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.

Gamma-aminobutyric acid supplementation improves olanzapine-induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue.

AIMS: To investigate whether gamma-aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms. MATERIALS AND METHODS: Insulin resistance and body weight gain were induced in mice by 10 weeks of olanzapine treatment. Simultaneously, the mice were administered GABA after 4 weeks of olanzapine administration. RESULTS: We found that mice treated with olanzapine had lower GABA levels in serum and subcutaneous white adipose tissue (sWAT). GABA supplementation restored GABA levels and improved olanzapine-induced lipid metabolism disorders and insulin resistance. Chronic inflammation in adipose tissue is one of the main contributors to insulin resistance. We found that GABA supplementation inhibited olanzapine-induced adipose tissue macrophage infiltration and M1-like polarization, especially in sWAT. In vitro studies showed that stromal vascular cells, rather than adipocytes, were sensitive to GABA. Furthermore, the results suggested that GABA improves olanzapine-induced insulin resistance at least in part through a GABAB receptor-dependent pathway. CONCLUSIONS: These findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine-induced metabolic disorders.

Targeted metabolomics profiling in pregnancy associated with vitamin D deficiency.

BACKGROUND: Vitamin D deficiency is common in pregnancy, however, its effects has not been fully elucidated. Here, we conducted targeted metabolomics profiling to study the relationship. METHODS: This study enrolled 111 pregnant women, including sufficient group (n = 9), inadequate group (n = 49) and deficient group (n = 53). Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)-based targeted metabonomics were used to characterize metabolite profiles associated with vitamin D deficiency in pregnancy. RESULTS: Many metabolites decreased in the inadequate and deficient group, including lipids, amino acids and others. The lipid species included fatty acyls (FA 14:3, FA 26:0; O), glycerolipids (MG 18:2), glycerophospholipids (LPG 20:5, PE-Cer 40:1; O2, PG 29:0), sterol lipids (CE 20:5, ST 28:0; O4, ST 28:1; O4). Decreased amino acids included aromatic amino acids (tryptophan, phenylalanine, tyrosine) and branched-chain amino acids (valine, isoleucine, leucine), proline, methionine, arginine, lysine, alanine, L-kynurenine,5-hydroxy-L-tryptophan, allysine. CONCLUSIONS: This targeted metabolomics profiling indicated that vitamin D supplementation can significantly affect lipids and amino acids metabolism in pregnancy.

Clinical characteristics and factors for serious outcomes among outpatients infected with the Omicron subvariant BF.7.

To evaluate clinical characteristics and identify risk factors associated with severe outcomes in outpatients infected with the Omicron subvariant BF.7, data were collected from outpatients diagnosed with Corona Virus Disease 2019 from December 19, 2022 to January 5, 2023. Clinical characteristics were analyzed using descriptive statistics. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with serious outcomes. Variables with a p < 0.10 in the univariate analysis were included in the multivariate model. Our study analyzed 770 patients, of whom 380 (49.4%) were male, with a median age of 59. The most common symptoms reported were cough (71.2%), fever (64.7%), and sore throat (37.7%). Fever lasted an average of 5.93 ± 3.37 days for the general population and 10.64 ± 7.12 days for impaired-immunity patients. Most cases were mild (68.7%), followed by moderate (27.1%). Severe cases accounted for 2.2%, with 0.5% critically ill. Serious outcomes occurred in 4.2% of cases, with 11 deaths during follow-up. Underlying-diseases patients had a higher rate of serious outcomes. Factors associated with serious outcomes included receiving a three-dose vaccination (odds ratio [OR] = 0.324, 95% confidence interval [CI]: 0.113-0.932, p = 0.037), male gender (OR = 2.890, 95% CI: 1.107-7.548, p = 0.030), age (OR = 1.060, 95% CI: 1.024-1.097, p = 0.001), and chest tightness or dyspnea at the time of visit (OR = 4.861, 95% CI: 2.054-11.507, p < 0.001). Our study found that cough, fever, and sore throat were the most common symptoms reported by patients. Receiving a three-dose vaccination was protective, while male gender, age, and chest tightness or dyspnea were identified as risk factors for serious outcomes.

Oral azvudine for mild-to-moderate COVID-19 in high risk, nonhospitalized adults: Results of a real-world study.

