Effectiveness and safety of nirmatrelvir-ritonavir in kidney transplant recipients with severe kidney dysfunction infected with COVID-19.

Transplant patients face an elevated risk of coronavirus disease 2019 (COVID-19) morbidity and mortality and commonly encounter renal dysfunction. Nirmatrelvir is primarily excreted through the kidneys. The dosage of nirmatrelvir/ritonavir (NR) needs to be adjusted according to the degree of renal function impairment. Nevertheless, NR is not recommended for patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min) due to a dearth of associated research. In this study, we focus on kidney transplant patients and document and analyze the experiences of using NR in individuals with severe kidney dysfunction. This was a retrospective multicenter study that included transplant recipients hospitalized for COVID-19 in five major tertiary hospitals in China from December 2022 to June 2023. The outcomes consisted of the disease progression rate by day 28, individual disease progression events, safety outcomes, information on adverse events (AEs), and the blood drug concentrations of immunosuppressants. Data were presented with descriptive statistics. All analyses were performed using SPSS version 22. In total, 40 patients were included in the analysis. Considering the potential interaction between drugs, all patients temporarily discontinued their immunosuppressants during the NR treatment. None of the 32 moderate patients experienced disease progression. However, among the eight patients with critical COVID-19, unfortunately, two of them died. During the medication period, four patients experienced a total of six AEs associated with NR. None of them experienced AEs with a maximum grade of ≥3. Blood drug concentrations of immunosuppressants were monitored in 22 of 40 patients, and the blood drug concentrations of immunosuppressants did not show a significant increase, but some patients experienced lower blood drug concentrations. Our findings supported the use of NR therapy for the treatment of COVID-19 in transplant patients with severe renal insufficiency. A modified dose of NR was well-tolerated.

Cost-effectiveness of rivaroxaban versus warfarin in non-valvular atrial fibrillation patients with chronic kidney disease in China.

WHAT IS KNOWN AND OBJECTIVE: In non-valvular atrial fibrillation (NVAF) patients with chronic kidney disease (CKD), rivaroxaban was not inferior to warfarin in preventing stroke and systemic embolism. However, a comparative evaluation of the cost-effectiveness of rivaroxaban and warfarin therapies for NVAF patients at different renal function levels has not yet been reported, and this study aimed to estimate the cost-effectiveness of rivaroxaban compared with warfarin in Chinese NVAF patients with CKD. METHODS: A Markov model was constructed to estimate quality-adjusted life years (QALYs) and lifetime costs associated with the use of rivaroxaban relative to warfarin in patients with NVAF at different estimated glomerular filtration rate (eGFR) levels as follows: 30 to <50, 50 to <80 and ≥80 mL/min. Input parameters were sourced from the clinical literature. Probabilistic sensitivity analyses were performed to assess model uncertainty. RESULTS AND DISCUSSION: The incrementalQALYs with rivaroxaban was slightly increased by approximately 0.3 QALY as compared with that with warfarin in all the subgroups, resulting in an ICER of $9,736/QALY (eGFR, 30 to <50 mL/min), $9,758/QALY (50 to <80 mL/min) and $9,969/QALY (≥80 mL/min). The probabilistic sensitivity analysis suggested a chance of >80% that the ICER would be lower than the willingness-to-pay threshold of three times the GDP of China in 2019 in all the subgroups. Results were consistent even under the assumption of anticoagulant discontinuation after major bleeding events. The model was most sensitive to event-free-related utility and survival rates. WHAT IS NEW AND CONCLUSION: The existing evidence supports the cost-effectiveness of rivaroxaban therapy as an alternative anticoagulant to warfarin for patients with NVAF at different renal function levels.

