Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitization.

BACKGROUND: There is limited data on the mechanisms of aspirin desensitization in patients with nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema (NIUA). OBJECTIVES: We sought to characterize the transcriptomic and metabolomic profiles of patients with NIUA undergoing aspirin desensitization. METHODS: PBMCs and plasma were separated from the blood of patients with NIUA undergoing aspirin desensitization for coronary artery disease and NSAID-tolerant controls. RNA was isolated from PBMCs and subjected to messenger RNA (mRNA)- and long noncoding RNA (lncRNA)-sequencing. Plasma samples were analyzed using LC-MS/MS for metabolite shifts using a semitargeted metabolomics panel. RESULTS: Eleven patients with NIUA and 10 healthy controls were recruited. The mRNA gene profiles of predesensitization versus postdesensitization and healthy control versus postdesensitization did not differ significantly. However, we identified 739 mRNAs and 888 lncRNAs as differentially expressed from preaspirin desensitization patients and controls. A 12-mRNA gene signature was trained using a machine learning algorithm to distinguish between controls, postdose, and predose samples. Ingenuity Pathway Analysis identified 5 canonical pathways that were significantly enriched in preaspirin desensitization samples. IL-22 was the most upregulated pathway. To investigate the potential regulatory roles of the differentially expressed lncRNA on the mRNAs, 9 lncRNAs and 12 mRNAs showed significantly correlated expression patterns in the IL-22 pathway. To validate the transcriptomics data, IL-22 was measured in the plasma samples of the subjects using ELISA. IL-22 was significantly higher in preaspirin desensitization patients compared with controls. In parallel, metabolomic analysis revealed stark differences in plasma profiles of preaspirin desensitization patients and healthy controls. In particular, 2-hydroxybenzoic acid (salicylic acid) was significantly lower in preaspirin desensitization patients compared with healthy controls. CONCLUSIONS: This is the first study to combine both transcriptomic and metabolomic approaches in patients with NIUA, which contributes to a deeper understanding about the pathogenesis of NIUA and may potentially pave the way toward a molecular diagnosis of NSAID hypersensitivity.

The Problems with Online Health Product Sales: How can Regulations be Improved?

With the rapid proliferation of online businesses, national authorities are facing challenges managing the online supply of illegal health products due to the anonymity of the internet, increasing number of global syndicates, new technologies, and inability to enforce against overseas sellers. This paper describes these challenges and the Health Sciences Authority's regulatory approaches to tackle the online sales of illegal health products. These include partnering with platform administrators to remove illegal online postings, leveraging technological tools and relevant legislation, empowering consumers to make informed decisions, and fostering closer collaborations across different jurisdictions to combat online pharmaceutical crimes.

Risk factors for infection/colonization caused by resistant Gram negative bacilli in critically ill patients (an observational study of 1633 critically ill patients).

OBJECTIVE: The objective of this study is to identify risk factors associated with multi-resistant Gram negative (RGNB) infection and colonization among critically ill patients. METHODS: A prospective cohort study of all patients aged 21-90 admitted for more than 24 hours in Medical and Surgical intensive care units (ICU) at a large teaching hospital in Singapore for the period of Aug '07-Dec '09 was conducted. Patient demographics, comorbidities, antibiotics, invasive devices, and culture results were collected. Forward stepwise logistic regression analyses were done to identify risk factors associated with RGNB infection and colonization. RESULTS: Of the 1373 patients included in the analysis, 13.5% developed RGNB infection. A logistic regression analysis including variables with a p value of <0.2 in the univariate analysis showed that recent surgery (OR 2.1, 95% CI 1.2-3.6), renal impairment (OR 2.9, 95% CI 1.5-5.4), liver disease (OR: 3.8, 95% CI 1.7-8.8), central line (OR 1.8, 95% CI 1.01-3.4) were independently associated with RGNB infection in the ICU. Surgery (OR 3.9, 95% CI 2.7-5.7), third-line antibiotics (carbapenem, vancomycin, linezolid) (OR 1.8, 95% CI 1.2-2.9) were independently associated with RGNB infection during their hospitalization. CONCLUSION: The major risk factors identified for RGNB infection and colonization in the ICU were mainly patient dependent. However, broad spectrum initial antibiotic treatment remains an important independent modifiable risk factor. Interventions aimed at reducing initial broad spectrum antibiotics are clearly needed to help control the spread of these difficult to treat infections.