Azvudine is recommended by Chinese health authorities for COVID-19 treatment but has not been tested in real-world clinical studies. This study aimed to evaluate the real-world effectiveness of Azvudine among COVID-19 nonhospitalized patients. This was a retrospective cohort study, looking at nonhospitalized patients who tested positive for SARS-CoV-2. Patients admitted between December 19, 2022 and January 5, 2023 were included. Those who received Azvudine treatment were in the Azvudine group, while those who received supportive treatment were the control group. The primary outcome was the disease progression rate by Day 28. Secondary outcomes were individual disease progression outcomes (death or COVID-19-related hospitalization) and duration of fever. The safety outcomes were assessed based on adverse events (AEs) overall, as well as AEs that were considered to be related to the drug. A total of 804 patients with high risk for progression were enrolled in our study. Among them, 317 (39.43%) received treatment with Azvudine. Our study found that Azvudine could reduce the rate of disease progression, as well as rate of COVID-19-related hospitalization in patients comparing the control group. Furthermore, if taken within 3 days of the onset of symptoms, it could also shorten the duration of fever. Despite a higher incidence of drug-related AEs compared to supportive treatment, the majority of these were mild. Azvudine has been found to be effective in reducing the rate of disease progression of COVID-19, albeit with a slight increase in AEs.

Metabolomic analysis reveals the metabolic disturbance in aortic dissection: Subtype difference and accurate diagnosis.

BACKGROUND AND AIMS: Aortic dissection (AD), a severe clinical emergency with high mortality, is easily misdiagnosed as are other cardiovascular diseases. This study aimed at discovering plasma metabolic markers with the potential to diagnose AD and clarifying the metabolic differences between two subtypes of AD. METHODS AND RESULTS: To facilitate the diagnosis of AD, we investigated the plasma metabolic profile by metabolomic approach. A total 482 human subjects were enrolled in the study: 80 patients with AD (50 with Stanford type A and 30 with Stanford type B), 198 coronary artery disease (CAD) patients, and 204 healthy individuals. Plasma samples were submitted to targeted metabolomic analysis. The partial least-squares discriminant analysis models were constructed to illustrate clear discrimination of AD patients with CAD patients and healthy control. Subsequently, the metabolites that were clinically relevant to the disturbances in AD were identified. Twenty metabolites induced the separation of AD patients and healthy control, 9 of which caused the separation of CAD patients and healthy control. There are 11 metabolites specifically down-regulated in AD group. Subgroup analysis showed that the levels of glycerol and uridine were dramatically lower in the plasma of patients with Stanford type A AD than those in the healthy control or Stanford type B AD groups. CONCLUSION: This study characterized metabolomic profiles specifically associated with the pathogenesis and development of AD. The findings of this research may potentially lead to earlier diagnosis and treatment of AD.

Effect of pharmacogenomics testing guiding on clinical outcomes in major depressive disorder: a systematic review and meta-analysis of RCT.

BACKGROUND: Pharmacogenomic testing guided treatment have been developed to guide drug selection or conversion in major depressive disorder patients. Whether patients benefit from pharmacogenetic testing remains unclear. We aim to evaluates the effect of pharmacogenomic testing guiding on clinical outcomes of major depressive disorder. METHODS: Pubmed, Embase, and Cochrane Library of Clinical Trials were searched from inception until August 2022. Key terms included pharmacogenomic and antidepressive. Odds ratios (RR) with 95% confidence intervals (95%CIs) were calculated using fixed-effects model for low or moderate heterogeneity or random-effects model for high heterogeneity. RESULTS: Eleven studies (5347 patients) were included. Compared with usual group, pharmacogenomic testing guided group was associated with an increased response rate at week 8 (OR 1.32, 95%CI 1.15-1.53, 8 studies, 4328 participants) and week 12 (OR 1.36, 95%CI 1.15-1.62, 4 studies, 2814 participants). Similarly, guided group was associated with an increased rate of remission at week 8 (OR 1.58, 95%CI 1.31-1.92, 8 studies, 3971 participants) and week 12 (OR 2.23, 95%CI 1.23-4.04, 5 studies, 2664 participants). However, no significant differences were found between the two groups in response rate at week 4 (OR 1.12, 95%CI 0.89-1.41, 2 studies, 2261 participants) and week 24 (OR 1.16, 95%CI 0.96-1.41, 2 studies, 2252 participants), and remission rate at week 4 (OR 1.26, 95%CI 0.93-1.72, 2 studies, 2261 participants) and week 24 (OR 1.06, 95%CI 0.83-1.34, 2 studies, 2252 participants). Medication congruence in 30 days was significantly reduced in the pharmacogenomic guided group compared with the usual care group (OR 2.07, 95%CI 1.69-2.54, 3 studies, 2862 participants). We found significant differences between subgroups of target population in response and remission rate. CONCLUSION: Patients with major depressive disorder may benefit from pharmacogenomic testing guided treatment by achieving target response and remission rates more quickly.