NLRC4 inflammasome activation regulated by TNF-α promotes inflammatory responses in nonalcoholic fatty liver disease.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is high and increasing throughout the world. The intense sterile inflammation stemming from steatosis plays a significant role in the development of NAFLD, but the mechanism is unclear. We found that the NLRC4 inflammasome was activated in an in vitro cell model of NAFLD, and that the secretion of inflammatory factors IL-18, IL-1ß, and tumor necrosis factor α (TNF-α) increased during this process and pyroptosis is triggered. In this study, we used NLRC4-targeting siRNA and an NLRC4-encoding plasmid to demonstrate that the increases in IL-18 and IL-1ß are mainly attributable to the activation of the NLR family CARD domain-containing protein 4 (NLRC4) inflammasome, which stimulates cellular pyroptosis. NLRC4 inflammasome activation is regulated by TNF-α and accompanies the translocation of NLRC4 from the cytoplasm into the mitochondria, but the specific mechanism is unclear. In summary, the increase in TNF-α during NAFLD promotes the activation of the NLRC4 inflammasome, which increases the production of IL-18 and IL-1ß and triggers pyroptosis. These exacerbate inflammation and promote disease development.

Characterization of endonuclease G and mitochondria-sarcoplasmic reticulum-related proteins during cardiac hypertrophy.

Endonuclease G (Endo G) is a novel determinant of cardiac hypertrophy. Here, we report the characterization of Endo G and mitochondria-sarcoplasmic reticulum-related proteins during cardiac hypertrophy, and hypothesize that Endo G regulate mitochondrial function partly through Mfn2 and Jp2 during cardiac hypertrophy. Our results show that Endo G levels gradually increased at the beginning of phenylephrine-induced cardiac hypertrophy, accompanied by an abnormal mitochondrial membrane potential. The up-regulation of Mfn2, Jp2, and Endo G appeared at an early stage of cardiac hypertrophy, whereas PGC1α was not up-regulated until a later stage. Abolishing Endo G with siRNA led to the uncoupling of the mitochondrial electron transport chain from ATP production and decreased PGC1α expression, likely by affecting the juxtaposition of the mitochondria and the sarcoplasmic reticulum via Mfn2 and Jp2. Furthermore, abolishing Jp2 altered the expression of Endo G expression and induced mitochondrial dysfunction, suggesting that mitochondrial abnormalities in cardiac hypertrophy are most likely caused by Endo G. Taken together, our study established a link between Endo G and mitochondrial function during cardiac hypertrophy, partly through the effects of Endo G on Mfn2 and Jp2, and revealed a role for Endo G in the crosstalk between the processes controlled by Mfn2 and Jp2 in maladaptive cardiac hypertrophy.

Icariin promotes expression of junctophilin 2 and Ca2+ related function during cardiomyocyte differentiation of murine embryonic stem cells.

Junctophilin2 (JP2) is a critical protein associated with cardiogenesis. Icariin (ICA) facilitated the directional differentiation of murine embryonic stem (ES) cells into cardiomyocytes. However, little is known about the effects of ICA on JP2 during cardiac differentiation. Here, we explored whether ICA has effects on the expression and Ca2+ related function of JP2 during cardiomyocyte differentiation of ES cells in vitro. Embryonid bodies (EBs) formed by hanging drop were treated with 10(-7) mol/L ICA from day 5 to promote the cardiac differentiation. Percentage of beating EBs and number of beating area within EBs were monitored. Cardiomyocytes were purified by discontinuous percoll gradient centrifugation from EBs. The expression of JP2, α-actinin and troponin-T within EBs or isolated cardiomyocytes were analyzed by immunocytochemistry, western blot and flow cytometry. The transient Ca2+ release was characterized in cardiomyocytes treated with/without 10 mmol/L caffeine and 8 mmol/L Ca2+. Our results showed that ES cell-derived cardiomyocytes were well characterized with JP2 proteins. ICA promoted cardiomyocyte differentiation as indicated by an increased percentage of beating EBs and number of beating area within EBs. The expression of JP2, α-actinin and troponin-T were up-regulated both in EBs and isolated cardiomyocytes from EBs. Furthermore, ICA-induced JP2 expression was accompanied by a remarkable increase of the amplitude of Ca2+ transients in cardiomyocytes before/after caffeine and Ca2+ stimulating. In conclusion, ICA promotes in cardiac differentiation partly through regulating JP2 and improved the Ca2+ modulatory function of cardiomyocytes.

