Myeloperoxidase to Risk Stratify Emergency Department Patients with Chest Pain

Previous studies suggest that serum myeloperoxidase (MPO) is a potentially useful biomarker to risk stratify troponin-negative patients with suspected myocardial ischemia. We hypothesized that the relationship between initial serum MPO levels would correlate with 30-day adverse cardiac outcomes for low risk emergency department (ED) patients with suspected myocardial ischemia. This prospective cohort study enrolled ED patients with chest pain or suspected myocardial ischemia, non-diagnostic ECG, and initially negative cardiac troponin I. We defined 30-day adverse cardiac events as death, myocardial infarction, or coronary revascularization. We calculated summary statistics, standard deviation (SD), odds ratios (OR), 95% confidence intervals (CI), and receiver operating characteristics (ROC). We enrolled 159 patients who had a mean age of 55 ± 13, were 56% female, of whom 5.2% suffered at least one adverse cardiac event. MPO test characteristics were poor, with an ROC area of only 0.47 (CI 0.23-0.71). MPO levels were not associated with adverse events (OR 0.99, CI 0.98-1.01, p=0.62). The optimal ROC cutpoint to predict adverse cardiac events had poor sensitivity and specificity (57% and 52%, respectively). Mean MPO concentrations in the event group did not differ from the non-event group. In this limited cohort of low risk ED patients with chest pain, we were unable to demonstrate utility of MPO for risk stratification. If confirmed in larger studies, these findings may call into question the routine use of MPO for low-risk chest pain

Ultrafast laser-writing of liquid crystal waveguides

With the development of conformable photonic platforms, particularly those that could be interfaced with the human body or integrated into wearable technology, there is an ever increasing need for mechanically flexible optical photonic elements in soft materials. Here, we realize mechanically flexible liquid crystal (LC) waveguides using a combination ultrafast direct laser writing and ultraviolet (UV) photo-polymerization. Results are presented that demonstrate that these laser-written waveguides can be either electrically switchable (by omitting the bulk UV polymerization step) or mechanically flexible. Characteristics of the waveguide are investigated for different fabrication conditions and geometrical configurations, including the dimensions of the waveguide and laser writing power. Our findings reveal that smaller waveguide geometries result in reduced intensity attenuation. Specifically, for a 10 μm wide laser written channel in a 14 μm-thick LC layer, a loss factor of -1.8 dB/mm at λ = 650 nm was observed. Following the UV polymerization step and subsequent delamination of the glass substrates, we demonstrate a free-standing flexible LC waveguide, which retains waveguide functionality even when bent, making it potentially suitable for on-skin sensors and other photonic devices that could interface with the human body. For the flexible LC waveguides fabricated in this study, the loss in a straight waveguide with a cross-sectional area of 20 μm × 20 μm was recorded to be -0.2 dB/mm. These results highlight the promising potential of electrically-responsive and mechanically moldable optical waveguides using laser writing and UV-assisted polymer network formation

Variation in the use of observation status evaluation in Massachusetts acute care hospitals, 2003–2006

Background Observation evaluation is an alternate pathway to inpatient admission following Emergency Department (ED) assessment. Aims We aimed to describe the variation in observation use and charges between acute care hospitals in Massachusetts from 2003 to 2006. Methods Retrospective pilot analysis of hospital administrative data. Patients discharged from a Massachusetts hospital between 2003 and 2006 after an observation visit or inpatient hospitalization for six emergency medical conditions, grouped by the Clinical Classification System (CCS), were included. Patients discharged with a primary obstetric condition were excluded. The primary outcome measure, “Observation Proportion ” (pOBS), was the use of observation evaluation relative to inpatient evaluation (pOBS = n Observation/(n Observation + n Inpatient). We calculated pOBS, descriptive statistics of use and charges by the hospital for each condition. Results From 2003 to 2006 the number of observation visits in Massachusetts increased 3.9 % [95 % confidence interval (CI) 3.8 % to 4.0%] from 128,825 to 133,859, while inpatient hospitalization increased 1.29 % (95 % CI 1.26 % to 1.31%) from 832,415 to 843,617. Nonspecific chest pain (CCS 102) was the most frequently observed condition with 85,843 (16.3 % of total) observation evaluations. Observation visits for nonspecific chest pain increased 43.5 % from 2003 to 2006. Relative observation utilization (pOBS) for nonspecific chest pain ranged from 25 % to 95% across hospitals. Wide variation in hospital use of observation and charges was seen for all six emergency medical conditions. Conclusions There was wide variation in use of observation across six common emergency conditions in Massachusetts in this pilot analysis. This variation may have a substantial impact on hospital resource utilization. Further investigation into the patient, provider and hospital-level characteristics that explain the variation in observation use could help improve hospital efficiency

Introduction of a novel magnetic resonance imaging-based scoring system for assessing disease activity in children with juvenile dermatomyositis

Objectives: We aimed to develop and assess the reliability of a novel MRI-based scoring system for reporting the severity of MRI findings in children with suspected JDM. Methods: Nine consultant paediatric radiologists independently assessed and scored 40 axial and 30 coronal thigh MR images of children with suspected JDM on two occasions using the juvenile dermatomyositis magnetic resonance Imaging Score (JIS). JIS was calculated for both reads for each plane and each limb, with possible scores ranging from 0 (normal) to 100 (severe). Inter- and intraobserver agreement was calculated using the intraclass correlation coefficient (ICC) and two- and one-way random effects models, respectively. Bland-Altman plots of the difference in JIS against the average JIS were also produced for each rater. Results: Overall, the interobserver reliability and agreement was good-for axial images, JIS ranged from 46.8 to 61.0 [ICC = 0.88 (95% CI: 0.82, 0.92)] for the left limb and 47.9-61.4 [ICC = 0.87 (95% CI: 0.81, 0.92)] for the right limb. For coronal images, JIS ranged from 56.7 to 65.1 [ICC = 0.90 (95% CI: 0.85, 0.95)] for the left limb and 55.7 to 66.8 [ICC = 0.90 (95% CI: 0.84, 0.94)] for the right limb. The intraobserver reliability and agreement was good, with ICC ranging from 0.90 to 0.94. Conclusion: JIS is a semi-objective scoring system with potential to serve as a reliable biomarker of disease severity and response to therapeutic interventions in children with JDM

Oncogenic PIK3CA Mutations Reprogram Glutamine Metabolism in Colorectal Cancer

Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to alpha-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110 alpha upregulates GPT2 gene expression through an AKT-independent, PDK1-RSK2-ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations

Oncogenic PIK3CA Mutations Reprogram Glutamine Metabolism in Colorectal Cancer

Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to alpha-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110 alpha upregulates GPT2 gene expression through an AKT-independent, PDK1-RSK2-ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations

Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation

Validation of Human Telomere Length Multi-Ancestry Meta-Analysis Association Signals Identifies POP5 and KBTBD6 as Human Telomere Length Regulation Genes

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation