Retrospective analysis of tigecycline shows that it may be an option for children with severe infections.

AIM: This study assessed the efficacy and safety of tigecycline in children with life-threatening infections. METHODS: We retrospectively reviewed the clinical records of patients treated with tigecycline from June 2012 to May 2014 in a Chinese tertiary centre. RESULTS: The study comprised 24 patients (14 male) with a median age of four years (range, 50 days-12 years). The most frequently isolated microorganism, most common isolation site and type of infection were Acinetobacter baumannii, tracheal aspirate fluid and ventilator-associated pneumonia, respectively. Tigecycline was administered at a loading dose of 1.5 or 2.0 mg/kg and 1.0 mg/kg every 12 hours after that. The average duration of treatment was 11.6 ± 5.8 days. The clinical response and microbiological eradication rate were 37.5% and 29.2%, respectively. Six of the patients we studied (25.0%) died, and three of these deaths were considered to be infection related. Adverse drug reactions were identified in four patients (16.7%) during the treatment, including abnormal liver function, prolonged prothrombin time and diarrhoea. CONCLUSION: Our findings suggest that tigecycline may be an option for children with severe infections. However, more prospective, controlled trials are required to objectively evaluate the efficacy and safety of tigecycline in children.

Impact of pharmacist antimicrobial dosing adjustments in septic patients on continuous renal replacement therapy in an intensive care unit.

BACKGROUND: Correct dosing of antimicrobial drugs in septic patients receiving continuous renal replacement therapy (CRRT) is complex. This study aimed to evaluate the effects of dosing adjustments performed by pharmacists on the length of intensive care unit (ICU) stay, ICU cost, and antimicrobial adverse drug events (ADEs). METHODS: A single-center, 2-phase (pre-/post-intervention) study was performed in an ICU of a university-affiliated hospital. Septic patients receiving CRRT in the post-intervention phase received a specialized antimicrobial dosing service from critical care pharmacists, whereas patients in the pre-intervention phase received routine medical care without involving pharmacists. The 2 phases were compared to evaluate the outcomes of pharmacist interventions. RESULTS: Pharmacists made 183 antimicrobial dosing adjustment recommendations for septic patients receiving CRRT. Changes in CRRT-related variables (116, 63.4%) were the most common risk factors for dosing errors, and ß-lactams (101, 55.2%) were the antimicrobials most commonly associated with dosing errors. Dosing adjustments were related to a reduced length of ICU stay from 10.7 ± 11.1 days to 7.7 ± 8.3 days (p = 0.037) in the intervention group, and to cost savings of $3525 (13,463 ± 12,045 vs. 9938 ± 8811, p = 0.038) per septic patient receiving CRRT in the ICU. Suspected antimicrobial adverse drug events in the intervention group were significantly fewer than in the pre-intervention group (19 events vs. 8 events, p = 0.048). CONCLUSIONS: The involvement of pharmacists in antimicrobial dosing adjustments in septic patients receiving CRRT is associated with a reduced length of ICU stay, lower ICU costs, and fewer ADEs. Hospitals may consider employing clinical pharmacists in ICUs.

TP53 mutation-related senescence is an indicator of hepatocellular carcinoma patient outcomes from multiomics profiles.

TP53 mutation frequently occurs in hepatocellular carcinoma (HCC). Senescence also plays a vital role in the ongoing process of HCC. P53 is believed to regulate the advancement of senescence in HCC. However, the exact mechanism of TP53 mutation-related senescence remains unclear. In this study, we found the TP53 mutation was positively correlated with senescence in HCC, and the differential expressed genes were primarily located in macrophages. Our results proved that the risk score could have an independent and vital role in predicting the prognosis of HCC patients. In addition, HCC patients with a high risk score may most probably benefit from immune checkpoint block therapy. We also found the risk score is elevated in chemotherapy-treated HCC samples, with a high level of senescence-associated secretory phenotype. Finally, we validated the risk-score genes in the protein level and noticed the risk score is positively related with M2 polarization. Of note, we considered that the risk score under the TP53 mutation and senescence is a promising biomarker with the potential to aid in predicting prognosis, defining tumor environment characteristics, and assessing the benefits of immunotherapy for HCC patients.

Comprehensive Pan-Cancer Genomic Analysis Reveals PHF19 as a Carcinogenic Indicator Related to Immune Infiltration and Prognosis of Hepatocellular Carcinoma.