Simultaneous determination of eight active components in the traditional Chinese Medicine Dan Deng Tong Nao capsules by HPLC-MS/MS.

An high-performance liquid chromatography-tandem mass spectrometry method has been optimised and established for the quality evaluation of the traditional Chinese medicine Dan Deng Tong Nao capsules through simultaneous determination of the following eight active components: danshensu, salvianolic acid A, salvianolic acid C, puerarin, scutellarin, apigenin, 3,4-dihydroxybenzaldehyde, and ferulic acid. All of the analytes were separated on a Waters Xbridge™ C18 column (4.6 × 150 mm, 3.5 µm particle size) with a mobile phase consisting of methanol/acetonitrile (50 : 50, v/v) and water containing 0.1 % formic acid. All of the compounds showed good linearity (R2 > 0.997). The recoveries, measured at three concentration levels, varied from 94.94 to 107.3 %. The validated method was successfully applied to evaluate the eight active components in Dan Deng Tong Nao capsules collected from different production batches. The results suggested that the method established in this study could be considered a good approach to controlling the quality of Dan Deng Tong Nao capsules and other related botanical drugs.

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.

The role of ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a condition that occurs during the progression of non-alcoholic fatty liver disease. Effective therapy for NASH is still lacking. In this study, we investigated the effects of Ursodeoxycholic acid (UDCA) in the treatment of NASH. METHODS: Western and Chinese databases were searched by independent investigators using appropriate MESH headings to identify randomized, controlled Western and Chinese clinical trials, published between January 1990 and October 2012, testing the effects of UDCA in patients with NASH. Patient characteristics and trial endpoints were analyzed, with quality assessment according to widely acknowledged criteria. P < 0.05 was defined as statistically significant in all trials. RESULTS: Twelve qualified randomized clinical trials, including six from China and involving 1160 subjects, were selected. Seven of these trials assessed the effects of UDCA Monotherapy, with the other five testing combinations of UDCA with vitamin E, polyene phosphatidylcholine, silymarin, glycyrrhizin and tiopronin. The duration of therapy ranged from 3 to 24 months, with two studies using high doses of UDCA (23-35 mg/kg/d). The average quality point was 2.69, and was significantly lower in articles from China than in those from Western countries (2.2 ± 0.4 vs. 3.8 ± 1.1, respectively, p < 0.05). UDCA Monotherapy significantly improved liver function in five studies and improved steatosis and fibrosis in two studies. All five studies assessing UDCA combination therapy showed significant improvements liver function, while two studies also improved steatosis and inflammation. One study of high-dose UDCA showed significant improvements in ALT, γGT and liver fibrosis, whereas the other study showed no significant change in ALT and liver pathology. CONCLUSIONS: UDCA therapy is effective in NASH, especially when combined with other drugs. However, the low quality of these studies and the heterogeneity of their results precluded further meta-analysis. Additional carefully designed clinical trials are needed, especially in China.

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.

[Characteristics of microsomal phase II metabolic enzymes in mouse embryonic stem cell-derived liver tissue].

OBJECTIVE: To investigate the characteristics of phase II metabolic enzymes in mouse embryonic stem (ES) cell-derived liver tissue. METHODS: Mature hepatocytes were differentiated from embryonic stem cells in cultured mouse embryoid bodies (EB) at d18. Western blot was used to detect the expression of uridine 5'-diphosphate glucronosyl transferase (UGT1a1,UGT1a6) and microsomal glutathione S-transferases 1(mGST1) during the differentiation course.The derived liver tissue was incubated with UDPGA and 7-HFC,the formation of 7-HFC glucuronide was detected by HPLC to examine the total activities of UGT1a1 and UGT1a6. Furthermore, the microsomes were incubated with CDNB and GSH,and the mGST1 activity was measured by spectrometry. RESULTS: An increase tendency of UGT1a1 expression was noticed during the differentiation course. UGT1a6 and mGST1 were not detected in the earlier stage until d18 of differentiation. The metabolic activity of mGST1 in the derived hepatocytes was 7.65 nmol/min/mg on d18. CONCLUSION: The ES cell-derived liver tissue possesses partial metabolic function of phase II enzymes on d18 of differentiation,which might be used as a model for in vitro research on hepatic pathophysiology and phase II drug metabolism.

