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[This corrects the article DOI: 10.1371/journal.pone.0227748.].

ObjectivesThe Laboratory Risk Indicator for Necrotizing Fasciitis score was developed as a clinical decision tool for distinguishing necrotizing fasciitis from other soft tissue infections. We prospectively evaluated the performance of the Laboratory Risk Indicator for Necrotizing Fasciitis score for the diagnosis of patients with necrotizing fasciitis in the extremities.MethodsWe conducted a prospective and observational cohort study of emergency department patients with necrotizing fasciitis or severe cellulitis in the extremities between April 2015 and December 2016. The Laboratory Risk Indicator for Necrotizing Fasciitis score was calculated for every enrolled patient. The sensitivity, specificity, positive predictive value, and negative predictive value of cut-off scores of 6 and 8 were evaluated. The accuracy of the Laboratory Risk Indicator for Necrotizing Fasciitis score was expressed as the area under the receiver operating characteristic curve.ResultsA total of 106 patients with necrotizing fasciitis and 825 patients with cellulitis were included. With an Laboratory Risk Indicator for Necrotizing Fasciitis cut-off score ≥6, the sensitivity was 43% (95% confidence interval 34% to 53%), specificity was 83% (95% confidence interval 80% to 86%), positive predictive value was 25% (95% confidence interval 20% to 30%), and negative predictive value was 92% (95% confidence interval 91% to 93%); with an Laboratory Risk Indicator for Necrotizing Fasciitis cut-off score ≥8, the sensitivity was 27% (95% confidence interval 19% to 37%), specificity was 93% (95% confidence interval 91% to 94%), positive predictive value was 33% (95% confidence interval 25% to 42%), and negative predictive value was 91% (95% confidence interval 90% to 92%). The area under the receiver operating characteristic curve for accuracy of the Laboratory Risk Indicator for Necrotizing Fasciitis score was 0.696 (95% CI 0.640 to 0.751).ConclusionThe Laboratory Risk Indicator for Necrotizing Fasciitis score may not be an accurate tool for necrotizing fasciitis risk stratification and differentiation between severe cellulitis and necrotizing fasciitis in the emergency department setting based on our study.

BACKGROUND:Predicting the survival of non-cancer related end-stage-liver-disease patients in general practice has been difficult for physicians because of the extremely variable trajectories due to multiple complex clinical factors, hence it remains a challenging issue to date. This study aimed to develop and validate a specific prognostic scoring system to early recognize the prognosis and improve the quality of end-of life care for non-cancer end-stage-liver-disease population. MATERIALS AND METHODS:A multicentre, retrospective cohort study was conducted during January 2010 ~ December 2012 and continued follow-up until December 2014. A cox proportional hazard regression analysis was used to derive and validate an optimized model. The main outcome measures were the 28-day, 3-month, 6-month, and 12-month mortality prediction. The performance of the novel model was evaluated, including discrimination and calibration. RESULTS:A total of 4,080 consecutive subjects were enrolled. The AUROCs for the 3-month survival discrimination in the MELD, MELD-Na and novel model were 0.787, 0.705 and 0.804 (P

Olanzapine (OLZ) is one of the most prescribed atypical antipsychotic drugs but its use is associated with unfavorable metabolic abnormalities. N-desmethyl-olanzapine (DMO), one of the OLZ metabolites by CYP1A2, has been reported to have a normalizing action on metabolic abnormalities, but this remains unclear. Our aim was to explore the correlation between the concentrations of OLZ or DMO with various metabolic parameters in schizophrenic patients.The chromatographic analysis was carried out with a solvent delivery system coupled to a Coulochem III coulometric detector to determine OLZ and DMO simultaneously in OLZ-treated patients. The correlation between the concentration of OLZ or DMO and the metabolic parameters was analyzed by the Spearman rank order correlation method (r s).The established analytical method met proper standards for accuracy and reliability and the lower limitation of quantification for each injection of DMO or OLZ was 0.02 ng. The method was successfully used for the analysis of samples from nonsmoking patients (n = 48) treated with OLZ in the dosage range of 5-20 mg per day. There was no correlation between OLZ concentrations and tested metabolic parameters. DMO concentrations were negatively correlated with glucose (r s = -0.45) and DMO concentrations normalized by doses were also negatively correlated with insulin levels (r s = -0.39); however, there was a marginally positive correlation between DMO and homocysteine levels (r s = +0.38).The observed negative correlations between levels of DMO and glucose or insulin suggest a metabolic normalization role for DMO regardless of its positive correlation with a known cardiovascular risk factor, homocysteine. Additional studies of the mechanisms underlying DMO's metabolic effects are warranted.