Metabonomic and transcriptomic analyses of Tripterygium glycosides tablet-induced hepatotoxicity in rats.

We aimed to explore novel biomarkers involved in alterations of metabolism and gene expression related to the hepatotoxic effects of Tripterygium glycosides tablet (TGT) in rats. Rats were randomly divided into groups based on oral administration of TGTs for 6 weeks: control, low-dose (9.5 mg/kg), and high-dose (18.9 mg/kg). Serum samples and total liver RNA were subjected to metabonomic and transcriptomic analyses. Thirteen metabolites were significantly up-regulated by liver injury induced by Tripterygium glycosides. Five potential biomarkers were more sensitive than Alanine aminotransferase (ALT) for accurate and timely prediction of hepatic damage. The four metabolic pathways most obviously regulated by hepatotoxicity were D-glutamine and D-glutamate metabolism, alanine, aspartate and glutamate metabolism, ether lipid metabolism, and tryptophan metabolism. Transcriptomics revealed significant differences in 1792 mRNAs and 400 long non-coding (lnc) RNAs. Dysregulated lncRNAs in the TGT-induced hepatotoxicity group were associated with genes involved in amino acid metabolism using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Up-regulated expression of Ehhadh, Gpt, and Got1, and down-regulated expression of dopa decarboxylase (Ddc), Cyp1a2, Ido2, Aldh1b1, and asparagine synthetase (Asns) was validated by quantitative real-time PCR. This multiomics study has elucidated the relationship between amino metabolism and liver injury, revealing potential biomarkers.

Development and validation of a robust and sensitive HPLC-MS/MS method for the quantitation of MRTX849 in plasma and its application in pharmacokinetics.

MRTX849 is a novel, highly selective, targeted inhibitor of KRAS (G12C), which significantly improves the objective response rate in patients with advanced solid tumors. However, neither an analytical HPLC-MS/MS assay nor pharmacokinetics has been reported for MRTX849 in plasma. In the present study, chromatography was accomplished on a reversed phase C18 column (50 × 2.1 mm, 3.5 µm). The limit of detection of MRTX849 was 0.02 ng mL-1 at S/N ≥ 3. Only 20 µL of plasma was utilized for accurate quantitation. The optimized analytical assay was fully validated and verified in accordance with guidelines. The calibration curve for MRTX849 was linear with a correlation coefficient >0.99 in the range of 0.05-200 ng mL-1. The intra- and inter-day accuracy and precision were all within ±10%. The matrix effect and recovery were consistent and acceptable under several quality control concentrations. This HPLC-MS/MS method was successfully applied for a pharmacokinetic study of MRTX849 at a dose of 15 mg kg-1.

Clinical practice guidelines for management of dual antiplatelet therapy in patients with noncardiac surgery: A critical appraisal using the AGREE II instrument.

WHAT IS KNOWN AND OBJECTIVE: Despite the availability of clinical practice guidelines (CPGs), there are considerable differences in their recommendations in the perioperative management of stented patients who need elective noncardiac surgery. Our aim was to systematically review the quality of CPGs for perioperative management of dual antiplatelet therapy (DAPT) and summarize the recommendations. METHODS: A systematic search for perioperative DAPT guidelines was conducted on PubMed, Embase and websites of guideline organizations and professional societies until 4 February 2021. Independently, two assessors appraised the quality of CPGs using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument and extracted the data. Recommendations were summarized, and a comparative study was conducted to analyse the consistency among guidelines. RESULTS AND DISCUSSION: A total of 10 guidelines fulfilled our inclusion criteria. The domain of scope and purpose and clarity of presentation obtained the highest median scores, while the domain of stakeholder involvement and rigour of development obtained the lowest median scores. Three guidelines (ACCP, ESC/ESA and ACC/AHA) with a score of at least 60% in most AGREE II domains were recommended. Recommendations across perioperative management of DAPT guidelines were inconsistent. WHAT IS NEW AND CONCLUSION: The ACCP, ESC/ESA and ACC/AHA CPGs were recommended. There is a need for high-quality prospective studies assessing different management strategies on this issue. Given the lack of consensus, the results of this study will help to guide perioperative dual antiplatelet management strategies for patients with coronary stents who are undergoing noncardiac surgery.