Background: As a crucial constituent part of Polycomb repressive complex 2, PHD finger protein 19 (PHF19) plays a pivotal role in epigenetic regulation, and acts as a critical regulator of multiple pathophysiological processes. However, the exact roles of PHF19 in cancers remain enigmatic. The present research was primarily designed to provide the prognostic landscape visualizations of PHF19 in cancers, and study the correlations between PHF19 expression and immune infiltration characteristics in tumor microenvironment. Methods: Raw data in regard to PHF19 expression were extracted from TCGA and GEO data portals. We examined the expression patterns, prognostic values, mutation landscapes, and protein-protein interaction network of PHF19 in pan-cancer utilizing multiple databases, and investigated the relationship of PHF19 expression with immune infiltrates across TCGA-sequenced cancers. The R language was used to conduct KEGG and GO enrichment analyses. Besides, we built a risk-score model of hepatocellular carcinoma (HCC) and validated its prognostic classification efficiency. Results: On balance, PHF19 expression was significantly higher in cancers in comparison with that in noncancerous samples. Increased expression of PHF19 was detrimental to the clinical prognoses of cancer patients, especially HCC. There were significant correlations between PHF19 expression and TMB or MSI in several cancers. High PHF19 levels were critically associated with the infiltration of myeloid-derived suppressor cells (MDSCs) and Th2 subsets of CD4+ T cells in most cancers. Enrichment analyses revealed that PHF19 participated in regulating carcinogenic processes including cell cycle and DNA replication, and was correlated with the progression of HCC. Intriguingly, GSEA suggested that PHF19 was correlated with the cellular components including immunoglobulin complex and T cell receptor complex in HCC. Based on PHF19-associated functional gene sets, an eleven-gene prognostic signature was constructed to predict HCC prognosis. Finally, we validated pan-cancer PHF19 expression, and its impacts on immune infiltrates in HCC. Conclusion: The epigenetic related regulator PHF19 participates in the carcinogenic progression of multiple cancers, and may contribute to the immune infiltration in tumor microenvironment. Our study suggests that PHF19 can serve as a carcinogenic indicator related to prognosis in pan-cancer, especially HCC, and shed new light on therapeutics of cancers for clinicians.

Protective Properties of FOXO1 Inhibition in a Murine Model of Non-alcoholic Fatty Liver Disease Are Associated With Attenuation of ER Stress and Necroptosis.

AIM: The pathogenesis of non-alcoholic fatty liver disease is currently unclear, however, lipid accumulation leading to endoplasmic reticulum stress appears to be pivotal in the process. At present, FOXO1 is known to be involved in NAFLD progression. The relationship between necroptosis and non-alcoholic steatohepatitis has been of great research interest more recently. However, whether FOXO1 regulates ER stress and necroptosis in mice fed with a high fat diet is not clear. Therefore, in this study we analyzed the relationship between non-alcoholic steatohepatitis, ER stress, and necroptosis. MAIN METHODS: Male C57BL/6J mice were fed with an HFD for 14 weeks to induce non-alcoholic steatohepatitis. ER stress and activation of necroptosis in AML12 cells were evaluated after inhibition of FOXO1 in AML12 cells. In addition, mice were fed with AS1842856 for 14 weeks. Liver function and lipid accumulation were measured, and further, ER stress and necroptosis were evaluated by Western Blot and Transmission Electron Microscopy. KEY FINDINGS: Mice fed with a high fat diet showed high levels of FOXO1, accompanying activation of endoplasmic reticulum stress and necroptosis. Further, sustained PA stimulation caused ER stress and necroptosis in AML12 cells. At the same time, protein levels of FOXO1 increased significantly. Inhibition of FOXO1 with AS1842856 alleviated ER stress and necroptosis. Additionally, treatment of mice with a FOXO1 inhibitor ameliorated liver function after they were fed with a high fat diet, displaying better liver condition and lighter necroptosis. SIGNIFICANCE: Inhibition of FOXO1 attenuates ER stress and necroptosis in a mouse model of non-alcoholic steatohepatitis.

Effectiveness of pharmacist dosing adjustment for critically ill patients receiving continuous renal replacement therapy: a comparative study.

BACKGROUND: The impact of continuous renal replacement therapy (CRRT) on drug removal is complicated; pharmacist dosing adjustment for these patients may be advantageous. This study aims to describe the development and implementation of pharmacist dosing adjustment for critically ill patients receiving CRRT and to examine the effectiveness of pharmacist interventions. METHODS: A comparative study was conducted in an intensive care unit (ICU) of a university-affiliated hospital. Patients receiving CRRT in the intervention group received specialized pharmacy dosing service from pharmacists, whereas patients in the no-intervention group received routine medical care without pharmacist involvement. The two phases were compared to evaluate the outcome of pharmacist dosing adjustment. RESULTS: The pharmacist carried out 233 dosing adjustment recommendations for patients receiving CRRT, and 212 (90.98%) of the recommendations were well accepted by the physicians. Changes in CRRT-related variables (n=144, 61.81%) were the most common risk factors for dosing errors, whereas antibiotics (n=168, 72.10%) were the medications most commonly associated with dosing errors. Pharmacist dosing adjustment resulted in a US$2,345.98 ICU cost savings per critically ill patient receiving CRRT. Suspected adverse drug events in the intervention group were significantly lower than those in the preintervention group (35 in 27 patients versus [vs] 18 in eleven patients, P<0.001). However, there was no significant difference between length of ICU stay and mortality after pharmacist dosing adjustment, which was 8.93 days vs 7.68 days (P=0.26) and 30.10% vs 27.36% (P=0.39), respectively. CONCLUSION: Pharmacist dosing adjustment for patients receiving CRRT was well accepted by physicians, and was related with lower adverse drug event rates and ICU cost savings. These results may support the development of strategies to include a pharmacist in the multidisciplinary ICU team.