Availability, Functionality, and Safety as well as Quality Control of Hepatocytes as Seeding Cells in Liver Regenerative Medicine: State of the Art and Challenges.

Hepatic disease is one of the most common causes of death worldwide and has become a global health problem. Liver transplantation is the only effective treatment strategy for patients with hepatic function failure, but the insufficient number of donated healthy livers is the main obstacle limiting this process. To alleviate the demand for donor's livers, alternative approaches are being actively explored using liver tissue engineering principles. Liver tissue engineering consists of three elements, including seeding cells, extracellular matrix, and bioreactors. Among them, seeding cell is the most key factor. In this regard, hepatocyte-based tissue engineering can overcome the above shortages for tissue repair and regeneration in hepatic disorders. Primary human hepatocytes in liver regenerative medicine are the most preferred seeding cells, although limited access to a sufficient number of functional hepatocytes are a major issue due to the difficulties in long-term function maintenance of hepatocyte as well as the lack of availability of healthy donors. Hepatocyte-like cells (HLCs), derived from various stem cells, including non-liver-derived stem cells and liver-derived stem cells, as well as trans-differentiation of other cell types, may provide adequate cell sources and could replace primary human hepatocytes as seeding cells. However, it is still a great difficulty that HLCs generated by stem cell differentiation meet the quality required for clinical therapy. Furthermore, none of the standardized protocols to generate high-quality HLCs is available. Whether primary hepatocytes or HLCs are from various sources, preventing the functional deterioration of hepatocytes or generating fully functional hepatocytes is also a big challenge, respectively. In addition, the adoptions of three-dimensional co-culture systems and some small-molecule compounds contribute to maintaining the hepatic functionality of primary hepatocytes and enhancing the liver-specific functions of HLCs. In short, hepatocyte-based liver regenerative medicine is an attractive alternative strategy for liver diseases, notwithstanding some challenges still exist from bench to bedside. This review summarizes the current status, issues, and challenges in availability, functionality, and safety, as well as quality control of seeding hepatocytes with regard to liver tissue engineering in regenerative medicine for the treatment of liver disorders.

Inflammatory mediators involved in the progression of the metabolic syndrome.

The metabolic syndrome is often associated with type 2 diabetes mellitus, dyslipidemia, atherosclerosis, hypertension, steatosis of the liver and other organs, as well as hypertension, type 2 diabetes mellitus, and atherosclerosis. Recent studies have implicated a number of inflammatory mediators including cytokines, adipokines and eicosanoids in the inflammatory responses that accompany the metabolic syndrome. Measurements of the circulating levels of the inflammatory molecules that accompany this syndrome might provide leads to therapeutic approaches to modulate the inflammatory responses and thereby alter disease progression. In this review, we summarize recent studies on classical and newer inflammatory mediators in the pathogenesis of the metabolic syndrome in humans and experimental models.

Poor Compliance Causes Acute Rejection in Kidney Transplant Recipients During COVID-19 Pandemic: 2 Cases Report.

