Medication reconciliation by pharmacists for pre-admission patients improves patient safety.

BACKGROUND: Medication errors related to the pre-admission medication history obtained on admission are a major cause of medication error during hospitalization. Medication reconciliation (MR) improves patient safety through the detection of inadvertent medication discrepancies at transitions of care. The aim of this study was to evaluate the effect of MR by pharmacists for patients prior to hospital admission on the incidence of medication errors in the early post-admission period. PATIENTS AND METHODS: Patients admitted to the orthopedic ward for surgery between April 2012 and March 2020 were included. Pharmacist-led MR for pre-admission patients was started on April 1, 2017. The incidence of medication errors related to pre-admission medications that occurred during hospitalization were compared between the pre- and post-initiation of pharmacist-led MR (pre-initiation: April 1, 2012 to March 31, 2015, post-initiation: April 1, 2017 to March 31, 2020). RESULT: In the post-initiation group, 94.2% (1245/1321) of patients who were taking medications on admission had a pharmacist-led MR before admission. The proportion of patients whose physicians ordered the prescription of their pre-admission medications at the time before hospitalization to continue from admission was significantly higher in the post-initiation group than in the pre-initiation group (47.4% vs. 1.0%, p < 0.001). The incidence of medication errors related to pre-admission medications during hospitalization was significantly lower in the post-initiation group than in the pre-initiation group (1.83% vs. 0.85%, p = 0.025). Pharmacist-led MR prior to admission was a significant protective factor against incidents related to pre-admission medication (odds ratio (OR), 0.3810; 95% confidence interval (CI); 0.156-0.9320, p = 0.035). CONCLUSION: Pharmacist-led MR for patients prior to hospital admission led to a reduction in medication errors related to pre-admission medications during hospitalization. Patient safety during hospitalization can be improved by accurate medication histories provided early by pharmacists.

Comparison of the incidence of vancomycin-associated nephrotoxicity following the change from trough-guided dosing to AUC-guided doing using trough-only data.

OBJECTIVES: Although use of AUC-guided vancomycin dosing was recommended in the revised 2020 consensus guideline, collection of multiple vancomycin serum samples to calculate AUC may cause clinical complications. AUC calculated from trough-only data (one-point AUC-guided dosing) has not been sufficiently validated. The aim of the present study was to compare the incidence of nephrotoxicity following the change from trough-guided to one-point AUC-guided dosing. METHODS: We conducted a single-centre, prospective cohort study to compare the incidence of nephrotoxicity between a trough-guided dosing group and one-point AUC-guided dosing group. RESULTS: One-point AUC-guided dosing significantly decreased the incidence of acute kidney injury (AKI) compared with trough-guided dosing (2.8% versus 17.4%, P = 0.002). Further, Kaplan-Meier plots for cumulative incidence of the AKI-free rate indicated that the onset of AKI was significantly longer in the one-point AUC-guided dosing group than in trough-guided dosing (HR, 6.5; 95% CI, 1.5-27.4; P = 0.011). Moreover, multivariate Cox proportional hazard analysis indicated that implementation of one-point AUC-guided dosing was a significant protective factor against the incidence of AKI (age-adjusted HR, 0.164; 95% CI, 0.04-0.69; P = 0.014). CONCLUSIONS: Compared with trough concentration-guided dosing, AUC-guided dosing using one-point sampling markedly reduced the incidence of AKI, without additional serum sampling.

IFN-γ-STAT1-ERK Pathway Mediates Protective Effects of Invariant Natural Killer T Cells Against Doxorubicin-Induced Cardiomyocyte Death.

Doxorubicin (DOX)-induced cardiomyopathy has poor prognosis, and myocardial inflammation is intimately involved in its pathophysiology. The role of invariant natural killer T (iNKT) cells has not been fully determined in this disease. We here demonstrated that activation of iNKT cells by α-galactosylceramide (GC) attenuated DOX-induced cardiomyocyte death and cardiac dysfunction. αGC increased interferon (IFN)-γ and phosphorylation of signal transducers and activators of transcription 1 (STAT1) and extracellular signal-regulated kinase (ERK). Administration of anti-IFN-γ neutralizing antibody abrogated the beneficial effects of αGC on DOX-induced cardiac dysfunction. These findings emphasize the protective role of iNKT cells in DOX-induced cardiomyopathy via the IFN-γ-STAT1-ERK pathway.

RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function.

