Clinical Characteristics and Epidemiological Analysis of Pneumocystis Jirovecii Pneumonia Infection in Kidney Transplant Patients with Trimethoprim-Sulfamethoxazole Dose Reduction Prophylaxis Strategy.

Background: The administration of trimethoprim-sulfamethoxazole (TMP-SMX) for the prophylaxis of Pneumocystis jirovecii pneumonia (PJP) has proven to be highly efficacious in individuals who have undergone kidney transplantation. Nevertheless, the potential for severe adverse reactions associated with this treatment cannot be overlooked, and the determination of an optimal dosage regimen continues to be a matter of investigation. The current study evaluated the effectiveness of low-dose TMP-SMX for PJP prophylaxis in kidney transplant patients and conducted an analysis of the clinical characteristics and epidemiological trends in patients with PJP infection. Methods: This retrospective analysis studied electronic medical records of 1763 kidney transplant recipients from 2017 to 2020. These patients were initially prescribed a daily half-strength TMP-SMX (40 mg/200 mg), and the efficacy of this regimen was assessed during a follow-up period of 3-51 months. Results: Under our PJP prevention and adjustment strategy, 24 patients were infected with PJP. The overall morbidity of PJP infection in our study was 1.36%, corroborates with findings from previously published studies. Among these 24 patients, up to 87.5% had their dosage adjusted due to increased creatinine or other adverse reactions, the most frequent dose was daily quarter-strength TMP-SMX (20 mg/100 mg). TMP-SMX prophylaxis successfully postponed and distributed the onset of PJP, with the mean duration from transplantation to the occurrence of PJP being 13.50±7.11 months. Conclusion: Daily administration of half-strength TMP-SMX can effectively prevent PJP, and prolonging prophylaxis with this medication may potentially reduce the incidence of infection.

Improvement in Hypertension Management with Pharmacological and Non- Pharmacological Approaches: Current Perspectives.

PURPOSE: Improving hypertension management is still one of the biggest challenges in public health worldwide. Existing guidelines do not reach a consensus on the optimal Blood Pressure (BP) target. Therefore, how to effectively manage hypertension based on individual characteristics of patients, combined with the pharmacological and non-pharmacological approach, has become a problem to be urgently considered. METHODS: Reports published in PubMed that covered Pharmacological and Non-Pharmacological Approaches in subjects taking hypertension management were reviewed by the group independently and collectively. Practical recommendations for hypertension management were established by the panel. RESULTS: Pharmacological mechanism, action characteristics, and main adverse reactions varied across different pharmacological agents, and patients with hypertension often require a combination of antihypertensive medications to achieve the target BP range. Non-pharmacological treatment provides an additional effective method for improving therapy adherence and long-term BP control, thus reducing the risk of cardiovascular diseases, and slowing down the progression of the disease. CONCLUSION: This review summarizes the available literature on the most convincing guideline principles, pharmacological treatment, biotechnology interference, interventional surgical treatment, managing hypertension with technical means of big data, Artificial Intelligence and Behavioral Intervention, as well as providing future directions, for facilitating Current and Developing knowledge into clinical implementation.

Assessment of the Potential Adverse Events Related to Ribavirin-Interferon Combination for Novel Coronavirus Therapy.

PURPOSE: We aimed to analyze and evaluate the safety signals of ribavirin-interferon combination through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS), so as to provide reference for the rationale use of these agents in the management of relevant toxicities emerging in patients with novel coronavirus pneumonia (COVID-19). METHODS: Reports to the FAERS from 1 January 2004 to 8 March 2020 were analyzed. The proportion of report ratio (PRR), reporting odds ratio (ROR), and Bayesian confidence interval progressive neural network (BCPNN) method were used to detect the safety signals. RESULTS: A total of 55 safety signals were detected from the top 250 adverse event reactions in 2200 reports, but 19 signals were not included in the drug labels. All the detected adverse event reactions were associated with 13 System Organ Classes (SOC), such as gastrointestinal, blood and lymph, hepatobiliary, endocrine, and various nervous systems. The most frequent adverse events were analyzed, and the results showed that females were more likely to suffer from anemia, vomiting, neutropenia, diarrhea, and insomnia. CONCLUSION: The ADE (adverse drug event) signal detection based on FAERS is helpful to clarify the potential adverse events related to ribavirin-interferon combination for novel coronavirus therapy; clinicians should pay attention to the adverse reactions of gastrointestinal and blood systems, closely monitor the fluctuations of the platelet count, and carry out necessary mental health interventions to avoid serious adverse events.

[Establishment of a rapid identification of adverse drug reaction program in R language implementation based on monitoring data].

