A novel score for early prediction of urinary tract infection risk in patients with acute ischemic stroke: a nomogram-based retrospective cohort study.

This study aimed to construct and externally validate a user-friendly nomogram-based scoring model for predicting the risk of urinary tract infections (UTIs) in patients with acute ischemic stroke (AIS). A retrospective real-world cohort study was conducted on 1748 consecutive hospitalized patients with AIS. Out of these patients, a total of 1132 participants were ultimately included in the final analysis, with 817 used for model construction and 315 utilized for external validation. Multivariate regression analysis was applied to develop the model. The discriminative capacity, calibration ability, and clinical effectiveness of the model were evaluated. The overall incidence of UTIs was 8.13% (92/1132), with Escherichia coli being the most prevalent causative pathogen in patients with AIS. After multivariable analysis, advanced age, female gender, National Institute of Health Stroke Scale (NIHSS) score ≥ 5, and use of urinary catheters were identified as independent risk factors for UTIs. A nomogram-based SUNA model was constructed using these four factors (Area under the receiver operating characteristic curve (AUC) = 0.810), which showed good discrimination (AUC = 0.788), calibration, and clinical utility in the external validation cohort. Based on four simple and readily available factors, we derived and externally validated a novel and user-friendly nomogram-based scoring model (SUNA score) to predict the risk of UTIs in patients with AIS. The model has a good predictive value and provides valuable information for timely intervention in patients with AIS to reduce the occurrence of UTIs.

Is Azvudine Comparable to Nirmatrelvir-Ritonavir in Real-World Efficacy and Safety for Hospitalized Patients with COVID-19? A Retrospective Cohort Study.

INTRODUCTION: Azvudine and nirmatrelvir-ritonavir are more extensively used to treat COVID-19 in China due to their earlier approval by the National Medical Products Administration. However, there has been a scarcity of research directly comparing the clinical outcomes between azvudine and nirmatrelvir-ritonavir till now. We aimed to make a head-to-head comparison of the efficacy and safety of azvudine or nirmatrelvir-ritonavir in hospitalized patients with COVID-19 in China. METHODS: This retrospective cohort study was conducted using data collected from Tongde Hospital of Zhejiang Province between December 2022 and January 2023. All-cause mortality, risk of progressing to a critical condition, proportion with nucleic-acid negative conversion (PNANC), time to first nucleic-acid negative conversion (TFNANC), length of hospital stay and incidence of adverse events were systematically assessed as outcomes. Multi-model regression analysis, propensity-score-matching analysis, subgroup analysis and several sensitivity analyses were applied to compare these outcomes. RESULTS: This study included a total of 1571 hospitalized patients with COVID-19, among whom 272 received nirmatrelvir-ritonavir and 156 received azvudine. We found no significant differences in all-cause mortality (HR 1.41; 95% CI 0.56-3.56; P = 0.471), risk of progressing to critical COVID-19 (HR 1.67; 95% CI 0.78-3.60; P = 0.189), PNANC (HR 0.87; 95% CI 0.69-1.09; P = 0.220), length of stay (ß - 0.82; 95% CI - 2.78 to 1.15; P = 0.414) and adverse event rate (3.21% vs. 4.41%, P = 0.538) between the two groups, although azvudine was slightly less effective than nirmatrelvir-ritonavir. Meanwhile, the azvudine group exhibited a significantly longer TFNANC (ß 2.53; 95% CI 0.76-4.29; P = 0.005) than the nirmatrelvir-ritonavir group. Results were similar for propensity-score matching and multiple sensitivity analyses. CONCLUSION: Azvudine probably possessed comparable efficacy and safety to nirmatrelvir-ritonavir, although it was less effective than nirmatrelvir-ritonavir for some outcomes.

Alisma Shugan Decoction attenuates hepatic fibrosis and endoplasmic reticulum stress in mice with carbon tetrachloride-induced fibrosis.

