Acute kidney injury with intravenous colistin sulfate compared with polymyxin B in critically ill patients: A real-world, retrospective cohort study.

BACKGROUND: Polymyxins have re-emerged as a last-resort therapeutic option for infections caused by carbapenem-resistant gram-negative bacteria. Nephrotoxicity induced by polymyxins is a significant limitation of its use in the clinic. Polymyxin B and colistin sulfate are two widely used active formulations of polymyxins. However, there is a lack of studies conducting a comparative assessment of nephrotoxicity between the two formulations. This study aimed to compare the nephrotoxicity of polymyxin B and colistin sulfate in critically ill patients. METHODS: We conducted a retrospective cohort study among critically ill patients who received intravenous polymyxin B or colistin sulfate for over 48 h from January 2017 to January 2024. The primary outcome was the incidence of acute kidney injury (AKI) associated with polymyxins, and the secondary outcome was 30-day all-cause mortality. Additionally, the risk factors of polymyxins-induced AKI and 30-day all-cause mortality were identified by Cox proportional hazard regression analysis. RESULTS: A total of 473 patients were included in this study. The overall incidence of AKI was significantly higher in patients who received polymyxin B compared to those who received colistin sulfate in the unmatched cohort (20.8% vs. 9.0%, p = 0.002) and in the propensity score matching cohort (21.1% vs. 7.0%, p = 0.004), respectively. However, there was no significant difference in 30-day all-cause mortality between the two groups. Polymyxin type, septic shock, and concomitant use of vasopressors were identified as independent risk factors for polymyxin-induced AKI. CONCLUSIONS: The prevalence of AKI was higher among patients who received polymyxin B compared to those treated with colistin sulfate. However, there was no significant difference in 30-day all-cause mortality between the two groups. Further prospective, multicenter studies with larger sample sizes are needed to validate these findings.

A pilot clinical risk model to predict polymyxin-induced nephrotoxicity: a real-world, retrospective cohort study.

OBJECTIVES: Polymyxin-induced nephrotoxicity (PIN) is a major safety concern and challenge in clinical practice, which limits the clinical use of polymyxins. This study aims to investigate the risk factors and to develop a scoring tool for the early prediction of PIN. METHODS: Data on critically ill patients who received intravenous polymyxin B or colistin sulfate for over 24 h were collected. Logistic regression with the least absolute shrinkage and selection operator (LASSO) was used to identify variables that are associated with outcomes. The eXtreme Gradient Boosting (XGB) classifier algorithm was used to further visualize factors with significant differences. A prediction model for PIN was developed through binary logistic regression analysis and the model was assessed by temporal validation and external validation. Finally, a risk-scoring system was developed based on the prediction model. RESULTS: Of 508 patients, 161 (31.6%) patients developed PIN. Polymyxin type, loading dose, septic shock, concomitant vasopressors and baseline blood urea nitrogen (BUN) level were identified as significant predictors of PIN. All validation exhibited great discrimination, with the AUC of 0.742 (95% CI: 0.696-0.787) for internal validation, of 0.708 (95% CI: 0.605-0.810) for temporal validation and of 0.874 (95% CI: 0.759-0.989) for external validation, respectively. A simple risk-scoring tool was developed with a total risk score ranging from -3 to 4, corresponding to a risk of PIN from 0.79% to 81.24%. CONCLUSIONS: This study established a prediction model for PIN. Before using polymyxins, the simple risk-scoring tool can effectively identify patients at risk of developing PIN within a range of 7% to 65%.

Identification and analysis of differently expressed transcription factors in aristolochic acid nephropathy.

BACKGROUND: Aristolochic acid nephropathy (AAN) is a rapidly progressive interstitial nephropathy caused by Aristolochic acid (AA). AAN is associated with the development of nephropathy and urothelial carcinoma. It is estimated that more than 100 million people worldwide are at risk of developing AAN. However, the underlying mechanisms driving renal deterioration in AAN remain poorly understood, and the treatment options are limited. METHODS: We obtained GSE27168 and GSE136276 series matrix data from the Gene Expression Omnibus (GEO) related to AAN. Using the R Studio environment, we applied the limma package and WGCNA package to identify co-differently expressed genes (co-DEGs). By GO/KEGG/GSVA analysis, we revealed common biological pathways. Subsequently, co-DEGs were subjected to the String database to construct a protein-protein interaction (PPI) network. The MCC algorithms implemented in the Cytohubba plugin were employed to identify hub genes. The hub genes were cross-referenced with the transcription factor (TF) database to identify hub TFs. Immune infiltration analysis was performed to identify key immune cell groups by utilizing CIBERSORT. The expressions of AAN-associated hub TFs were verified in vivo and in vitro. Finally, siRNA intervention was performed on the two TFs to verify their regulatory effect in AAN. RESULTS: Our analysis identified 88 co-DEGs through the "limma" and "WGCNA" R packages. A PPI network comprising 53 nodes and 34 edges was constructed with a confidence level >0.4. ATF3 and c-JUN were identified as hub TFs potentially linked to AAN. Additionally, expressions of ATF3 and c-JUN positively correlated with monocytes, basophils, and vessels, and negatively correlated with eosinophils and endothelial cells. We observed a significant increase in protein and mRNA levels of these two hub TFs. Furthermore, it was found that siRNA intervention targeting ATF3, but not c-JUN, alleviated cell damage induced by AA. The knockdown of ATF3 protects against oxidative stress and inflammation in the AAN cell model. CONCLUSION: This study provides novel insights into the role of ATF3 in AAN. The comprehensive analysis sheds light on the molecular mechanisms and identifies potential biomarkers and drug targets for AAN treatment.