The COVID-19 pandemic has lasted for more than one year, which caused much trouble to the health management of kidney transplant recipients. Numerous patients cancelled their review appointment or even lost connection with doctors because of the great pressure medical system undergoing, strict travel restrictions, and the worries about COVID-19 infection risk. Herein, we introduce two kidney transplant recipients, a 33-year-old man and a 32-year-old man, who did not take the immunosuppressant drugs and did not go back to the hospital to do the renal function examination as the doctor's request. When they paid their first return visit several months after the pandemic outbreak, they were both diagnosed with acute rejection and admitted to the hospital. After receiving pulse steroid therapy, they were in remission but failed to reverse the rejection. The level of serum creatinine did not recover to the one before pandemic outbreak. These cases suggest that it is necessary to ensure that kidney transplant recipients follow the doctor's advice to take drugs and follow-up regularly to examine their renal function over pandemic period. Additionally, typical pulse steroid therapy may not that effective toward these patients.

Towards the Antiviral Agents and Nanotechnology-Enabled Approaches Against Parvovirus B19.

Parvovirus B19 (B19V) as a human pathogenic virus, would cause a wide range of clinical manifestations. Besides the supportive and symptomatic treatments, the only FDA-approved antiviral drug for the treatment of B19V is intravenous immunoglobulins, which however, have limited efficacy and high cost. By far, there are still no virus-specific therapeutics clinically available to treat B19V infection. Therefore, exploiting the potential targets with a deep understanding of the life cycle of B19V, are pivotal to the development of B19V-tailored effective antiviral approaches. This review will introduce antiviral agents via blocking viral invasion, inhibiting the enzymes or regulatory proteins involved in DNA synthesis, and so on. Moreover, nanotechnology-enabled approaches against B19V will also be outlined and discussed through a multidisciplinary perspective involving virology, nanotechnology, medicine, pharmaceutics, chemistry, materials science, and other fields. Lastly, the prospects of the antiviral agents and nanosystems in terms of fabrication, clinical translation and potential breakthroughs will be briefly discussed.

Population pharmacokinetics of polymyxin B: a systematic review.

Background: Polymyxin B (PMB) is a basic cyclic polypeptide antibiotic produced by Bacillus polymyxa, and is one of the last options for treating multi-drug-resistant negative bacterial infections in clinical practice. In recent years, many population pharmacokinetic studies of PMB have been conducted. This paper sought to comprehensively summarize the characteristics of population pharmacokinetic models of PMB and provide a theoretical basis for the individualized use of PMB. Methods: In this review, we systematically searched the PubMed and Embase databases to find articles on population pharmacokinetic models published from database establishment to August 2021. Results: A total of 10 studies were included in this review, including studies on various types of severe infections caused by multi-drug-resistant bacteria, hospital-acquired infections with fibrosis and other male and female populations, and a study of 2 continuous renal replacement therapy (CRRT) patients, aged 16-94 years, who received PMB doses of 10-360 mg/day (0.13-3.45 mg/kg/day), at an administration time of 0.5-6 hours. First-order linear elimination was used in all the studies; a 1-compartment model was used in 5 studies, and a 2-compartment model was used in 5 studies. The most common covariates were creatinine clearance (CrCL) and body weight. Discussion: Although these studies included several covariates and total clearance (CL) was close, but the external validation of some models was poorly correlated between the actual and predicted value. Novel or potential covariates represent important directions for further study.

Carcinogenicity risk associated with tacrolimus use in kidney transplant recipients: a systematic review and meta-analysis.