Background: Over the years, Alisma Shugan Decoction (ASD), because of its potent anti-inflammation activity, has been used in traditional Chinese medicine (TCM) for treatment of many inflammation-associated disorders including those of the heart, blood vessel and brain. Methods: Herein, we examined the probable therapeutic effect of ASD in carbon tetrachloride (CCl4)-induced liver injury and fibrosis mice models. Results: Our results demonstrate that ASD dose-dependently reduced the fibrosis-related increased collagen deposition secondary to liver tissue exposure to CCl4. Data from our biochemical analyses showed significantly less liver damage biomarkers including ALT, AST and hydroxyproline in the ASD-treated samples, suggesting hepato-protective effect of ASD. Furthermore, we demonstrated that treatment with ASD significantly reversed CCl4-induced elevation of TNF-α, IL-6, IL-1ß and MP-1. Interestingly, NF-κB signalling, a principal regulator of inflammation was markedly suppressed by ASD treatment. In addition, treatment with ASD deregulated stress signalling pathways by suppressing the expression of markers of unfolded protein response, such as ATF6, IRE and GRP78. Conclusion: In conclusion, the present study provides preclinical evidence for the use of ASD as an efficacious therapeutic option in cases of chemical-induced liver damage and/or fibrosis. Further large-cohort validation of these findings is warranted.

Prediction of allergic reaction risk of Shenmai injection based on real-world evidence coupled with UPLC-Q-TOF-MS.

The allergic reaction (AR) of Chinese herbal injection (CHI) has become one of the most noticeable focuses of public health in China. However, it still remains a considerable controversy as to whether low-molecular-weight components in CHI have potential sensitization. In this study, the relationship between AR and low-molecular-weight component profile of Shenmai injection was explored by an interdisciplinary technology integrating real-world evidence and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectroscopy (UPLC-Q-TOF-MS). The AR information of hospitalized patients was obtained by comprehensively analyzing real-world evidence from January 2015 to June 2019 at two Chinese hospitals. The UPLC-Q-TOF-MS was exploited to systematically investigate the low-molecular-weight component profile with 50-1500 m/z mass range, and 3725 MS1 peaks were detected. The optimized partial least squares discriminant analysis model was established to map the influence of low-molecular-weight components on AR. The results of this study showed that high levels of organic acids administered intravenously might be a potential risk factor for inducing AR. By using this method, Shenmai injection with high AR risk could be recognized precisely with 100% accuracy before clinical use.

Overcoming Multidrug Resistance in Bacteria Through Antibiotics Delivery in Surface-Engineered Nano-Cargos: Recent Developments for Future Nano-Antibiotics.

In the recent few decades, the increase in multidrug-resistant (MDR) bacteria has reached an alarming rate and caused serious health problems. The incidence of infections due to MDR bacteria has been accompanied by morbidity and mortality; therefore, tackling bacterial resistance has become an urgent and unmet challenge to be properly addressed. The field of nanomedicine has the potential to design and develop efficient antimicrobials for MDR bacteria using its innovative and alternative approaches. The uniquely constructed nano-sized antimicrobials have a predominance over traditional antibiotics because their small size helps them in better interaction with bacterial cells. Moreover, surface engineering of nanocarriers offers significant advantages of targeting and modulating various resistance mechanisms, thus owe superior qualities for overcoming bacterial resistance. This review covers different mechanisms of antibiotic resistance, application of nanocarrier systems in drug delivery, functionalization of nanocarriers, application of functionalized nanocarriers for overcoming bacterial resistance, possible limitations of nanocarrier-based approach for antibacterial delivery, and future of surface-functionalized antimicrobial delivery systems.

Xiaokeping-containing serum suppresses high-glucose-induced proliferation of mesangial cells involved in the regulation of cell cycle progression and the p38 mitogen-activated protein kinase pathway.