Protein arginine methyltransferase (PRMT) 1 is the most conserved and widely distributed PRMT in eukaryotes. PRMT8 is a vertebrate-restricted paralogue of PRMT1 with an extra N-terminal sequence and brain-specific expression. We use zebrafish (Danio rerio) as a vertebrate model to study PRMT8 function and putative redundancy with PRMT1. The transcripts of zebrafish prmt8 were specifically expressed in adult zebrafish brain and ubiquitously expressed from zygotic to early segmentation stage before the neuronal development. Whole-mount in situ hybridization revealed ubiquitous prmt8 expression pattern during early embryonic stages, similar to that of prmt1. Knockdown of prmt8 with antisense morpholino oligonucleotide phenocopied prmt1-knockdown, with convergence/extension defects at gastrulation. Other abnormalities observed later include short body axis, curled tails, small and malformed brain and eyes. Catalytically inactive prmt8 failed to complement the morphants, indicating the importance of methyltransferase activity. Full-length prmt8 but not prmt1 cRNA can rescue the phenotypic changes. Nevertheless, cRNA encoding Prmt1 fused with the N-terminus of Prmt8 can rescue the prmt8 morphants. In contrast, N-terminus- deleted but not full-length prmt8 cRNA can rescue the prmt1 morphants as efficiently as prmt1 cRNA. Abnormal brain morphologies illustrated with brain markers and loss of fluorescent neurons in a transgenic fish upon prmt8 knockdown confirm the critical roles of prmt8 in neural development. In summery, our study is the first report showing the expression and function of prmt8 in early zebrafish embryogenesis. Our results indicate that prmt8 may play important roles non-overlapping with prmt1 in embryonic and neural development depending on its specific N-terminus.

Akt1 is well known for its role in regulating cell proliferation, differentiation, and apoptosis and is implicated in tumors and several neurological disorders. However, the role of Akt1 in neural development has not been well defined. We have isolated zebrafish akt1 and shown that this gene is primarily transcribed in the developing nervous system, and its spatiotemporal expression pattern suggests a role in neural differentiation. Injection of akt1 morpholinos resulted in loss of neuronal precursors with a concomitant increase in post-mitotic neurons, indicating that knockdown of Akt1 is sufficient to cause premature differentiation of neurons. A similar phenotype was observed in embryos deficient for Notch signaling. Both the ligand (deltaA) and the downstream target of Notch (her8a) were downregulated in akt1 morphants, indicating that Akt1 is required for Delta-Notch signaling. Furthermore, akt1 expression was downregulated in Delta-Notch signaling-deficient embryos and could be induced by constitutive activation of Notch signaling. In addition, knockdown of Akt1 was able to nullify the inhibition of neuronal differentiation caused by constitutive activation of Notch signaling. Taken together, these results provide in vivo evidence that Akt1 interacts with Notch signaling reciprocally and provide an explanation of why Akt1 is essential for the inhibition of neuronal differentiation.

Understanding how diversity of neural cells is generated is one of the main tasks of developmental biology. The Hairy/E(spl) family members are potential targets of Notch signaling, which has been shown to be fundamental to neural cell maintenance, cell fate decisions, and compartment boundary formation. However, their response to Notch signaling and their roles in neurogenesis are still not fully understood. In the present study, we isolated a zebrafish homologue of hairy/E(spl), her8a, and showed this gene is specifically expressed in the developing nervous system. her8a is positively regulated by Su(H)-dependent Notch signaling as revealed by a Notch-defective mutant and injection of variants of the Notch intracellular regulator, Su(H). Morpholino knockdown of Her8a resulted in upregulation of proneural and post-mitotic neuronal markers, indicating that Her8a is essential for the inhibition of neurogenesis. In addition, markers for glial precursors and mature glial cells were down-regulated in Her8a morphants, suggesting Her8a is required for gliogenesis. The role of Her8a and its response to Notch signaling is thus similar to mammalian HES1, however this is the converse of what is seen for the more closely related mammalian family member, HES6. This study not only provides further understanding of how the fundamental signaling pathway, Notch signaling, and its downstream genes mediate neural development and differentiation, but also reveals evolutionary diversity in the role of H/E(spl) genes.