In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand-1 inhibitor in anaplastic lymphoma kinase-rearranged non-small-cell lung cancer.

Both ceritinib (CER) and programmed cell death (PD)-1/PD ligand-1 (PD-L1) have brought significant breakthroughs for anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). However, the overall clinical efficacy of either CER or PD-1/PD-L1 inhibitor monotherapy has been limited to a large extent. In addition, the antitumor effect of combined CER and PD-L1 inhibitor in ALK-rearranged NSCLC is not fully understood. In H2228 cells, we examined the tumor killing effect of CER plus PD-L1 inhibitor in vitro by quantitative RT-PCR, flow cytometry, ELISA, western blot analysis, PBMC coculture system, and plasmid and transfection experiments. A Ba/F3 (EML4-ALK-WT) xenograft mouse model was also utilized to further evaluate the synergistic anticancer effects of CER and PD-L1 inhibitor in vivo. The coculture system of PBMCs with H2228 cells promotes the expression of PD-L1 and phospho-ERK, and combined treatments facilitate lymphocyte proliferation and activation, inhibit PD-L1 expression, and enhance lymphocyte cytotoxicity and cell death. In the in vivo NSCLC xenograft model, the volumes of tumors treated with CER and PD-L1 inhibitor in combination were significantly smaller than those treated with CER or PD-L1 alone. The relative tumor growth inhibitions were 84.9%, 20.0%, and 91.9% for CER, PD-L1 inhibitor, and CER plus PD-L1 groups, respectively. Ceritinib could synergize with PD-1/PD-L1 blockade to yield enhanced antitumor responses along with favorable tolerability of adverse effects. Ceritinib and PD-L1 inhibitor combined produced a synergistic antineoplastic efficacy in vitro and in vivo, which provides a key insight and proof of principle for evaluating CER plus PD-L1 blockade as combination therapy in clinical therapeutic practice.

A single-injection targeted metabolomics profiling method for determination of biomarkers to reflect tripterygium glycosides efficacy and toxicity.

Metabolomics is a powerful tool for studying physiological state of the system. In this study, we proposed a single-injection targeted metabolomics method to identify reliable tripterygium glycosides efficacy and toxicity related biomarkers based on ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Through careful optimization of the UHPLC-MS/MS conditions, a total of 289 metabolites can be quantified in single-injection of 27 min using both positive and negative scanning modes with rapid polarity switching. Tripterygium glycosides is widely used in clinical for its excellent anti-inflammatory and immunosuppressive functions. However, it is the most common drug that can cause hepatotoxicity. In this study, the established metabolomics method was used for determination of biomarkers to reflect tripterygium glycosides efficacy and toxicity. Two different dosages were designed in the animal experiment, including therapeutic dosage and toxic dosage. Statistical analysis based on metabolite concentrations showed that the glutathione metabolism and pyrimidine metabolism were the obvious interfering pathways. This was highly consistent with previous studies. A total of 22 and 47 metabolites were screened as potential biomarkers related to the efficacy and hepatotoxicity of tripterygium glycosides, respectively. Receiver operating characteristic curve (ROC) analysis showed that ten metabolites, including cytosine, 5-methyluridine, deoxyuridine, 5-methylcytidine, deoxycytidine triphosphate (DCTP), keto-glutarate, d-ribose, dihydrofolate, nordeoxycholic acid and isodeoxycholic acid possessed area under the curve (AUC) of 1. The metabolites filtered here can better distinguish tripterygium glycosides treated rats from the control rats compared with the traditional blood indicators of liver function.

Cytomegalovirus Infection Is a Risk Factor in Gastrointestinal Cancer: A Cross-Sectional and Meta-Analysis Study.