Novel Oxidative Stress Biomarkers with Risk Prognosis Values in Heart Failure.

Oxidative stress (OS) is mediated by reactive oxygen species (ROS), which in cardiovascular and other disease states, damage DNA, lipids, proteins, other cellular and extra-cellular components. OS is both initiated by, and triggers inflammation, cardiomyocyte apoptosis, matrix remodeling, myocardial fibrosis, and neurohumoral activation. These have been linked to the development of heart failure (HF). Circulating biomarkers generated by OS offer potential utility in patient management and therapeutic targeting. Novel OS-related biomarkers such as NADPH oxidases (sNox2-dp, Nrf2), advanced glycation end-products (AGE), and myeloperoxidase (MPO), are signaling molecules reflecting pathobiological changes in HF. This review aims to evaluate current OS-related biomarkers and their associations with clinical outcomes and to highlight those with greatest promise in diagnosis, risk stratification and therapeutic targeting in HF.

Deep phenotyping of oxidative stress in emergency room patients reveals homoarginine as a novel predictor of sepsis severity, length of hospital stay, and length of intensive care unit stay.

Background: We aimed to determine primary markers of oxidative stress (OS) in ED patients which predict hospital length of stay (LoS), intensive care unit (ICU) LoS, and sepsis severity. Materials and methods: This prospective, single center observational study was conducted in adult patients recruited from the ED who were diagnosed with either sepsis, infection without sepsis, or non-infectious, age-matched controls. 290 patients were admitted to the hospital and 24 patients had direct admission to the ICU. A panel of 269 OS and related metabolic markers were profiled for each cohort. Clinical outcomes were direct ICU admission, hospital LoS, ICU LoS, and post-hoc, adjudicated sepsis severity scoring. Bonferroni correction was used for pairwise comparisons. Principal component regression was used for dimensionality reduction and selection of plasma metabolites associated with sepsis. Multivariable negative binomial regression was applied to predict admission, hospital, and ICU LoS. Results: Homoarginine (hArg) was the top discriminator of sepsis severity [sepsis vs. control: ROC-AUC = 0.86 (95% CI 0.81-0.91)], [sepsis vs. infection: ROC-AUC = 0.73 (95% CI 0.68-0.78)]. The 25th percentile of hArg [odds ratio (OR) = 8.57 (95% CI 1.05-70.06)] was associated with hospital LoS [IRR = 2.54 (95% CI 1.83-3.52)] and ICU LOS [IRR = 18.73 (95% CI 4.32-81.27)]. In prediction of outcomes, hArg had superior performance compared to arginine (Arg) [hArg ROC-AUC = 0.77 (95% CI 0.67-0.88) vs. Arg ROC-AUC = 0.66 (95% CI 0.55-0.78)], and dimethylarginines [SDMA ROC-AUC 0.68 (95% CI 0.55-0.79) and ADMA ROC-AUC = 0.68 (95% CI 0.56-0.79)]. Ratio of hArg and Arg/NO metabolic markers and creatinine clearance provided modest improvements in clinical prediction. Conclusion: Homoarginine is associated with sepsis severity and predicts hospital and ICU LoS, making it a useful biomarker in guiding treatment decisions for ED patients.

Differential Response of Coral Assemblages to Thermal Stress Underscores the Complexity in Predicting Bleaching Susceptibility.