Layer-by-Layer Assembly of Renal-Targeted Polymeric Nanoparticles for Robust Arginase-2 Knockdown and Contrast-Induced Acute Kidney Injury Prevention.

The mitochondrial enzyme arginase-2 (Arg-2) is implicated in the pathophysiology of contrast-induced acute kidney injury (CI-AKI). Therefore, Arg-2 represents a candid target for CI-AKI prevention. Here, layer-by-layer (LbL) assembled renal-targeting polymeric nanoparticles are developed to efficiently deliver small interfering RNA (siRNA), knockdown Arg-2 expression in renal tubules, and prevention of CI-AKI is evaluated. First, near-infrared dye-loaded poly(lactic-co-glycolic acid) (PLGA) anionic cores are electrostatically coated with cationic chitosan (CS) to facilitate the adsorption and stabilization of Arg-2 siRNA. Next, nanoparticles are coated with anionic hyaluronan (HA) to provide protection against siRNA leakage and shielding against early clearance. Sequential electrostatic layering of CS and HA improves loading capacity of Arg-2 siRNA and yields LbL-assembled nanoparticles. Renal targeting and accumulation is enhanced by modifying the outermost layer of HA with a kidney targeting peptide (HA-KTP). The resultant kidney-targeting and siRNA loaded nanoparticles (PLGA/CS/HA-KTP siRNA) exhibit proprietary accumulation in kidneys and proximal tubular cells at 24 h post-tail vein injection. In iohexol-induced in vitro and in vivo CI-AKI models, PLGA/CS/HA-KTP siRNA delivery alleviates oxidative and nitrification stress, and rescues mitochondrial dysfunction while reducing apoptosis, thereby demonstrating a robust and satisfactory therapeutic effect. Thus, PLGA/CS/HA-KTP siRNA nanoparticles offer a promising candidate therapy to protect against CI-AKI.

Arginase2 mediates contrast-induced acute kidney injury via facilitating nitrosative stress in tubular cells.

Contrast-induced acute kidney injury(CI-AKI) is the third cause of AKI. Although tubular injury has been regarded as an important pathophysiology of CI-AKI, the underlying mechanism remains elusive. Here, we found arginase2(ARG2) accumulated in the tubules of CI-AKI mice, and was upregulated in iohexol treated kidney tubular cells and in blood samples of CI-AKI mice and patients, accompanied by increased nitrosative stress and apoptosis. However, all of the above were reversed in ARG2 knockout mice, as evidenced by the ameliorated kidney dysfunction and the tubular injury, and decreased nitrosative stress and apoptosis. Mechanistically, HO-1 upregulation could alleviate iohexol or ARG2 overexpression mediated nitrosative stress. Silencing and overexpressing ARG2 was able to upregulate and downregulate HO-1 expression, respectively, while HO-1 siRNA had no effect on ARG2 expression, indicating that ARG2 might inhibit HO-1 expression at the transcriptional level, which facilitated nitrosative stress during CI-AKI. Additionally, CREB1, a transcription factor, bound to the promoter region of ARG2 and stimulated its transcription. Similar findings were yielded in cisplatin- or vancomycin-induced AKI models. Taken together, ARG2 is a crucial target of CI-AKI, and activating CREB1/ARG2/HO-1 axis can mediate tubular injury by promoting nitrosative stress, highlighting potential therapeutic strategy for treating CI-AKI.

Trends of the burden of type 2 diabetes mellitus attributable to high body mass index from 1990 to 2019 in China.

