this study, AGP is shown to up-regulate intracellular reactive oxygen species (ROS) levels and induce apoptosis in melanoma but not normal melanocyte cells. By screening genes involved in apoptosis, we identify tumor necrosis factor (TNF)-family members as the most differentially expressed cellular genes upon AGP treatment of melanoma cells. TNF receptor 1 (TNFR1) antagonist-neutralizing antibody specifically inhibits AGP-induced apoptosis signal, regulating apoptosis signal-regulating kinase 1 (ASK1) activity and subsequent ASK1-dependent apoptosis. Treatment of cells with intracellular ROS scavenger N-acetyl-l-cysteine also inhibits AGP-induced activation of ASK1, as well as apoptosis. Moreover, depletion of intracellular ASK1 reduces the level of AGP-induced oxidative stress and apoptosis. The evidence for TNF-signaling dependence of ASK1-mediated apoptosis suggests possible mechanisms for AGP activation and regulation of apoptosis-signaling pathways in tumor cells.