Although several ribosomal protein paralogs are expressed in a tissue-specific manner, how these proteins affect translation and why they are required only in certain tissues have remained unclear. Here we show that RPL3L, a paralog of RPL3 specifically expressed in heart and skeletal muscle, influences translation elongation dynamics. Deficiency of RPL3L-containing ribosomes in RPL3L knockout male mice resulted in impaired cardiac contractility. Ribosome occupancy at mRNA codons was found to be altered in the RPL3L-deficient heart, and the changes were negatively correlated with those observed in myoblasts overexpressing RPL3L. RPL3L-containing ribosomes were less prone to collisions compared with RPL3-containing canonical ribosomes. Although the loss of RPL3L-containing ribosomes altered translation elongation dynamics for the entire transcriptome, its effects were most pronounced for transcripts related to cardiac muscle contraction and dilated cardiomyopathy, with the abundance of the encoded proteins being correspondingly decreased. Our results provide further insight into the mechanisms and physiological relevance of tissue-specific translational regulation.

ZBP1 Protects Against mtDNA-Induced Myocardial Inflammation in Failing Hearts.

BACKGROUND: Mitochondrial DNA (mtDNA)-induced myocardial inflammation is intimately involved in cardiac remodeling. ZBP1 (Z-DNA binding protein 1) is a pattern recognition receptor positively regulating inflammation in response to mtDNA in inflammatory cells, fibroblasts, and endothelial cells. However, the role of ZBP1 in myocardial inflammation and cardiac remodeling remains unclear. The aim of this study was to elucidate the role of ZBP1 in mtDNA-induced inflammation in cardiomyocytes and failing hearts. METHODS: mtDNA was administrated into isolated cardiomyocytes. Myocardial infarctionwas conducted in wild type and ZBP1 knockout mice. RESULTS: We here found that, unlike in macrophages, ZBP1 knockdown unexpectedly exacerbated mtDNA-induced inflammation such as increases in IL (interleukin)-1ß and IL-6, accompanied by increases in RIPK3 (receptor interacting protein kinase 3), phosphorylated NF-κB (nuclear factor-κB), and NLRP3 (nucleotide-binding domain and leucine-rich-repeat family pyrin domain containing 3) in cardiomyocytes. RIPK3 knockdown canceled further increases in phosphorylated NF-κB, NLRP3, IL-1ß, and IL-6 by ZBP1 knockdown in cardiomyocytes in response to mtDNA. Furthermore, NF-κB knockdown suppressed such increases in NLRP3, IL-1ß, and IL-6 by ZBP1 knockdown in response to mtDNA. CpG-oligodeoxynucleotide, a Toll-like receptor 9 stimulator, increased RIPK3, IL-1ß, and IL-6 and ZBP1 knockdown exacerbated them. Dloop, a component of mtDNA, but not Tert and B2m, components of nuclear DNA, was increased in cytosolic fraction from noninfarcted region of mouse hearts after myocardial infarction compared with control hearts. Consistent with this change, ZBP1, RIPK3, phosphorylated NF-κB, NLRP3, IL-1ß, and IL-6 were increased in failing hearts. ZBP1 knockout mice exacerbated left ventricular dilatation and dysfunction after myocardial infarction, accompanied by further increases in RIPK3, phosphorylated NF-κB, NLRP3, IL-1ß, and IL-6. In histological analysis, ZBP1 knockout increased interstitial fibrosis and myocardial apoptosis in failing hearts. CONCLUSIONS: Our study reveals unexpected protective roles of ZBP1 against cardiac remodeling as an endogenous suppressor of mtDNA-induced myocardial inflammation.

Iron Overload via Heme Degradation in the Endoplasmic Reticulum Triggers Ferroptosis in Myocardial Ischemia-Reperfusion Injury.

Ischemia-reperfusion (I/R) injury is a promising therapeutic target to improve clinical outcomes after acute myocardial infarction. Ferroptosis, triggered by iron overload and excessive lipid peroxides, is reportedly involved in I/R injury. However, its significance and mechanistic basis remain unclear. Here, we show that glutathione peroxidase 4 (GPx4), a key endogenous suppressor of ferroptosis, determines the susceptibility to myocardial I/R injury. Importantly, ferroptosis is a major mode of cell death in I/R injury, distinct from mitochondrial permeability transition (MPT)-driven necrosis. This suggests that the use of therapeutics targeting both modes is an effective strategy to further reduce the infarct size and thereby ameliorate cardiac remodeling after I/R injury. Furthermore, we demonstrate that heme oxygenase 1 up-regulation in response to hypoxia and hypoxia/reoxygenation degrades heme and thereby induces iron overload and ferroptosis in the endoplasmic reticulum (ER) of cardiomyocytes. Collectively, ferroptosis triggered by GPx4 reduction and iron overload in the ER is distinct from MPT-driven necrosis in both in vivo phenotype and in vitro mechanism for I/R injury. The use of therapeutics targeting ferroptosis in conjunction with cyclosporine A can be a promising strategy for I/R injury.