Background: Overweight and obesity are well-known risk factors for developing type 2 diabetes (T2DM). However, details on the evolution of the T2DM burden attributed to China's high body mass index (BMI) in China have not been thoroughly studied. This study aimed to investigate the temporal trends of the T2DM burden attributable to a high BMI in China from 1990 to 2019 and to evaluate the independent effects of age, period, and cohort on the burden of T2DM attributed to a high BMI. Methods: Data on T2DM burden attributable to a high BMI from 1990 to 2019 were obtained from the Global Burden of Disease Study 2019. Deaths, disability-adjusted life years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALY rate (ASDR) of T2DM attributable to a high BMI were estimated by age and sex. The joinpoint regression model was performed to calculate the annual percentage change (APC) and the average annual percentage change (AAPC) in the burden of T2DM attributed to a high BMI. The age-period-cohort analysis was applied to estimate the independent effects of age, period, and cohort on the temporal trends of mortality and the DALY rate. Results: In 2019, deaths and DALYs from T2DM attributable to a high BMI in China were 47.53 thousand and 3.74 million, respectively, five times higher than in 1990. Among those under 60 years of age, men had higher deaths and DALYs than women, while the gender differences reversed in those over 60 years of age. Furthermore, the ASMR and ASDR in 2019 were 2.39 per 100,000 (95%UI 1.12-3.90) and 181.54 per 100,000 (95%UI 93.71-286.33), respectively, representing a 91% and 126% increase since 1990. In China, women previously had a higher ASMR and ASDR than men, while the differences in the ASMR and ASDR between the sexes were reversed in recent years. From 1990 to 2019, the ASMR in women increased before 2004 and then decreased from 2004 to 2015, and increased again after, with an overall AAPC value of 1.6%. In contrast, the ASMR in men continued to increase, with an overall AAPC value of 3.2%. The ASDR continued to increase in men and women, with AAPCs of 2.2% and 3.5%, respectively. The age effect showed that the relative risk of mortality increased with age in both men and women, except for the 75-84 age group. The impact of the age on the DALY rate revealed a trend of first rising and then decreasing, peaking at 65-69 years. The effect of the period on the burden of T2DM attributable to a high BMI increased from 1990 to 2019. The cohort effect generally showed a downward trend. Conclusion: The burden of T2DM attributed to a high BMI in China increased substantially from 1990 to 2019, particularly in men. Therefore, there is an urgent need for gender- and age-based public health guidelines on prevention strategies, early diagnosis, and effective management of T2DM, overweight, and obesity in China.

Identification and validation of hub genes in drug induced acute kidney injury basing on integrated transcriptomic analysis.

Background: Drug-induced acute kidney damage (DI-AKI) is a clinical phenomenon of rapid loss of kidney function over a brief period of time as a consequence of the using of medicines. The lack of a specialized treatment and the instability of traditional kidney injury markers to detect DI-AKI frequently result in the development of chronic kidney disease. Thus, it is crucial to continue screening for DI-AKI hub genes and specific biomarkers. Methods: Differentially expressed genes (DEGs) of group iohexol, cisplatin, and vancomycin's were analyzed using Limma package, and the intersection was calculated. DEGs were then put into String database to create a network of protein-protein interactions (PPI). Ten algorithms are used in the Cytohubba plugin to find the common hub genes. Three DI-AKI models' hub gene expression was verified in vivo and in vitro using PCR and western blot. To investigate the hub gene's potential as a biomarker, protein levels of mouse serum and urine were measured by ELISA kits. The UUO, IRI and aristolochic acid I-induced nephrotoxicity (AAN) datasets in the GEO database were utilized for external data verification by WGCNA and Limma package. Finally, the Elisa kit was used to identify DI-AKI patient samples. Results: 95 up-regulated common DEGs and 32 down-regulated common DEGs were obtained using Limma package. A PPI network with 84 nodes and 24 edges was built with confidence >0.4. Four hub genes were obtained by Algorithms of Cytohubba plugin, including TLR4, AOC3, IRF4 and TNFAIP6. Then, we discovered that the protein and mRNA levels of four hub genes were significantly changed in the DI-AKI model in vivo and in vitro. External data validation revealed that only the AAN model, which also belonged to DI-AKI model, had significant difference in these hub genes, whereas IRI and UUO did not. Finally, we found that plasma TLR4 levels were higher in patients with DI-AKI, especially in vancomycin-induced AKI. Conclusion: The immune system and inflammation are key factors in DI-AKI. We discovered the immunological and inflammatory-related genes TLR4, AOC3, IRF4, and TNFAIP6, which may be promising specific biomarkers and essential hub genes for the prevention and identification of DI-AKI.

Global, regional, and national burden of chronic kidney disease attributable to high sodium intake from 1990 to 2019.