OBJECTIVE: To establish a clinically applicable model of rapid identification of adverse drug reaction program (RiADP) for risk management and decision-making of clinical drug use. METHODS: Based on the theory of disproportion analysis, frequency method and Bayes method, a clinically applicable RiADP model in R language background was established, and the parameters of the model were interpreted by MedDRA coding. Based on the actual monitoring data of FDA, the model was validated by the assessing hepatotoxicity of lopinavir/ritonavir (LPV/r). RESULTS: The established RiADP model included four parameters: standard value of adverse drug reaction signal information, empirical Bayesian geometric mean value, ratio of reporting ratio and number of adverse drug reaction cases. Through the application of R language parameter package "phViD", the model parameters could be output quickly. After being encoded by MedDRA, it was converted into clinical terms to form a clinical interpretation report of adverse drug reactions. In addition, the evaluation results of LPV/r hepatotoxicity by the model were matched with the results reported in latest literature, which also proved the reliability of the model results. CONCLUSIONS: In this study, a rapid identification method of adverse reactions based on post marketing drug monitoring data was established in R language environment, which is capable of sending rapid warning of adverse reactions of target drugs in public health emergencies, and providing intuitive evidence for risk management and decision-making of clinical drugs.

The Role of the Sodium-taurocholate Co-transporting Polypeptide (NTCP) and Bile Salt Export Pump (BSEP) in Related Liver Disease.

BACKGROUND: Sodium Taurocholate Co-transporting Polypeptide (NTCP) and Bile Salt Export Pump (BSEP) play significant roles as membrane transporters because of their presence in the enterohepatic circulation of bile salts. They have emerged as promising drug targets in related liver disease. METHODS: We reviewed the literature published over the last 20 years with a focus on NTCP and BSEP. RESULTS: This review summarizes the current perception about structure, function, genetic variation, and regulation of NTCP and BSEP, highlights the effects of their defects in some hepatic disorders, and discusses the application prospect of new transcriptional activators in liver diseases. CONCLUSION: NTCP and BSEP are important proteins for transportation and homeostasis maintenance of bile acids. Further research is needed to develop new models for determining the structure-function relationship of bile acid transporters and screening for substrates and inhibitors, as well as to gain more information about the regulatory genetic mechanisms involved in the processes of liver injury.

Identification of key gene pathways and coexpression networks of islets in human type 2 diabetes.

PURPOSE: The number of people with type 2 diabetes (T2D) is growing rapidly worldwide. Islet ß-cell dysfunction and failure are the main causes of T2D pathological processes. The aim of this study was to elucidate the underlying pathways and coexpression networks in T2D islets. MATERIALS AND METHODS: We analyzed the differentially expressed genes (DEGs) in the data set GSE41762, which contained 57 nondiabetic and 20 diabetic samples, and developed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein-protein interaction (PPI) network, the modules from the PPI network, and the gene annotation enrichment of modules were analyzed as well. Moreover, a weighted correlation network analysis (WGCNA) was applied to screen critical gene modules and coexpression networks and explore the biological significance. RESULTS: We filtered 957 DEGs in T2D islets. Then GO and KEGG analyses identified that key pathways like inflammatory response, type B pancreatic cell differentiation, and calcium ion-dependent exocytosis were involved in human T2D. Three significant modules were filtered from the PPI network. Ribosome biogenesis, extrinsic apoptotic signaling pathway, and membrane depolarization during action potential were associated with the modules, respectively. Furthermore, coexpression network analysis by WGCNA identified 13 distinct gene modules of T2D islets and revealed four modules, which were strongly correlated with T2D and T2D biomarker hemoglobin A1c (HbA1c). Functional annotation showed that these modules mainly enriched KEGG pathways such as NF-kappa B signaling pathway, tumor necrosis factor signaling pathway, cyclic adenosine monophosphate signaling pathway, and peroxisome proliferators-activated receptor signaling pathway. CONCLUSION: The results provide potential gene pathways and underlying molecular mechanisms for the prevention, diagnosis, and treatment of T2D.

Chicken interferon regulatory factor 1 (IRF1) involved in antiviral innate immunity via regulating IFN-ß production.

Interferon regulatory factors (IRFs) is an important family for IFN expression regulating while viral infection. IRF1, IRF3, and IRF7 are the primary regulators that trigger type I IFN response in mammals. However, IRF3, which has been identified as the most critical regulator in mammals, is absent in chickens, and it is unknown whether IRF1 is involved in type I IFN signaling pathways in IRF3-deficient chicken cells. Here, we identified chicken IRF1 (chIRF1) as a critical IFN-ß mediator in response to viral infection. Overexpression of chIRF1 activated IFN-ß intensively and suppressed AIV and NDV viral replication. Moreover, the mRNA levels of IFN-ß and ISGs increased during chIRF1 overexpression. In addition, deletion mutant analysis revealed that the first four domains of chIRF1 are indispensable for IFN-ß induction. Together, our studies demonstrate that chIRF1 is an important regulator of IFN-ß and is involved in chicken antiviral innate immunity.