OBJECTIVE: To investigate the efficacy of Xiaokeping (XKP)-containing serum on the proliferation of high-glucose-induced mesangial cells (MCs) and the potential underlying mechanism. METHODS: XKP-containing serum was prepared by the intragastric administration of XKP in rats. HBZY-1 cells were cultured with normal glucose (NC group), high glucose (HG group), and high glucose with different XKP concentrations. Cell proliferation was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the cell cycle distribution was detected by flow cytometry. The expression of p38 mitogen-activated protein kinase (p38MAPK) pathway components in MCs was detected by Western blotting and quantitative real-time polymerase chain reaction. RESULTS: The MC proliferation level in the high-glucose group was significantly higher than that in the normal control group, and XKP suppressed the HG-induced proliferation of MCs dose dependently. Moreover, flow cytometry revealed that XKP blocked cell cycle progression by inducing cell cycle arrest in G1 phase and inhibiting S phase entry. XKP down-regulated the protein and mRNA expression of p38MAPK in MCs (P < 0.05 vs HG). CONCLUSION: The present study demonstrated that XKP-containing serum inhibits high-glucoseinduced proliferation of MCs by causing cell cycle arrest at G1 phase and inhibiting S phase entry. The underlying mechanism involves the down-regulation of the p38MAPK signaling pathway, providing a theoretical basis for the use of XKP to treat diabetic kidney disease.

ZDHHC12-mediated claudin-3 S-palmitoylation determines ovarian cancer progression.

The membrane protein claudin-3 (CLDN3) is critical for the formation and maintenance of tight junction and its high expression has been implicated in dictating malignant progression in various cancers. However, the post-translational modification of CLDN3 and its biological function remains poorly understood. Here, we report that CLDN3 is positively correlated with ovarian cancer progression both in vitro and in vivo. Of interest, CLDN3 undergoes S-palmitoylation on three juxtamembrane cysteine residues, which contribute to the accurate plasma membrane localization and protein stability of CLDN3. Moreover, the deprivation of S-palmitoylation in CLDN3 significantly abolishes its tumorigenic promotion effect in ovarian cancer cells. By utilizing the co-immunoprecipitation assay, we further identify ZDHHC12 as a CLDN3-targating palmitoyltransferase from 23 ZDHHC family proteins. Furthermore, the knockdown of ZDHHC12 also significantly inhibits CLDN3 accurate membrane localization, protein stability and ovarian cancer cells tumorigenesis. Thus, our work reveals S-palmitoylation as a novel regulatory mechanism that modulates CLDN3 function, which implies that targeting ZDHHC12-mediated CLDN3 S-palmitoylation might be a potential strategy for ovarian cancer therapy.

Alisma Shugan Decoction (ASD) Ameliorates Hepatotoxicity and Associated Liver Dysfunction by Inhibiting Oxidative Stress and p65/Nrf2/JunD Signaling Dysregulation In Vivo.

BACKGROUND Liver fibrosis, defined as the aberrant accumulation of extracellular matrix (ECM) proteins such as collagen in the liver, is a common feature of chronic liver disease, and often culminates in portal hypertension, liver cirrhosis, and hepatic failure. Though therapeutically manageable, fibrosis is not always successfully treated by conventional antifibrotic agents. While the traditional Chinese medicine (TCM) Alisma Shugan Decoction (ASD) has several health benefits, including anti-inflammation, anti-oxidation, and limitation of cardiovascular and respiratory disorders, it remains unclear if it has any hepato-protective potential. MATERIAL AND METHODS The present study examined the therapeutic effect of ASD in thioacetamide (TAA)-induced liver injury and fibrosis rat models. RESULTS We demonstrated that 50 mg/kg ASD significantly reversed TAA-induced elevation of alanine or aspartate transaminase levels, elicited no dyscrasia, and conferred a 40% (p<0.01) or 20% (p<0.05) survival advantage, compared to rats treated with TAA or TAA+ASD, respectively. Treatment with ASD reversed TAA-induced liver injury and fibrogenesis via repression of alpha-SMA protein and reduction of the collagen area and fibrosis score. Concurrently, ASD markedly suppressed the mRNA expression of fibrogenic procollagen, ICAM-1, MMP2, MMP9, and MMP13, and production of TIMP-1, ICAM-1, CXCL7, or CD62L cytokine in rat liver injury models. Interestingly, ASD-elicited reduction of liver injury and fibrogenesis was mediated by dysregulated p65/NrF-2/JunD signaling, with a resultant 3.18-fold (p<0.05) increase in GSH/GSSH ratio, and a 3.61-fold (p<0.01) or 1.51-fold (p<0.01) reduction in the 4-hydroxynonenal and malondialdehyde (MDA) levels, respectively, indicating reduced oxidative stress in the ASD-treated rats, and suggesting an hepato-protective role for ASD. CONCLUSIONS In conclusion, the present study provides supplementary evidence of the therapeutic benefit of ASD as an efficient treatment option in cases of liver injury and fibrosis. Further large-cohort validation of these findings is warranted.