Background: High sodium intake is a crucial risk factor for the development and progression of chronic kidney disease (CKD). However, the latest global spatiotemporal patterns of CKD burden attributable to high sodium intake still remain unclear. We aimed to evaluate the level and trends of the CKD burden associated with high sodium intake according to sex, age, socio-demographic index (SDI), region, and country from 1990 to 2019. Methods: Data on CKD burden attributable to high sodium intake from 1990 to 2019 were extracted from the Global Burden of Disease (GBD) Study 2019. The CKD-related deaths, disability-adjusted life years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR) attributable to high sodium intake were estimated by age, sex, SDI, region, and country. The estimated annual percentage change (EAPC) was calculated to evaluate the secular trends of ASMR and ASDR of CKD attributable to high sodium intake from 1990 to 2019. We further explored the associations of SDI with the ASMR and ASDR of CKD attributable to high sodium intake. Results: Globally, the number of CKD-related deaths and DALYs attributable to high sodium intake were 45,530 (95% UI: 12,640 to 93,830) and 1.32 million (95% UI: 0.43 to 2.8) in 2019, both twice as many as those in 1990. However, the ASMR and ASDR slightly grew, with an EAPC of 0.22 (95% CI: 0.16 to 0.28) and 0.10 (95% CI: 0.04 to 0.16), respectively. The age-specific numbers and rates of deaths, as well as DALYs of CKD attributable to high sodium intake, rose with age and were greater in males than in females. The rates of deaths and DALYs peaked in the >95 age group for both females and males in 2019. From 1990 to 2019, the trends of both age-specific rates of mortality and DALYs of CKD attributable to high sodium intake were down in people under 60, while in people over 60, the trends were the opposite. The burden of CKD attributable to high sodium intake in 2019 and its temporal trends from 1990 to 2019 varied greatly by SDI quintile and geographic location. The ASMR or ASDR showed a non-linear negative correlation with SDI at the regional level. The EAPC in ASMR or ASDR showed a markedly negative correlation with ASMR or ASDR in 1990, with a coefficient of -0.40. Nevertheless, the EAPC in ASMR rather than ASDR was positively correlated with SDI in 2019, with a coefficient of 0.18. Conclusion: Our findings suggest that there are significant sexual and geographic variations in the burden of CKD attributable to high sodium intake and its temporal trends. Globally, the high sodium intake-caused CKD burden continues to elevate, posing a major challenge to public health. In response to this, strengthened and tailored approaches for CKD prevention and sodium intake management are needed, especially for elderly populations, males, and the population in the middle SDI regions.

Analysis of the clinical characteristics of pembrolizumab-induced bullous pemphigoid.

Background: Pembrolizumab, a programmed cell death protein 1 checkpoint inhibitor, is a novel drug used to treat a variety of advanced malignancies. However, it can also result in many immune-related adverse events, with cutaneous toxicities being the most frequent. Regarding pembrolizumab-induced skin adverse reactions, bullous pemphigoid (BP) has the worst effects on quality of life. Recently, there have been more and more reports of BP incidents resulting from pembrolizumab therapy in patients with cancer. This study aimed to define the clinical characteristics, diagnosis and management of pembrolizumab-induced BP and identify potential differences between classical BP and pembrolizumab-induced BP. Methods: Case reports, case series, and case analyses of pembrolizumab-induced BP up to 10 December 2022 were collected for retrospective analysis. Results: Our study included 47 patients (33 males and 14 females) from 40 studies. The median age was 72 years (range 42-86 years). The median time to cutaneous toxicity was 4 months (range 0.7-28 months), and the median time to bullae formation was 7.35 months (range 0.7-32 months). The most common clinical features were tense bullae and blisters (85.11%), pruritus (72.34%), and erythema (63.83%) on the limbs and trunk. In 20 of the 22 cases tested, the serum anti-BP180 autoantibodies were positive. However, in 10 cases (91.90%, 10/11) the circulating autoantibodies of anti-BP230 were negative. 40 patients had skin biopsies and the skin biopsy revealed subepidermal bullae or blister eosinophil infiltration in 75.00% of patients with pembrolizumab-induced BP, 10.00% of patients with lymphocyte infiltration and 20.00% of patients with neutrophil infiltration. There were 20 patients (50%) with eosinophilic infiltration around the superficial dermis vessels, 8 patients (20.00%) with lymphocyte infiltration around the superficial dermis vessels, and 4 patients (10.00%) with neutrophil infiltration around the superficial dermis vessels. Direct immunofluorescence detected linear immunoglobulin G (IgG) IgG and/or complement C3 along the dermo-epidermal junction in 36 patients (94.74%) with BP. IgG positivity was detected by indirect immunofluorescence in 81.82% of patients with BP. All patients were in complete remission (95.65%,44/46) or partial remission (4.35%, 2/46) of BP, whereas 9/46 patients had a relapse or refractory. The majority of patients achieved BP remission after discontinuation of pembrolizumab with a combination of topically and systemically administered steroid treatments, or other medications. The median duration of BP remission was 2 months (range 0.3-15 months). Conclusion: A thorough diagnosis of pembrolizumab-induced BP should be made using clinical signs, biochemical markers, histopathological and immunopathological tests. Pembrolizumab-induced BP had similar clinical characteristics to classic BP. Temporary or permanent discontinuation of pembrolizumab therapy may be required in patients with perbolizumab-induced BP depending on the severity of BP and the response to medication. Pembrolizumab-induced BP may be effectively treated using topical and systemic steroid treatments in combination with other medications (e.g., doxycycline, niacinamide, dapsone, rituximab, intravenous immunoglobulins, dupilumab, cyclophosphamide, methotrexate, mycophenolate mofetil, and infliximab). Clinicians should provide better management to patients with BP receiving pembrolizumab to prevent progression and ensure continuous cancer treatment.