Background: Currently, tacrolimus is the preferred anti-rejection therapy for kidney transplant recipients due to its greater protection against acute rejections compared to cyclosporin A (CsA). Despite the advantages of kidney transplantation, it has been associated with an increased incidence of de novo malignancies. Furthermore, a systematic review in 2005 revealed no statistical difference in tumorigenicity between tacrolimus and CsA. This report provides an up to date systematic review and evaluation of all relevant studies in the literature to determine the risk of malignancy in kidney transplant recipients exposed to tacrolimus. Methods: A systematic literature search was performed using the Medline (PubMed and Ovid), Embase, Clinical Trials, and Cochrane databases (from creation to May 2021). We performed a meta-analysis of 11 studies with 36,985 kidney transplant recipients that compared the tacrolimus group with the control group. Outcomes of this study were incidence of malignancies and skin cancer risk. Risk of Bias was assessed in terms of whether there was random sequence generation, allocation concealment, blinding, completeness of results, selective reporting, etc. This meta-analysis was performed in accordance with PRISMA guidelines. Results: Of the 11 included studies, 8 were high quality studies, 1 was assessed as medium quality, and 2 were low quality studies. The results showed a significantly increased risk of overall malignancy associated with tacrolimus exposure compared to non-tacrolimus therapy [risk ratio (RR) =1.59; 95% confidence interval (CI): 1.19-2.11; P=0.002], and especially with sirolimus (SRL) (RR =2.58; 95% CI: 1.62-4.09; P<0.0001). The incidence of skin cancer was consistent with the overall study (RR =2.03; 95% CI: 1.25-3.28; P=0.004). However, there was no significant difference in the incidence of tumors between tacrolimus and cyclosporine A treatment (RR =1.12; 95% CI: 0.80-1.56; P=0.52), even in studies with long follow-up periods of more than 3 years. Discussion: The data demonstrated that patients treated with tacrolimus had a higher risk of carcinogenicity compared to patients treated with SRL. However, patients treated with tacrolimus had a similar incidence of carcinogenicity compared to patients treated with CsA. Further clinical studies are warranted to confirm these findings.

Risk factors of tigecycline-associated fibrinogen reduction in patients with renal transplantation: a case-control study.

Background: Hypofibrinogenemia is a serious adverse reaction related to tigecycline administered against multidrug-resistant (MDR) bacteria and can lead to therapy termination. High dose and prolonged tigecycline therapy, renal failure, and base level of fibrinogen (FIB) were reported risk factors of tigecycline-associated FIB reduction. But results are unknown in patients with renal transplantation. Methods: A single-center and a case-control study involving renal transplantation patients was conducted. From January, 2017 to January, 2020, patients with a tigecycline course more than 2 days and a baseline FIB level greater than 2 g/L were enrolled. Hypofibrinogenemia was defined as plasma FIB <2.0 g/L. The extent of FIB reduction was calculated based on the baseline of FIB level before tigecycline administration. FIBRO was defined as the extent of FIB reduction over 50%, and FIBRB referred to the extent of FIB reduction below 50%. Univariate and multivariate analyses were performed by logistic regression models to identify independent risk factors of tigecycline-associated FIB reduction. Results: In total, 120 patients were enrolled. A total of 114 patients (95.00%) developed with hypofibrinogenaemia. Hypofibrinogenemia mainly occurred 3 days after tigecycline administration. Of them, 79 (65.83%) developed FIBRO with a median occurrence of 3 [2-4] days after initiation of tigecycline. Multivariable regression analysis demonstrated that the FIB level before tigecycline use [odds ratio (OR): 3.225, 95% confidence interval (CI): 1.801-5.772] and total tigecycline dose (OR: 4.930, 95% CI: 1.433-16.959) were risk factors for FIBRO. Conclusions: The FIB level before tigecycline use and total tigecycline dose were significantly associated with FIBRO, suggesting that FIB level and coagulation-related indicators should be closely monitored during tigecycline treatment to avoid life-threatening bleeding events.

TPGS-based and S-thanatin functionalized nanorods for overcoming drug resistance in Klebsiella pneumonia.

Tigecycline is regarded as the last line of defense to combat multidrug-resistant Klebsiella pneumoniae. However, increasing utilization has led to rising drug resistance and treatment failure. Here, we design a D-alpha tocopheryl polyethylene glycol succinate-modified and S-thanatin peptide-functionalized nanorods based on calcium phosphate nanoparticles for tigecycline delivery and pneumonia therapy caused by tigecycline-resistant Klebsiella pneumoniae. After incubation with bacteria, the fabricated nanorods can enhance tigecycline accumulation in bacteria via the inhibitory effect on efflux pumps exerted by D-alpha tocopheryl polyethylene glycol succinate and the targeting capacity of S-thanatin to bacteria. The synergistic antibacterial capacity between S-thanatin and tigecycline further enhances the antibacterial activity of nanorods, thus overcoming the tigecycline resistance of Klebsiella pneumoniae. After intravenous injection, nanorods significantly reduces the counts of white blood cells and neutrophils, decreases bacterial colonies, and ameliorates neutrophil infiltration events, thereby largely increasing the survival rate of mice with pneumonia. These findings may provide a therapeutic strategy for infections caused by drug-resistant bacteria.