The Impact Of Pharmaceutical Interventions On The Use Of Carbapenems In A Chinese Hospital: A Pre-Post Study.

BACKGROUND: The challenge of drug resistance to carbapenems is of international concern with leading to increased hospital lengths of stay, costs, and mortality rates. How to get rid of the vicious cycle of drug resistance, new drugs, and re-resistance, and even the emergence of all-drug-resistant bacteria that humans cannot cope with, are the major challenges we face. To date, data about pharmaceutical interventions on the use of carbapenems are currently limited. PATIENTS AND METHODS: A retrospective cohort study was conducted to compare pre- and post-intervention in Tongde Hospital of Zhejiang Province. Pharmaceutical interventions were performed in the post-intervention group, including real time monitoring of medication orders, educative group activities, and making interventions to physicians. Intervention acceptance and outcomes, including the length of hospital stay, readmission rates, 30-day mortality, and utilization of carbapenems, which was evaluated by the daily defined doses (DDDs), the days of therapy (DOTs), and the cost of carbapenems, were reviewed. RESULTS: During the study, 593 interventions were provided by clinical pharmacists with an average acceptance rate of 82.79%. Compared with the pre-intervention group, prescriptions of carbapenems for pathogen-directed therapy were improved significantly in the post-intervention group (59.27% vs 21.74%, p=0.022). The DDDs decreased from 281.96 to 174.28 and DOTs decreased from 9.19 to 5.18 after pharmaceutical intervention, and the pharmaceutical interventions had significantly lower mean total cost of carbapenems ($13,828.8 vs $8137.1, p=0.004) and length of hospital stay (9.3±1.5 vs 15.9±2.2, p=0.014). There was a significant reduction in 30-day mortality in the post-intervention group (9.46% vs 17.86%, p=0.013) while there were no differences found in the 30-day readmission (20.19% vs 20.66%, p=0.99). CONCLUSION: Implementation of pharmaceutical interventions in our hospital successfully improved the appropriateness of carbapenem prescribing overall, and reduced the DDDs, DOTs, length of hospital day, and cost of carbapenems.

Xiaokeping Mixture Attenuates Diabetic Kidney Disease by Modulating TGF-ß/Smad Pathway in db/db Mice.

Xiaokeping mixture (XKP), a traditional Chinese medicine compound preparation, has achieved widespread use for diabetes mellitus and its kidney damage in clinical practice. The current study was carried out to assess the protective effect of XKP in spontaneous diabetic db/db mice and the underlying mechanism whereby XKP regulates TGF-ß/Smad pathway. Male C57BLKS/J db/db mice, 12 weeks old, were randomly divided into 3 groups: the model group, 17.5 mg/kg irbesartan-treated group (IST group), and 8 g/kg XKP-treated group (XKP group), while age-matched db/m mice were selected as a control group. After 8 weeks of administration, serum and urea samples were collected from mice for biochemical tests, while the kidneys were removed for histological analysis. The expression of TGF-ß/Smad pathway-related mRNA and protein were measured by RT-PCR and western blot analysis. Treatment with XKP significantly improved renal function and attenuated the pathological change of diabetic kidney disease (DKD) in renal histopathology. Furthermore, the overexpression of TGF-ß1, Smad3, and p-Smad3 was inhibited, as well as the reduction of Smad7 and SIP1 was weakened by XKP. In conclusion, these results suggest that XKP could attenuate DKD by modulating TGF-ß/Smad pathway.

Insights Into the Resistance Mechanisms of Inhibitors to FLT3 F691L Mutation via an Integrated Computational Approach.