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Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use.

Multidisciplinary Guidelines for the Rational Use of Topical Non-Steroidal Anti-Inflammatory Drugs for Musculoskeletal Pain (2022).

(1) Background: Topical non-steroidal anti-inflammatory drugs (NSAIDs) are one of the primary drugs for treating musculoskeletal pain. However, there are currently no evidence-based recommendations about drug selection, drug administration, drug interactions, and use in special populations or other pharmacology-related content of such medications. To this end, the Chinese Pharmaceutical Association Hospital Pharmacy Professional Committee developed multidisciplinary guidelines on using topical NSAIDs to treat musculoskeletal pain. (2) Methods: The guidelines development process followed the World Health Organization guideline development handbook, the GRADE methodology, and the statement of Reporting Items for Practice Guidelines in Healthcare. The guideline panel used the Delphi method to identify six clinical questions to be addressed in the guidelines. An independent systematic review team conducted a systematic search and integration of evidence. (3) Results: Based on the balance between the benefits and harms of an intervention, the quality of the evidence, patient preferences and values, and resource utilization, the guideline panel developed 11 recommendations and nine expert consensuses on using topical NSAIDs to treat acute and chronic musculoskeletal pain. (4) Conclusions: Based on the effectiveness and overall safety of topical NSAIDs, we recommend patients with musculoskeletal pain use topical NSAIDs and suggest high-risk patients use topical NSAIDs, such as those with other diseases or receiving other concurrent treatments. The evidenced-based guidelines on topical NSAIDs for musculoskeletal pain incorporated a pharmacist perspective. The guidelines have the potential to facilitate the rational use of topical NSAIDs. The guideline panel will monitor the relevant evidence and update the recommendations accordingly.

An in vivo and in vitro model on the protective effect of cilnidipine on contrast-induced nephropathy via regulation of apoptosis and CaMKâ ¡/mPTP pathway.

Contrast-induced nephropathy (CIN) is an acute kidney injury (AKI) observed after the administration of contrast media. Calcium channel blockers (CCBs) have been reported to exert a renal protective effect. This study aims to investigate the role of cilnidipine, a novel CCBs, on CIN by regulating the calcium/calmodulin-dependent protein kinase Ⅱ(CaMKⅡ)/mitochondrial permeability transition pore (mPTP) pathway. Here, iohexol, a representative contrast media, was used to establish CIN model. KN-93 (CaMKⅡ inhibitor) and atractyloside (mPTP opener) were administered in rats, and CaMKⅡ overexpression was used in Human proximal tubular epithelial cells. Markers of renal injury (serum creatinine, blood urea nitrogen, and urinary NAGL), hematoxylin-eosin stain, oxidative stress (ROS, superoxide dismutase [SOD], and malondialdehyde [MDA] levels), cell death (MTT and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling [TUNEL]), mitochondrial function (mPTP, mitochondrial membrane potential [MMP], and ATP) were assessed. Western blots were used to measure the expression levels of Bax/Bcl-2, caspase-3, CaMKⅡ/mPTP signaling pathways. Results showed that cilnidipine markedly improved kidney function, and alleviated tubular cell apoptosis, oxidative stress and mitochondrial damage induced by iohexol in vitro and in vivo. The underlying mechanism may be that cilnidipine relieved CaMKⅡ activation and mPTP opening induced by iohexol. All of these protective effects of cilnidipine were attenuated by CaMKⅡ overexpression and atractyloside (mPTP opener) pretreatment. Moreover, KN-93 (CaMKⅡ inhibitor) treatment showed a similar renal protective effect with cilnidipine, while the protective effect of cilnidipine on kidney in CIN rats was not further suppressed by KN-93 cotreatment. These in vitro and in vivo results point toward the fact that cilnidipine might be a novel therapeutic drug against contrast-induced nephrotoxicity in a CaMKⅡ-dependent manner.