Efficacy and safety of roxadustat in the treatment of renal allograft anemia patients: a case series.

BACKGROUND: To observe the efficacy and safety of roxadustat, an inhibitor of proline hydroxylase, in renal allograft anemia patients. METHODS: This prospective study collected the clinical data of renal transplant patients treated with roxadustat for anemia at the Kidney Disease Center of the First Affiliated Hospital of Zhejiang University from April to August 2020. The patients were followed up every 2 weeks, and the changes in their hemoglobin index and any adverse reactions were recorded during 10 weeks of treatment. The efficacy of roxadustat for treatment of anemia after kidney transplantation was analyzed by comparing the change and increase in average hemoglobin levels before and after treatment. Rates of treatment response and achievement of the standard hemoglobin level were statistically analyzed. In addition, any potential adverse events and the glomerular filtration rate were recorded for 10 weeks to assess the safety of roxadustat in renal allograft anemia patients. RESULTS: After 10 weeks of roxadustat treatment, the mean hemoglobin level was 10.4±3.9 g/dL, which was significantly higher than at baseline. Over the entire period, treatment was observed to have a therapeutic effect at weeks 2-4, with mean hemoglobin levels increasing as treatment time increased. At the 10-week endpoint, the percentage of patients reaching the standard hemoglobin level and exhibiting a response to treatment was 52.4% and 71.4%, respectively. During the treatment, there was no rejection, and the glomerular filtration rate was stable. Only one person showed symptoms of fatigue, and there were no other obvious adverse reactions reported. CONCLUSIONS: Roxadustat significantly improves hemoglobin levels and can be safely used in renal transplant anemia patients.

Cost-effectiveness analysis of cinacalcet for haemodialysis patients with moderate-to-severe secondary hyperparathyroidism in China: evaluation based on the EVOLVE trial.

OBJECTIVE: As the cost-effectiveness evaluation of cinacalcet and conventional therapy in China has not been reported, the objective of this study was to make a pharmacoeconomic evaluation of cinacalcet specific to the Chinese healthcare setting in patients with moderate-to-severe secondary hyperparathyroidism (SHPT) undergoing dialysis. DESIGNS: Data from Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events trial were used for this analysis. A semi-Markov model was constructed to estimate quality-adjusted life years (QALYs) and lifetime costs in cinacalcet plus conventional therapy (cinacalcet strategy) compared with conventional therapy (standard strategy), in patients with moderate-to-severe SHPT undergoing dialysis. Treatment effect estimates from the unadjusted intent-to-treat (ITT) analysis and covariate-adjusted ITT analysis were used as the main analyses. Model sensitivity to variations in individual inputs and overall decision uncertainty were assessed through probabilistic sensitivity analyses. PRIMARY AND SECONDARY OUTCOME MEASURES: Incremental cost-effectiveness ratio (ICER) as measured by cost per QALY gained. RESULTS: The ICER for cinacalcet strategy was US$44 400 per QALY gained using the covariate-adjusted ITT analysis. Probabilistic sensitivity analysis suggested a 46.2% chance of the ICER being below a willingness-to-pay threshold of US$26 508. Treatment effects from unadjusted ITT analysis yielded an ICER of US$87 210 per QALY. The model was most sensitive to the treatment effect on mortality. CONCLUSIONS: Existing evidence does not support the cost-effectiveness of cinacalcet strategy in patients with moderate-to-severe SHPT undergoing dialysis when applying a willingness-to-pay threshold of US$26 508 per QALY, whether it is using the treatment effect from covariate-adjusted ITT analysis or unadjusted ITT analysis.