Predictors of functional outcome and hemorrhagic complications in acute ischemic stroke patients treated with intravenous thrombolysis - A retrospective analysis
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Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) within 4.5 hours is an effective and routine therapy for acute ischemic stroke (AIS). The purpose of the study was to identify predictors of functional outcome at 3 months and hemorrhagic complications after IVT. A total of 123 AIS patients treated with intravenous alteplase within 4.5 hours after stroke were enrolled. Baseline clinical characteristics, medication and disease history, radiographic and laboratory data were collected. The clinical functional outcome at 3 months was measured by the modified Rankin Scale dichotomized at 0 - 1 (favorable) vs. 2 - 6 (unfavorable). Hemorrhagic complications were measured within 36 hours after IVT. Univariate and multivariate analysis was applied in the study, and the logistic regression identified the predictors for functional outcome at 3 months and hemorrhagic complications within 36 hours. In univariate analysis, the favorable outcome was significantly associated with short hospitalization, low initial National Institute of Health Stroke Scale scores, previous smoking, previous statin use, and absence of post-stroke cerebral edema or pneumonia. Hemorrhagic complications were significantly associated with high initial NIHSS scores, low platelet count, high D-dimer level, previous atrial fibrillation, and onset seasons (except summer). Multivariate regression analyses identified that seasons (spring and summer), short hospital stays, and absence of post-stroke cerebral edema or pneumonia were the predictors of a favorable functional outcome. Meanwhile, seasons (except summer), low platelet count, and high D-dimer levels were correlation factors for prognosis of high hemorrhagic complications.
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H-NS Mutation-Mediated CRISPR-Cas Activation Inhibits Phage Release and Toxin Production of Escherichia coli Stx2 Phage Lysogen.

Shiga toxin-converting bacteriophages (Stx phages) carry the stx gene and convert nonpathogenic bacterial strains into Shiga toxin-producing bacteria. There is limited understanding of the effect that an Escherichia coli (E. coli) clustered regularly interspaced short palindromic repeats (CRISPR)-Cas adaptive immune system has on Stx phage lysogen. We investigated heat-stable nucleoid-structuring (H-NS) mutation-mediated CRISPR-Cas activation and its effect on E. coli Stx2 phage lysogen. The Δhns mutant (MG1655Δhns) of the E. coli K-12 strain MG1655 was obtained. The Δhns mutant lysogen that was generated after Stx phage lysogenic infection had a repressed growth status and showed subdued group behavior, including biofilm formation and swarming motility, in comparison to the wild-type strain. The de-repression effect of the H-NS mutation on CRISPR-Cas activity was then verified. The results showed that cas gene expression was upregulated and the transformation efficiency of the wild-type CRISPR plasmids was decreased, which may indicate activation of the CRISPR-Cas system. Furthermore, the function of CRISPR-Cas on Stx2 phage lysogen was investigated by activating the CRISPR-Cas system, which contains an insertion of the protospacer regions of the Stx2 phage Min27. The phage release and toxin production of four lysogens harboring the engineered CRISPRs were investigated. Notably, in the supernatant of the Δhns mutant lysogen harboring the Min27 spacer, both the progeny phage release and the toxin production were inhibited after mitomycin C induction. These observations demonstrate that the H-NS mutation-activated CRISPR-Cas system plays a role in modifying the effects of the Stx2 phage lysogen. Our findings indicated that H-NS mutation-mediated CRISPR-Cas activation in E. coli protects bacteria against Stx2 phage lysogeny by inhibiting the phage release and toxin production of the lysogen.

[Inhibitory effects of astragaloside IV on cytochrome P450 enzyme of rat liver microsomes].

OBJECTIVE: To provide a scientific basis for the drug-combination and aim to examine whether astragaloside IV has the impact on the cytochrome P450 enzymes. METHOD: Tolbutamide, chlorzoxazone, coumarin, nifedipine, and phenacetin were as probe substrates of rat CYP2C9, CYP2E1, CYP2A6, CYP3A4, and CYP1A2, and were incubated in rat liver microsomes with astragaloside IV. Triplicate samples were run to generate IC50 value by incubating P450 probe substrates in the presence of five concentrations of astragaloside IV in the incubation mixture. The K(i) values were determined by fitting the probe substrate at various inhibitor concentrations to the equations for competitive inhibition, noncompetitive inhibition, noncompetitive inhibition, and mixed-type inhibition. RESULT: IC50 and K(i) values were estimated, and the types of inhibition were determined. Among the five probe substrates, astragaloside IV might not significantly affect CYP2E1, CYP2A6 and CYP1A2-mediated metabolism in rats, but was a competitive inhibitor of CYP2C9 (IC50 35.40 micromol x L(-1), K(i) 42.88 micromol x L(-1)), and was a uncompetitive inhibitor of CYP3A4 (IC50 88.24 micromol x L(-1), K(i) 33.31 micromol x L(-1)). CONCLUSION: These results suggested that astragaloside IV inhibited CYP2C9 and CYP3A4, which provided useful information for safe and effective use of astragaloside IV.