Comparison of single trough-based area under the concentration-time curve versus trough concentration for the incidence of vancomycin-associated nephrotoxicity.

INTRODUCTION: While the revised 2020 consensus guideline recommends the use of area under the concentration-time curve (AUC)-guided vancomycin monitoring, collecting multiple vancomycin serum samples to calculate the AUC may cause clinical complications. The aim of the present retrospective study was to evaluate whether AUC-guided vancomycin monitoring, in which AUC was calculated based on a single trough concentration, is a better predictor of nephrotoxicity than trough-guided monitoring in patients receiving vancomycin therapy. METHODS: A single-center, retrospective cohort study was conducted at the 614-bed Gifu University Hospital in Japan. Patients who received intravenous vancomycin for a documented or suspected infection and had their serum vancomycin trough concentration monitored between October 1, 2016 and September 30, 2020 were enrolled in the present study. RESULTS: Multivariate Cox proportional hazard analysis indicated that AUC (>600 µg•h/mL) was a significant risk factor for the incidence of acute kidney injury (AKI), while trough concentration (≥15 µg/mL) was not. Moreover, the AUC (>600 µg•h/mL) showed higher specificity and similar sensitivity to the trough concentration (≥15 µg/mL). Kaplan-Meier plots of the cumulative incidence of the AKI-free rate in patients indicated that the onset of AKI was significantly longer in patients with AUC ≤600 µg•h/mL than in patients with AUC >600 µg•h/mL (HR, 16.1; 95% CI, 6.3-41.2; p < 0.001). CONCLUSION: AUC based on a single trough concentration was a better predictor of nephrotoxicity than trough concentration.

GFAT2 mediates cardiac hypertrophy through HBP-O-GlcNAcylation-Akt pathway.

Molecular mechanisms mediating cardiac hypertrophy by glucose metabolism are incompletely understood. Hexosamine biosynthesis pathway (HBP), an accessory pathway of glycolysis, is known to be involved in the attachment of O-linked N-acetylglucosamine motif (O-GlcNAcylation) to proteins, a post-translational modification. We here demonstrate that glutamine-fructose-6-phosphate amidotransferase 2 (GFAT2), a critical HBP enzyme, is a major isoform of GFAT in the heart and is increased in response to several hypertrophic stimuli, including isoproterenol (ISO). Knockdown of GFAT2 suppresses ISO-induced cardiomyocyte hypertrophy, accompanied by suppression of Akt O-GlcNAcylation and activation. Knockdown of GFAT2 does not affect anti-hypertrophic effect by Akt inhibition. Administration of glucosamine, a substrate of HBP, induces protein O-GlcNAcylation, Akt activation, and cardiomyocyte hypertrophy. In mice, 6-diazo-5-oxo-L-norleucine, an inhibitor of GFAT, attenuates ISO-induced protein O-GlcNAcylation, Akt activation, and cardiac hypertrophy. Our results demonstrate that GFAT2 mediates cardiomyocyte hypertrophy by HBP-O-GlcNAcylation-Akt pathway and could be a critical therapeutic target of cardiac hypertrophy.

DPP (Dipeptidyl Peptidase)-4 Inhibitor Attenuates Ang II (Angiotensin II)-Induced Cardiac Hypertrophy via GLP (Glucagon-Like Peptide)-1-Dependent Suppression of Nox (Nicotinamide Adenine Dinucleotide Phosphate Oxidase) 4-HDAC (Histone Deacetylase) 4 Pathway.