Coral bleaching events have been predicted to occur more frequently in the coming decades with global warming. The susceptibility of corals to bleaching during thermal stress episodes is dependent on many factors and an understanding of these underlying drivers is crucial for conservation management. In 2013, a mild bleaching episode ensued in response to elevated sea temperature on the sediment-burdened reefs in Singapore. Surveys of seven sites highlighted variable bleaching susceptibility among coral genera-Pachyseris and Podabacia were the most impacted (31% of colonies of both genera bleached). The most susceptible genera such as Acropora and Pocillopora, which were expected to bleach, did not. Susceptibility varied between less than 6% and more than 11% of the corals bleached, at four and three sites respectively. Analysis of four of the most bleached genera revealed that a statistical model that included a combination of the factors (genus, colony size and site) provided a better explanation of the observed bleaching patterns than any single factor alone. This underscored the complexity in predicting the coral susceptibility to future thermal stress events and the importance of monitoring coral bleaching episodes to facilitate more effective management of coral reefs under climate change.

Increase in cholesterol and cholesterol oxidation products, and role of cholesterol oxidation products in kainate-induced neuronal injury.

Little is known about changes in sterols, in particular cholesterol, and cholesterol oxidation products (COPs) in oxidative injury in neural tissues. We have therefore examined changes in cholesterol and COPs using a model of excitotoxic injury. Intracerebroventricular injections of kainate in rats resulted in an increase in immunoreactivity to cholesterol in the affected CA fields of the hippocampus. The increase was confirmed by increased filipin staining of cholesterol in adjacent sections from the same animals, and in hippocampal slice or neuronal cultures after kainate treatment. In neuronal cultures, addition of lovastatin, an inhibitor of cholesterol synthesis, attenuated the increased filipin staining after kainate treatment, indicating that the increase in cholesterol could involve increased cholesterol synthesis. Furthermore, gas chromatographic mass spectrometric (GC/MS) analysis of cholesterol and COPs in kainate-injected rat brain showed a marked increase in cholesterol and COPs including 7-ketocholesterol, 3 days after kainate treatment. The addition of some COPs, including 7-ketocholesterol and cholesterol epoxides to hippocampal slices resulted in neuronal injury as reflected by decreased staining of a neuronal marker in the affected CA fields. The ability of these COPs to produce neuronal injury was attenuated by glutathione, suggesting that oxidative mechanisms are involved in neuronal injury induced by these products. These results, together with GC/MS results that showed significant increase in 7-ketocholesterol at 3 days post-kainate injury suggest that 7-ketocholesterol may be a factor in aggravating oxidative damage to neurons, after the initial stages of kainate-induced neuronal injury.

Inappropriate empirical antimicrobial therapy for multidrug-resistant organisms in critically ill patients with pneumonia is not an independent risk factor for mortality: Results of a prospective observational study of 758 patients.

The benefits of broad-spectrum initial empirical antibiotic therapy for all patients in intensive care units (ICUs) with high rates of multidrug-resistant organisms (MDROs) have not been critically evaluated. In this study, 758 ICU patients with pneumonia were prospectively evaluated. Of 349 positive respiratory cultures, 119 (34.1%) were with MDRO isolates. These were associated with increased mortality [adjusted hazard ratio (HR)=1.65, 95% confidence interval (CI) 1.01-2.68; P=0.04] as was increasing age and Acute Physiology and Chronic Health Evaluation (APACHE) II score. Among the patients with MDRO-associated pneumonia, increasing age, APACHE II score and inappropriate definitive antimicrobial therapy (IDAT) were found to be significant risk factors for mortality (in-ICU mortality, adjusted HR=2.8, 95% CI 1.3-5.8; P=0.007), but inappropriate empirical antimicrobial therapy (IEAT) was not (in-ICU mortality, unadjusted HR=1.6, 95% CI 0.7-3.6; P=0.3). In conclusion, we found that among critically ill patients with MDRO-associated pneumonia, IEAT is not an independent risk factor for ICU mortality. Hence, we do not recommend the use of broad-spectrum initial empirical antimicrobial therapy for all patients, as its benefits may not outweigh the potential risks. Early microbiological diagnosis to facilitate implementation of early definitive antimicrobial therapy through use of novel technologies is likely to have a major impact.