The resistance to antibacterials therapy has been increasing in recent years.1,2 The rational use of anti-bacterials should include: (1) choosing the right drugs according to the scope of their antibacterials function and making sure they are suitable for treatment of the microorganisms that have induced the infection;3 (2) administering anti-bacterials by a rational method according to their pharmacodynamics;4 (3) paying attention to the systemic condition of the patients according to pharmacokinetics of the drugs.5,6 There are many pharmacodynamic/pharmacokinetic (PK/PD) parameters to be considered in order to use anti-bacterials rationally.7,8 For the purpose of giving consideration to these factors, maximally increasing the curative effect and decreasing the adverse effects, the antibacterial-application software called Laenne™ Clinical Pharmacodynamic Monitoring (Laenne™ CPM) was created by Pulmonary Department and Pharmacy Department of East Hospital, and was developed by the Boartland Health Technology Co., Ltd, China. CLINICAL DATA Case 1: Selection of the appropriate dosage of cefepime to avoid epileptic seizure The first patient was a 41 years old female with postpartum hemorrhage, disseminated intravascular coagulation (DIC), hemorrhagic shock, hysterectomy, laparotomy and sepsis. On March 21, 2007, the patient had an epileptic seizure, right Babinski sign (+). MRI displayed multi-cerebral infarcts and a left hippocampus compressed by edema. Electroencephalogram exam showed eleptiform discharge. Sodium valproate and phenobarbital sodium were given to treat the epileptic seizure. The result of a sputum culture showed an Enterobacter cloacae which was cefepime sensitive. According to the usual prescription, cefepime was given 2.0 g i.v, bid. However, cefepime may accumulate and induce an epileptic attack.9 A judicious dosage choice was needed for cefepime that has an effective therapeutic activity to infection of Enterobacter cloacae while avoiding its possibility of exacerbating epileptic seizure. With the antibacterial-application software (2.0 version), we selected Enterobacter cloacae in the “Bacterium information” column, and selected sensitive in the “minimum inhibitory concentration” (MIC) column according to the results of the sensitivity test. In the “patient's information” column we input the demographic data, then added cefepime in the “Medication information” column, and then clicked “pharmacokinetic parameter selection”. The recommended dosage of cefepime was 2000 mg, q12 h, time for intravenous injection was 0.5 hour, for 7 days. Cefepime is a time-dependent agent, so we selected T/MIC and clicked the “calculation” button; T/MIC was 100%, suggesting that the regimen might exacerbate epileptic seizure (Figure 1A). Therefore we reduced the dosage to 1000 mg, i.v, q12 h, and the T/MIC was 86.13%, still over 50%. Considering the patient's infection was severe, the regimen was appropriate (Figure 1B). According to this calculation analysis, cefepime was given 1000 mg i.v q12 h for 7 days, and the temperature returned to normal range. Moist rales in both lung disappeared. The patient had no epileptic seizure and the infection was well controlled until discharge. Case 2: Over dose of levofloxacin induced renal dysfunction and hepatic damage The second patient was an 82 years old male with hypertension, diabetes, coronary heart disease and primary hypothyroidism. With “right limbs debility and dysphrasia for 4 hours” he was admitted on May 8, 2005. Diagnosis was a cerebral infarction and pulmonary infection. On admission examination, serum creatinine was 149 mol/L (normal range 59–104 mol/L). Liver function was normal. The result of sputum culture was Klebsiella pneumoniae with sensitivity to levofloxacin (MIC=2 mg/L). On May 13, levofloxacin was given (0.3 g, i.v, bid). After 3 days, the serum creatinine was up to 235 mol/L, alanine transaminase (ALT) was 662 IU/L (normal range <64 IU/L). As a result, levofloxacin was immediately withdrawn. Retrospective analysis of the software According to the drug description (Beijing No. 1 Pharmaceuticals Company, China), the initial dose of levofloxacin should be 0.4 g, then 0.2 g per day afterwards. Administering levofloxacin (0.3 g, i.v, bid) was easier to start levofloxacin accumulation and kidney crystallization. All of these aggravated kidney inadequacy and damaged liver function.10 On May 15, the software showed further accumulation of levofloxacin in the body (Figure 2A).Figure 1. A:: Case 1 (Version 2.0), administering cefepime 2000 mg, i.v, q12 h, T/MIC was 100%. B: Case 1, cefepime was reduced to 1000 mg, i.v, q12 h and T/MIC was 86.13%.Figure 3. A:: Case 3 (software Version 3.0), the single dose of imipenam was 500 mg. i.v, q8 h; T/MIC was 100 %. B: Case 3, if the dose was reduced to 250 mg, i.v, q8 h, T/MIC was 90.17%.On May 17 (3 days after withdrawing levofloxacin), the