Research has shown that FMS-like tyrosine kinase 3 (FLT3) may be a vital drug target for acute myeloid leukemia (AML). However, even though the clinically relevant F691L gatekeeper mutation conferred resistance to current FLT3 drug quizartinib, PLX3397 remained unaffected. In this study, the protein-ligand interactions between FLT3 kinase domain (wild-type or F691L) and quizartinib or PLX3397 were compared via an integrated computational approach. The classical molecular dynamics (MD) simulations in conjunction with dynamic cross-correlation (DCC) analysis, solvent-accessible surface area (SASA), and free energy calculations indicated that the resistant mutation may induce the conformational change of αC-helix and A-loop of the FLT3 protein. The major variations were controlled by the electrostatic interaction and SASA, which were allosterically regulated by residues Glu-661 and Asp-829. When FLT3-F691L was bound to quizartinib, a large conformational change was observed via combination of accelerated MD simulations (aMDs), principal component analysis (PCA), and free energy landscape (FEL) calculations. The umbrella sampling (US) simulations were applied to investigate the dissociation processes of the quizartinib or PLX3397 from FLT3-WT and FLT3-F691L. The calculated results suggested that PLX3397 had similar dissociation processes from both FLT3-WT and FLT3-F691L, but quizartinib dissociated more easily from FLT3-F691L than from FLT3-WT. Thus, reduced residence time was responsible for the FLT3-F691L resistance to inhibitors. These findings indicated that both the conformational changes of αC-helix and A-loop and the drug residence time should be considered in the design of drugs so that rational decisions can be made to overcome resistance to FLT3-F691L.

The impact of pharmacist-managed clinic on medication adherence and health-related quality of life in patients with COPD: a randomized controlled study.

INTRODUCTION: COPD is rapidly becoming one of the most challenging health problems worldwide, which is characterized by not fully reversible airflow limitation. Although a lot of treatment medications have been delivered, the treatment goals of COPD are often not achieved. Furthermore, few well-designed randomized controlled trials in the People's Republic of China have been reported to evaluate the impact of pharmacist-managed clinic (PMC) on medication adherence and health-related quality of life in patients with COPD. METHODS: A prospective randomized controlled study (on a PMC group and a control group) was conducted between January 2015 and December 2015. A structured education about COPD was provided by a clinical pharmacist to the PMC group. Primary outcomes were medication adherence (assessed by medication refill adherence scores) and health-related quality of life (assessed by St George's Respiratory Questionnaire). Secondary outcomes were exacerbation rate, hospitalization rate, and smoking behavior. RESULTS: A total of 244 patients were enrolled for our study. The PMC group showed a significantly greater improvement in medication adherence compared with the baseline (93.1±14.2 vs 78.8±12.3, P<0.01). When compared with the control group, there were more patients whose medication refill adherence score was ≥80 in the PMC group (83.3% vs 51.3%, P<0.01). The total St George's Respiratory Questionnaire scores was found to be improved significantly in the PMC group (42.7±3.2 vs 52.4±5.2, P<0.05). There was a lower hospitalization rate in the PMC group, and more patients in the PMC group quit smoking (71.0% vs 52.2%, P<0.05). CONCLUSION: The PMC may result in improvement of medication adherence and the health-related quality of life in patients with COPD. In the PMC group, a significant reduction in exacerbation rate, hospitalization rate, and smoking behavior was observed; therefore, our study provides support for a greater involvement of PMC in the care of patients with COPD.

Xiaokeping mixture inhibits diabetic nephropathy in streptozotocin-induced rats through blocking TGF-ß1/Smad7 signaling.

BACKGROUND: Diabetic nephropathy (DN) is a major cause of chronic kidney failure and characterized by excessive deposition of extracellular matrix. Evidence have shown that transforming growth factor-ß1 (TGF-ß1) is a key mediator in the development of DN. However, treatment of DN by blocking the TGF-ß1/Smad7 pathway remains limited. Xiaokeping mixture (XKP), a traditional Chinese herbal compound, has been used for treatment in patients with DN for many years. METHODS: In the present study, TGF-ß1/Smad7 pathway analysis was used to evaluate the therapeutic effect of XKP on DN rats induced by streptozotocin and to address the underlying molecular mechanism. Male rats were divided into four groups: normal control, untreated control group (fed with high fat), irbesartan-treated DN, and XKP-treated DN, respectively. Levels of serum creatinine, blood urea nitrogen, urine protein of 24 hours, and triacylglycerol were detected. Pathological changes of renal tissues were observed by hematoxylin-eosin staining. Immunohistochemical and Western blot analysis were used to detect the expressions of TGF-ß1 and Smad7. RESULTS: The results demonstrated that XKP can effectively reduce the levels of glucose, serum creatinine, blood urea nitrogen, urine protein of 24 hours, and triacylglycerol. Further studies indicated that inhibition of DN in XKP-treated DN rats was associated with inhibition of TGF-ß1/Smad7 signaling as demonstrated by downregulation of TGF-ß1 but upregulation of Smad7. CONCLUSION: The data obtained from the present study indicate that XKP may be a therapeutic agent for DN.