Nox4 (NADPH [Nicotinamide adenine dinucleotide phosphate] oxidase 4) is a major source of oxidative stress and is intimately involved in cardiac hypertrophy. DPP (Dipeptidyl peptidase)-4 inhibitor has been reported to regulate Nox4 expression in adipose tissues. However, its effects on Nox4 in cardiac hypertrophy are still unclear. We investigated whether DPP-4 inhibitor could ameliorate cardiac hypertrophy by regulating Nox4 and its downstream targets. Ang II (Angiotensin II; 1.44 mg/kg per day) or saline was continuously infused into C57BL/6J mice with or without teneligliptin (a DPP-4 inhibitor, 30 mg/kg per day) in the drinking water for 1 week. Teneligliptin significantly suppressed plasma DPP-4 activity without any significant changing aortic blood pressure or metabolic parameters such as blood glucose and insulin levels. It attenuated Ang II-induced increases in left ventricular wall thickness and the ratio of heart weight to body weight. It also significantly suppressed Ang II-induced increases in Nox4 mRNA, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4 (histone deacetylase 4), a downstream target of Nox4 and a crucial suppressor of cardiac hypertrophy, in the heart. Exendin-3 (150 pmol/kg per minute), a GLP-1 (glucagon-like peptide 1) receptor antagonist, abrogated these inhibitory effects of teneligliptin on Nox4, 4-hydroxy-2-nonenal, phosphorylation of HDAC4, and cardiac hypertrophy. In cultured neonatal cardiomyocytes, exendin-4 (100 nmol/L, 24 hours), a GLP-1 receptor agonist, ameliorated Ang II-induced cardiomyocyte hypertrophy and decreased in Nox4, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4. Furthermore, exendin-4 prevented Ang II-induced decrease in nuclear HDAC4 in cardiomyocytes. In conclusion, GLP-1 receptor stimulation by DPP-4 inhibitor can attenuate Ang II-induced cardiac hypertrophy by suppressing of the Nox4-HDAC4 axis in cardiomyocytes.

Blockade of L-type Ca2+ channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-kappa B (NF-κB) play crucial roles in pathogenesis of doxorubicin (DOX)-induced cardiomyopathy. Their activities are regulated by intracellular Ca2+. We hypothesized that blockade of L-type Ca2+ channel (LTCC) could attenuate DOX-induced cardiomyopathy by regulating CaMKII and NF-κB. DOX activated CaMKII and NF-κB through their phosphorylation and increased cleaved caspase 3 in cardiomyocytes. Pharmacological blockade or gene knockdown of LTCC by nifedipine or small interfering RNA, respectively, suppressed DOX-induced phosphorylation of CaMKII and NF-κB and apoptosis in cardiomyocytes, accompanied by decreasing intracellular Ca2+ concentration. Autocamtide 2-related inhibitory peptide (AIP), a selective CaMKII inhibitor, inhibited DOX-induced phosphorylation of NF-κB and cardiomyocyte apoptosis. Inhibition of NF-κB activity by ammonium pyrrolidinedithiocarbamate (PDTC) suppressed DOX-induced cardiomyocyte apoptosis. DOX-treatment (18 mg/kg via intravenous 3 injections over 1 week) increased phosphorylation of CaMKII and NF-κB in mouse hearts. Nifedipine (10 mg/kg/day) significantly suppressed DOX-induced phosphorylation of CaMKII and NF-κB and cardiomyocyte injury and apoptosis in mouse hearts. Moreover, it attenuated DOX-induced left ventricular dysfunction and dilatation. Our findings suggest that blockade of LTCC attenuates DOX-induced cardiomyocyte apoptosis via suppressing intracellular Ca2+ elevation and activation of CaMKII-NF-κB pathway. LTCC blockers might be potential therapeutic agents against DOX-induced cardiomyopathy.

Six new ergostane-type steroids from king trumpet mushroom (Pleurotus eryngii) and their inhibitory effects on nitric oxide production.

Six new ergostane-type steroids; (22E)-3ß,5α,6α,11-tetrahydroxy-9(11)-seco-ergosta-7,22-dien-9-one (1), (22E)-8,14-epoxyergosta-6,22-diene-3ß,5α,9α-triol (2), (22E)-4α,5α-epoxyergosta-7,22-diene-3ß,6ß-diol (3), (22E)-3ß,4ß,5α-trihydroxyergosta-7,22-dien-6-one (4), (22E)-ergosta-7,22-diene-3ß,5ß,6α-triol (5), and (22E)-6ß-methoxyergosta-7,22-diene-3ß,5α-diol 3-O-ß-d-glucopyranoside (6) were isolated from the fruiting bodies of king trumpet mushroom (Pleurotus eryngii), along with fourteen known compounds (7-20). All isolated compounds were evaluated for their inhibitory effects on macrophage activation using a nitric oxide production inhibition assay.