serum creatinine was 214 mol/L, ALT was 464 IU/L. On May 22, the serum creatinine was 187 mol/L, GPT was in normal range. According to the dispensatory, and as displayed by the software (Figure 2B), the initial dose of levofloxacin was 0.4 g, and then 0.2 g per day, the concentration of levofloxacin in this patient should be stable (AUC/MIC 104.12), which obtained anti-infection efficacy and avoided renal and liver function damage concurrently. Case 3: Isepamicin and isosorbide mononitrate led to acute kidney function failure, imipenam led to severe liver function damage The patient was a 74 years old female, with “repeated cough and wheezing more than 8 years, aggravated one day”, who was admitted on February 22, 2007, diagnosed as chronic bronchitis with infection, emphysema, respiratory failure, hypertension and basal ganglia cerebral infarction. On admission, liver and kidney functions were normal. Isepamicin was used (i.v.) for 3 days (February 26–28), imipenam 500 mg i.v q8 h for 7 days (February 28-March 6), isosorbide mononitrate orally and amiodarone for atrial premature intravenously were given concurrently. From March 1, the patient presented with hypotension. On March 5, the patient suffered from renal failure. Retrospective analysis by the software The patient had respiratory failure and hypertension, possibily followed by infectious shock that lead to hypovolemia; all can induce renal parenchyma damage. In addition, isepamicin can lead to acute renal tubular necrosis. After using isosorbide mononitrate, the patient had severe hypotension. There is report that imipenem can lead to more than 50% patients' ALT rise.10 Renal failure can lead to the accumulation of imipenam. Imipenam is a time-dependent antibiotic. According to software analysis, if the dose of imipenam was 500 mg, i.v, q8 h, T/MIC was 100% representing an overdose (Figure 3A). When reducing the dose to 250 mg, i.v, q8 h, T/MIC was 90.17%, this regimen might be appropriate (Figure 3B).Figure 2. A:: Case 2, On May 15, serum creatinine was 235 mol/L, showing a further tendency towards accumulation of levofloxacin (Cmax/MIC was 13.76, AUC/MIC 146.71) (Cmax=maximum concentration; AUC=area under curve). B: Case 2, according to the dispensatory, the initial dose of levofloxacin was 0.4 g, and then 0.2 g per 24 hours, having no tendency toward accumulation in the body.The clinicians didn't decrease the dose of imipenam when the patient suffered from renal failure, so it resulted in an over dose accumulation that led to liver function damage. Other reasons that caused liver function damage might be amiodarone, isosorbide mononitrate and the severe infection or hypoxia. DISCUSSION The main factor that influences the effect of the antibacterials is the interaction between the parameters of the pharmacodynamics and the antimicrobial susceptibility.11–13 (1) Aminoglycosides and quinolones are the concentration-dependent agents. For quinolones, if the ratio of serum area under the curve to MIC in 24 hours (AUC/MIC) >125, it has therapeutic efficacy. For aminoglycosides, if Cmax/MIC >12, it can be anticipated as having efficacy.14,15 (2) Time-dependence agents include β-lactam, macrolides, clindamycin, and glycopeptides. When T >MIC is 50%-70%, the dosage and regimen of the agents are considered suitable. The software system collects the information that comes from the American National Clinical Laboratory Standard Commission (NCCLS).16 The function of this software includes: (1) Establishing mathematical models according to the pharmodynamics and pharmacokinetics equations; (2) For time-dependent anti-bacterials, displaying the ratio of the antibacterials concentration beyond MIC; (3) For concentration-dependent anti-bacterials, displaying serum Cmax/MIC and the AUC/MIC; (4) realizing the cure of the infectious disease by computer technology. The software can reflect the dynamic blood curve of antibacterials, offer a quick reference to adjust the regimen, and give more effective and more economical therapy. We can adjust the accuracy of the dosage of the antibacterials and offer a referenced therapeutic regimen by the software. We have completed analysis of about 200 infectious cases with this software, and have proved that it can analyze the clinical data quickly and to satisfy the demand of the clinic. The software is based on the theories of the pharmacodynamics and pharmacokinetics, reflecting the dynamic serum curve of antibacterials. It can give quick reference to devise or adjust dosage and regimen for a rational application of antibacterials and more economical therapy to the infectious patients while avoiding adverse effects. To our knowledge this software is the first tool to establish a direct relationship between the theory of PK/PD and clinical practice in China. This software has already obtained a patent from China National Copyright Bureau (No. 2007SR00479).