Effect of pharmaceutical care on medication adherence of patients newly prescribed insulin therapy: a randomized controlled study.

BACKGROUND: Poor adherence to insulin medications leads to a high rate of hospital admissions and poor health-related quality of life in the patients with diabetes mellitus. However, few strategies are effective and acceptable in improving medication adherence. The objectives of this study are to evaluate the effectiveness of pharmaceutical care by clinical pharmacists on medication adherence of patients newly prescribed insulin therapy. PATIENTS AND METHODS: A single-center, prospective randomized controlled study (pharmaceutical care group and control group) was performed from January 1, 2014 to December 30, 2014. Medication adherence was measured at the baseline and up to 12 months with Morisky-Green test and computerized dispensed medication history. The absolute change in A1c vs baseline, the change of hospitalization between two groups, and the number of patients to achieve Chinese Diabetes Society (CDS) goals at the baseline were the main outcome measures. RESULTS: A total of 322 patients were included in the study. After the 12-month interventions, significant improvements in the medication adherence were verified for the pharmaceutical care group according to the Morisky-Green test (50.8% of adherent patients at baseline vs 80.7% of adherent patients after 12-month interventions; P<0.01) and the computerized dispensed medication history (55.2% at baseline vs 83.3% after interventions; P<0.01), while no significant changes were verified in the control group. After follow-up, the pharmaceutical care group showed a greater percent change in A1c (2.2±0.4 vs 0.8±0.2, P<0.05). CONCLUSION: This study provides new evidence from a randomized controlled trial on the beneficial effect of pharmaceutical care to enhance adherence in patients newly prescribed insulin therapy. Intervention by the pharmacist might potentially improve clinical outcomes on reducing hemoglobin A1c and enhancing the number of patients fulfilling the Chinese Diabetes Society goal on hemoglobin A1c.

The impact of pharmaceutical care on improving outcomes in patients with type 2 diabetes mellitus from China: a pre- and postintervention study.

OBJECTIVE: To evaluate the effectiveness of pharmaceutical care services in management teams by assessing the change in hemoglobin A1c (A1C), cholesterol, and blood pressure for patients with type 2 diabetes in a diabetes ward. SETTING: Tongde hospital of Zhejiang province, a 1,200 bed South China teaching hospital, serving the local community. METHOD: A single-center, 2-phase (pre-/postintervention phase) designs was performed. Patients in postintervention phase (July 2013 to December 2013) received pharmaceutical care from a clinical pharmacist, while patients in the preintervention phase (January 2013 to June 2013) received routine medical care. The pre- and postintervention phases were then compared to evaluate the outcomes of pharmaceutical care services. MAIN OUTCOME MEASURE: The primary end point was the absolute change in A1C versus baseline, the change in cholesterol and blood pressure and the number of patients to achieve Chinese Diabetes Society (CDS) goals at the baseline and at the end of pharmaceutical care were the main outcome measures. RESULTS: During the 6-month study period, the postintervention phase showed a greater percent change in A1C (-1.45 vs. -0.43 %, P = 0.03). Another end points for achieving CDS goals were statistically significantly different in low-density lipoprotein, triglycerides and blood pressure. In the phase that received the participation of pharmacists, the number of patients that improved in A1C increased from 327 to 406 (P = 0.02); the number of rehospitalization was 29 for the postintervention phase and 75 for the preintervention phase (P = 0.05).The drug cost per patient day decreased from 254.74 to 219.85 (P = 0.095), and the Length of stay (LOS) did not change significantly (16.35 vs. 15.91 days; P = 0.15). CONCLUSION: Including a pharmacist as a part of the diabetes management team may result in lower A1C, cholesterol and blood pressure in patients versus a health care.