Trametinib for patients with recurrent low-grade serous ovarian cancer: A cost-effectiveness analysis.

OBJECTIVE: The GOG 281/LOGS trial found that trametinib prolonged progression-free survival (PFS) in patients with recurrent low-grade serous ovarian cancer (LGSOC), compared with standard of care (SOC). The current study aimed to evaluate the cost-effectiveness of trametinib versus standard of care for recurrent LGSOC from the US payer perspective. METHODS: A Markov model was adopted to compare the cost and effectiveness of trametinib and standard of care group in patients with recurrent LGSOC. Life years (LYs), quality-adjusted LYs (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) were calculated. One-way, and probabilistic sensitivity analyses were performed to explore the model robustness. RESULT: Trametinib group provided an additional 0.58 QALYs (1.14 LYs) and an incremental cost of $248,214 compared with the SOC group. The incremental cost-effectiveness ratio was $424,097 per QALY. The results of one-way sensitivity analyses suggested that our model was sensitive to the hazard ratio of OS and PFS between trametinib and SOC group, utility of PFS and the cycle cost of trametinib. Probabilistic sensitivity analyses revealed that there was 6% probability of the trametinib group being cost-effective at a willingness-to-pay (WTP) threshold of $150,000 per QALY. CONCLUSIONS: From the US payer perspective, trametinib is not cost-effective for patients with recurrent LGSOC at the assumed WTP threshold of $150,000 per QALY. Based on the value standpoint, price reduction of trametinib is expected to improve the cost-effectiveness of trametinib in patients with recurrent LGSOC.

Voriconazole therapeutic drug monitoring and hepatotoxicity in critically ill patients: A nationwide multi-centre retrospective study.

OBJECTIVES: To characterize trough concentrations (Cmin) of voriconazole and associated hepatotoxicity, and to determine predictors of hepatotoxicity and identify high-risk groups in critically ill patients. METHODS: This was a nationwide, multi-centre, retrospective study. Cmin and hepatotoxicity were studied from 2015 to 2020 in 363 critically ill patients who received voriconazole treatment. Logistic regression and classification and regression tree (CART) models were used to identify high-risk patients. RESULTS: Large interindividual variability was observed in initial voriconazole Cmin and concentrations ranged from 0.1 mg/L to 18.72 mg/L. Voriconazole-related grade ≥2 hepatotoxicity developed in 101 patients, including 48 patients with grade ≥3 hepatotoxicity. The median time to hepatotoxicity was 3 days (range 1-24 days), and 83.2% of cases of hepatotoxicity occurred within 7 days of voriconazole initiation. Voriconazole Cmin was significantly associated with hepatotoxicity. The CART model showed that significant predictors of grade ≥2 hepatotoxicity were Cmin >3.42 mg/L, concomitant use of trimethoprim-sulfamethoxazole or tigecycline, and septic shock. The model predicted that the incidence of grade ≥2 hepatotoxicity among these high-risk patients was 48.3-63.4%. Significant predictors of grade ≥3 hepatotoxicity were Cmin >6.87 mg/L, concomitant use of at least three hepatotoxic drugs, and septic shock; the predictive incidence among these high-risk patients was 22.7-36.8%. CONCLUSION: Higher voriconazole Cmin, septic shock and concomitant use of hepatotoxic drugs were the strongest predictors of hepatotoxicity. Plasma concentrations of voriconazole should be monitored early (as soon as steady state is achieved) to avoid hepatotoxicity.

Prevalence of polymyxin-induced nephrotoxicity and its predictors in critically ill adult patients: A meta-analysis.

BACKGROUND: Polymyxin-induced nephrotoxicity is a major safety concern in clinical practice due to long-term adverse outcomes and high mortality. AIM: To conducted a systematic review and meta-analysis of the prevalence and potential predictors of polymyxin-induced nephrotoxicity in adult intensive care unit (ICU) patients. METHODS: PubMed, EMBASE, the Cochrane Library and Reference Citation Analysis database were searched for relevant studies from inception through May 30, 2022. The pooled prevalence of polymyxin-induced nephrotoxicity and pooled risk ratios of associated factors were analysed using a random-effects or fixed-effects model by Stata SE ver. 12.1. Additionally, subgroup analyses and meta-regression were conducted to assess heterogeneity. RESULTS: A total of 89 studies involving 12234 critically ill adult patients were included in the meta-analysis. The overall pooled incidence of polymyxin-induced nephrotoxicity was 34.8%. The pooled prevalence of colistin-induced nephrotoxicity was not higher than that of polymyxin B (PMB)-induced nephrotoxicity. The subgroup analyses showed that nephrotoxicity was significantly associated with dosing interval, nephrotoxicity criteria, age, publication year, study quality and sample size, which were confirmed in the univariable meta-regression analysis. Nephrotoxicity was significantly increased when the total daily dose was divided into 2 doses but not 3 or 4 doses. Furthermore, older age, the presence of sepsis or septic shock, hypoalbuminemia, and concomitant vancomycin or vasopressor use were independent risk factors for polymyxin-induced nephrotoxicity, while an elevated baseline glomerular filtration rate was a protective factor against colistin-induced nephrotoxicity. CONCLUSION: Our findings indicated that the incidence of polymyxin-induced nephrotoxicity among ICU patients was high. It emphasizes the importance of additional efforts to manage ICU patients receiving polymyxins to decrease the risk of adverse outcomes.