High-quality, diverse harmful data is essential to addressing real-time applications in content moderation. Current state-of-the-art approaches to toxic content detection using GPT series models are costly and lack explainability. This paper investigates the use of prompt engineering and fine-tuning techniques on open-source LLMs to enhance harmful data augmentation specifically for toxic content detection. We conduct a two-stage empirical study, with stage 1 evaluating six open-source LLMs across multiple datasets using only prompt engineering and stage 2 focusing on fine-tuning. Our findings indicate that Mistral can excel in generating harmful data with minimal hallucination. While fine-tuning these models improves data quality and diversity, challenges such as data duplication and overfitting persist. Our experimental results highlight scalable, cost-effective strategies for enhancing toxic content detection systems. These findings not only demonstrate the potential of open-source LLMs in creating robust content moderation tools. The application of this method in real industrial scenarios further proves the feasibility and efficiency of the fine-tuned open-source LLMs for data augmentation. We hope our study will aid in understanding the capabilities and limitations of current models in toxic content detection and drive further advancements in this field.
Inflammation and apoptosis play important roles in the initiation and progression of acute lung injury (ALI). Our previous study has shown that progranulin (PGRN) exerts lung protective effects during LPS-induced ALI. Here, we have investigated the potential roles of PGRN-targeting microRNAs (miRNAs) in regulating inflammation and apoptosis in ALI and have highlighted the important role of PGRN. LPS-induced lung injury and the protective roles of PGRN in ALI were first confirmed. The function of miR-34b-5p in ALI was determined by transfection of a miR-34b-5p mimic or inhibitor in intro and in vivo. The PGRN level gradually increased and subsequently significantly decreased, reaching its lowest value by 24 hr; PGRN was still elevated compared to the control. The change was accompanied by a release of inflammatory mediators and accumulation of inflammatory cells in the lungs. Using bioinformatics analysis and RT-PCR, we demonstrated that, among 12 putative miRNAs, the kinetics of the miR-34b-5p levels were closely associated with PGRN expression in the lung homogenates. The gain- and loss-of-function analysis, dual-luciferase reporter assays, and rescue experiments confirmed that PGRN was the functional target of miR-34b-5p. Intravenous injection of miR-34b-5p antagomir in vivo significantly inhibited miR-34b-5p up-regulation, reduced inflammatory cytokine release, decreased alveolar epithelial cell apoptosis, attenuated lung inflammation, and improved survival by targeting PGRN during ALI. miR-34b-5p knockdown attenuates lung inflammation and apoptosis in an LPS-induced ALI mouse model by targeting PGRN. This study shows that miR-34b-5p and PGRN may be potential targets for ALI treatments.
Abstract Background: Since the outbreak of the novel coronavirus disease (COVID-19), the fever outpatient clinic has been open in Shanghai East Hospital (SEH). We analyzed the data for all 4,699 patients from SEH and the 27 confirmed COVID-19 cases among them to determine the clinical and epidemiological characteristics of confirmed COVID-19 cases identified in the SEH. Methods: Data were collected for patients who visited the fever outpatient clinic in the SEH between January 23 and April 30, 2020. We compared the characteristics of confirmed cases, including age, occupation, area, symptoms, laboratory results, and computed tomography (CT) scans, by month. Results: By April 30, 4,699 patients had visited the fever outpatient clinic of the SEH; of those, 27 (0.57%) were confirmed COVID-19 cases. Among the confirmed domestic cases identified between January and February, four of five were from Wuhan, Hubei. Following the spread of the epidemic to other parts of the world, all confirmed cases identified in March–April were cases of individuals who were returning from abroad, mainly Chinese students living abroad. Further, all cases were from outside Shanghai, and no local residents were diagnosed in the clinic. Symptoms, laboratory tests, and CT scans were consistent with previous literature reports of positive COVID-19 cases. Conclusions: Given the necessity to control the spread of this epidemic domestically and abroad, the focus of COVID-19 prevention and control has shifted. In Shanghai, measures taken to prevent COVID-19 spread were very successful. Early isolation and quarantine are necessary and effective measures.
Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first-line treatment of Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC).Stage IIIB-IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4-6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127).Between December 15th , 2017, and May 15th , 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25th , 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1-6) and median duration of treatment of 3.0 (range 0.0-5.1) months. ORR of response-evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80-1.04, within the prespecified equivalence margin of 0.75-1.33). Up to May 15th , 2020, with a median follow-up of 13.6 (range 0.8-28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1-year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups.LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non-squamous NSCLC patients in the first-line setting.
MicroRNA (miRNA) are a class of conserved highly, approximately 22 nucleotideslong,non-protein coding, single-stranded small molecule RNA belonging to small RNA family. The researches were focused on cancer,genetic diseases,cardiovascular diseases and viral infections,and some miRNA have been used in clinical studies. The effect of miRNA in respiratory related diseases have also attracted considerable attention in recent years. We will expatiate the scientific research of miRNA in lung disease in this article.
Key words:
MicroRNA; Target genes; Pathogensis; Respiratory system
Podocyte dysfunction is important in the onset and development of diabetic nephropathy (DN). Histone deacetylases (HDACs) have been recently proved to play critical roles in the pathogenesis of DN. As one subtype of the class IIa HDACs, HDAC9 is capable to repress/de-repress their target genes in tumor, inflammation, atherosclerosis and metabolic diseases. In the present study, we investigate whether HDAC9 is involved in the pathophysiologic process of DN, especially the podocyte injury. Firstly, we explored the expression patterns and localization of HDAC9 and found that HDAC9 expression was significantly up-regulated in high glucose (HG)-treated mouse podocytes, as well as kidney tissues from diabetic db/db mice and patients with DN. Secondly, knockdown of HDAC9 in mouse podocytes significantly suppressed HG-induced reactive oxygen species (ROS) generation, cell apoptosis and inflammation through JAK2/STAT3 pathway and reduced the podocytes injury by decreasing the expression levels of Nephrin and Podocin. Moreover, in diabetic db/db mice, silencing of HDAC9 attenuated the glomerulosclerosis, inflammatory cytokine release, podocyte apoptosis and renal injury. Collectively, these data indicate that HDAC9 may be involved in the process of DN, especially podocyte injury. Our study suggest that inhibition of HDAC9 may have a therapeutic potential in DN treatment.
The aim of this study is to clarify the changes of peripheral CD3-CD56+CD16+ NK cells and their correlation with Th1/Th2 immunity profiles in asthma during the phase of acute upper respiratory viral infections (AURVIs).Peripheral venous blood and induced sputum samples were collected from 56 mild asthma patients, 49 asthma patients with AURVIs and 50 healthy subjects. Peripheral CD3-CD56+CD16+ NK cells were monitored by flow cytometry during the course of acute viral infections. Meanwhile, the induced sputum Th2 cytokines IL-4 and IL-5, and Th1 cytokine IFN-γ were also detected by ELISA assay.The asthmatics had lower levels of peripheral CD3-CD56+CD16+ NK cells populations as well as higher induced sputum cytokines (IL-4, IL-5 and IFN-γ) compared to healthy controls at baseline. Upon upper respiratory viral infections, peripheral CD3-CD56+CD16+ NK cells numbers in asthma patients sharply elevated on day 3 and slowly decreased by day 14, in accordance with induced sputum IFN-γ changes. IL-4 and IL-5 levels spiked much later (day 8) and lasted until day 14. Compared with asthma alone group, the IFN-γ/IL-4 and IFN-γ/IL-5 ratios of the asthma patients with AURVIs on day 1 were higher and peaked on day 3. The changes of peripheral CD3-CD56+CD16+ NK cells proportions positively correlated with the IFN-γ/IL-4 and IFN-γ/IL-5 ratios on day 1 to day 3 in asthma subsequent to upper respiratory viral infections.Our findings showed an imbalanced Th1/Th2 immunity in airways of asthma with acute upper respiratory viral infections. Upregulated peripheral CD3-CD56+CD16+ NK cells play a crucial role in biased Th1 immunity of airways in asthma during the acute phase of viral infections. The anti-viral Th1 immunity by targeting NK cells may be a possible therapeutic option for virus-induced asthma exacerbation.
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