Population pharmacokinetics of intravenous colistin sulfate and dosage optimization in critically ill patients.

Aims: To explore the population pharmacokinetics of colistin sulfate and to optimize the dosing strategy for critically ill patients. Methods: The study enrolled critically ill adult patients who received colistin sulfate intravenously for more than 72 h with at least one measurement of plasma concentration. Colistin concentrations in plasma or urine samples were measured by ultraperformance liquid chromatography tandem mass spectrometry (LC-MS/MS). The population pharmacokinetics (PPK) model for colistin sulfate was developed using the Phoenix NLME program. Monte Carlo simulation was conducted to evaluate the probability of target attainment (PTA) for optimizing dosing regimens. Results: A total of 98 plasma concentrations from 20 patients were recorded for PPK modeling. The data were adequately described by a two-compartment model with linear elimination. During modeling, creatinine clearance (CrCL) and alanine aminotransferase (ALT) were identified as covariates of the clearance (CL) and volume of peripheral compartment distribution (V2), respectively. In addition, colistin sulfate was predominantly cleared by the nonrenal pathway with a median urinary recovery of 10.05% with large inter-individual variability. Monte Carlo simulations revealed a greater creatinine clearance associated with a higher risk of sub-therapeutic exposure to colistin sulfate. The target PTA (≥90%) of dosage regimens recommended by the label sheet was achievable only in patients infected by pathogens with MIC ≤0.5 mg/L or with renal impairments. Conclusion: Our study showed that the dose of intravenous colistin sulfate was best adjusted by CrCL and ALT. Importantly, the recommended dosing regimen of 1.0-1.5 million units daily was insufficient for patients with normal renal functions (CrCL ≥80 ml/min) or those infected by pathogens with MIC ≥1.0 mg/L. The dosage of colistin sulfate should be adjusted according to renal function and drug exposure.

Renal safety evaluation of aspirin plus edaravone in patients with ischaemic stroke: a retrospective cohort study.

BACKGROUND AND OBJECTIVE: Aspirin combined with edaravone is more effective than aspirin or edaravone alone in the treatment of ischaemic stroke. Aspirin is defined as a nephrotoxic drug while the renal safety of edaravone is controversial. We aimed to evaluate whether edaravone will increase the nephrotoxicity of aspirin in patients with ischaemic stroke. DESIGN: A propensity score-matched retrospective cohort study. SETTING: A tertiary hospital in China. PARTICIPANTS: Patients with ischaemic stroke were treated with aspirin from February 2007 to May 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Acute kidney injury (AKI, diagnosed by the Acute Kidney Injury Network), decreased estimated glomerular filtration rate (eGFR,>10%), gastrointestinal bleeding and in-hospital adverse outcomes (defined as dying or giving up treatment in our hospital). RESULTS: We included 3061 patients, and 986 pairs were successfully matched. Of the 986 pairs of patients included, the incidence of AKI between the aspirin group and the combination group showed no significant difference (7.71% vs 6.29%, p=0.217). While the incidence of eGFR decline (24.75% vs 16.94%, p<0.001) was significantly lower in the combination group. The protective effect was significant in patients with baseline eGFR >30 mL/min/1.73 m2, especially in eGFR 60-90 mL/min/1.73 m2. In patients with different complications, the incidence of AKI showed no significant differences in patients with chronic kidney injury, hypertension, anaemia, age above 75 years, except in patients with cardiovascular disease (OR, 2.82; 95% CI 1.50 to 5.29; p<0.001). However, the incidence of gastrointestinal bleeding (1.22% vs 2.84%, p=0.011) and in-hospital adverse outcomes (3.25% vs 7.00%, p<0.001) were significantly higher in the combination group. CONCLUSIONS: Our study indicated that edaravone in patients with ischaemic stroke didn't increase the nephrotoxicity of aspirin, and even had a protective effect on mild renal deterioration. Nevertheless, there is a need to be cautious when patients are in bad pathophysiological conditions and at high risk of bleeding.

Safety and Efficacy of Low Molecular Weight Heparin for Thromboprophylaxis in the Elderly: A Network Meta-Analysis of Randomized Clinical Trials.

Background: Given their changing pathophysiology, elderly patients carry a high risk of embolism and bleeding events; hence, use of appropriate anticoagulants is very important. Low molecular weight heparin (LMWH) is one of the most widely used anticoagulants although LMWHs differ in their anti-Xa, antithrombin, and anticoagulant activities. To date, no study has directly compared the safety and efficacy of different LMWHs in the elderly. We aimed to compare such differences by conducting a network meta-analysis. Methods: We searched the Pubmed, Embase, and Cochrane databases for randomized controlled trials (RCTs) of LMWHs that included patients ≥60 years old up to July 22, 2020. Safety outcomes included venous thromboembolism (VTE) or VTE-related death, deep thrombus embolism, and pulmonary embolism. Safety outcomes were clinically relevant bleeding, major bleeding, minor bleeding, and all-cause death. We calculated relative ratios (RR) and 95% confidence intervals (CI) for all outcomes. The cumulative ranking probabilities (SUCRA) were conducted to rank the comparative effects and safety of all LMWHs. Results: We included 27 RCTs (30,441 elderly), comprising five LMWHs. LMWH was more effective than placebo in preventing VTE or VTE-related death (RR 0.36, 95% CI 0.25-0.53) but less effective than a novel oral anticoagulant (RR 1.59, 95% CI 1.33-1.91) and safer than acenocoumarol regarding risk of clinically relevant bleeding (RR 0.67, 95% CI 0.49-0.90). However, indirect comparison of efficacy and safety of the five LMWHs showed no significant difference in our network analysis, and the subgroup analyses (such as in patients with deep venous thrombosis, cardiac disease, or age >65 years old) supported the results. The SUCRA showed that tinzaparin performed best in preventing VTE or VTE-related death (SUCRA 68.8%, cumulative probability 42.3%) and all-cause death (SUCRA 84.2%, cumulative probability 40.7%), whereas nadroparin was predominant in decreasing the risk of clinically relevant bleeding (SUCRA 84.8%, cumulative probability 77.0%). Conclusions: On present evidence, there are no significant differences in the efficacy and safety of different LMWHs for the elderly. According to the rank probability analysis, nadroparin seems to be safer for the elderly with a high risk of bleeding, whereas tinzaparin is more effective for those with low bleeding risk.

Interactive Effects of Glucocorticoids and Cytochrome P450 Polymorphisms on the Plasma Trough Concentrations of Voriconazole.

Aims: To explore the interactive influence of glucocorticoids and cytochrome P450 (CYP450) polymorphisms on voriconazole (VRC) plasma trough concentrations (Cmin) and provide a reliable basis for reasonable application of VRC. Methods: A total of 918 VRC Cmin from 231 patients was collected and quantified using high-performance liquid chromatography in this study. The genotypes of CYP2C19, CYP3A4, and CYP3A5 were detected by DNA sequencing assay. The effects of different genotypes and the coadministration of glucocorticoids on VRC Cmin were investigated. Furthermore, the interactive effects of glucocorticoids with CYP450s on VRC Cmin were also analyzed. Results: The median Cmin of oral administration was lower than that of intravenous administration (1.51 vs. 4.0 mg l-1). Coadministration of glucocorticoids (including dexamethasone, prednisone, prednisolone, and methylprednisolone) reduced the VRC Cmin/dose, respectively, among which dexamethasone make the median of the VRC Cmin/dose ratio lower. As a result, when VRC was coadministrated with glucocorticoids, the proportion of VRC Cmin/dose in the subtherapeutic window was increased. Different CYP450 genotypes have different effects on the Cmin/dose of VRC. Mutations of CYP2C19*2 and *3 increased Cmin/dose of VRC, while CYP2C19*17 and CYP3A4 rs4646437 polymorphisms decreased Cmin/dose of VRC. The mutation of CYP3A5 has no significant effect. Furthermore, CYP2C19*17 mutants could strengthen the effects of glucocorticoids and decrease VRC Cmin/dose to a larger extent. Conclusion: Our study revealed that glucocorticoids reduced the Cmin/dose levels of VRC and different SNPs of CYP450 have different effects on the Cmin/dose ratio of VRC. Glucocorticoids and CYP2C19*17 mutants had a synergistic effect on reducing VRC Cmin/dose. The present results suggested that when VRC is combined with glucocorticoids, we should pay more attention to the clinical efficacy of VRC, especially when CYP2C19*17 mutants exist.