BACKGROUND: This study was planned to investigate the association betweenhuman cytomegalovirus (HCMV) infection and gastrointestinal cancer (GIC) risk, by undertaking a meta-analysis and case-control cross-sectional study. SUMMARY: A cross-sectional study analysis of 160 GIC patients and 100 control subjects indicated significantly higher HCMV prevalence in GIC patients based on the HCMV IgM test. However, a similar analysis based on an IgG test revealed no significant relationship. Further meta-analysis of 11 studies, including 1,044 patients and 991 healthy subjects, displayed HCMV infection as an important risk factor for not only colorectal cancer occurrence and development based on a HCMV DNA test, but also for GIC based on a HCMV IgM test. However, the IgG test again displayed no significant relationship between HCMV infection and GIC occurrence. Key Message: Overall, our study revealed that HCMV infection is associated with an increased GIC risk. However, additional studies are warranted to elucidate the molecular mechanism underlying this association.

Simultaneous quantitative determination of arachidonic acid and cascade metabolites in rat serum by UPLC-MS/MS: application for longitudinal metabolomics of anlotinib.

Arachidonic acid (AA) and cascade metabolites have been shown to be involved in cancer pathologic states. Anlotinib, a novel oral small molecule inhibitor of multiple receptor tyrosine kinases, has brought significant improvement to the survival of patients with advanced lung cancer. Here, a robust and reproducible ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed, optimized and validated for quantitating AA and cascade metabolites for the first time. Through careful optimization of the analytical conditions, a total of 69 analytes can be efficiently separated and quantitated in a single run of 17 min. A simple and labor-saving protein precipitation procedure was utilized for serum sample pretreatment. The validation parameters and quality control chart of all analytes satisfy the acceptance criteria of bioanalytical method guidelines. The limit of detection (LOD) ranged from 0.005 ng mL-1 to 1 ng mL-1, and the volume of serum was only 20 µL. This rapid and sensitive UPLC-MS/MS method was successfully applied to a longitudinal metabolomics study in rat serum after a single administration of anlotinib (6 mg kg-1). Finally, a total of 41 metabolites can be calculated under the present conditions. Serum samples from the same rat were segregated into a tight cluster in both unsupervised principal component analysis (PCA) and supervised orthogonal partial least-squares discriminant analysis (OPLS-DA) at different sampling time points after anlotinib treatment. Moreover, the number of analytes whose variable importance (VIP) values were larger than 1.0 was 17. The present study not only offers a UPLC-MS/MS analytical reference for AA but also brings out insights for future mechanistic studies or biomarkers to predict the efficacy, toxicity and clinical outcomes in patients with cancer.

A selective and robust UPLC-MS/MS method for the simultaneous quantitative determination of anlotinib, ceritinib and ibrutinib in rat plasma and its application to a pharmacokinetic study.

A selective and robust UPLC-MS/MS method has been firstly developed for simultaneous determination of three anti-tumor tyrosine kinase inhibitors (anlotinib, ANL; ceritinib, CER; ibrutinib, IBR) in rat plasma using cost-effective protein precipitation extraction. LC separation was achieved on Waters XBrige C18 column (50 mm × 2.1 mm, 3.5 µm) under gradient conditions in a run time of 5 min. ESI+ was involved through mass spectrometry. Multiple reaction monitoring transitions were at m/z 408.2 → 339.2 for ANL, 558.2 → 433.2 for CER, 441.0 → 138.0 for IBR, 285.0 → 193.1 for diazepam (internal standard), respectively. The optimized method was validated based on US FDA guideline, EMEA guideline as well as Pharmacopoeia of the People's Republic of China. The assay was linear in the range of 0.1-20 ng mL-1 for ANL, 2-1000 ng mL-1 for CER, 1-500 ng mL-1 for IBR. Intra- and inter-day accuracy and precision for all analytes were ≦13.84% and ≦12.56%, respectively. ANL, CER and IBR were sufficiently stable under most investigated conditions. The optimized method was successfully applied for a pharmacokinetic study after single oral gavage administration of mixture (ANL, CER and IBR) at dose of 6 mg kg-1, 25 mg kg-1 and 10 mg kg-1.

Mechanism of curcumin resistance to human cytomegalovirus in HELF cells.

BACKGROUND: We have previously shown that curcumin exhibited an outstanding anti-HCMV effect in vitro and in vivo. However, the underlying mechanism for the anti-HCMV effect remains unclear. METHODS: Levels of IL-6 and TNF-α cytokine secretions in HELF cells were determined by enzyme-linked immunosorbent assay (ELISA); cell cycles were assessed by flow cytometry; ie and ul83 gene expressions were evaluated using reverse transcriptase real-time quantitative PCR; HCMV IE and UL83 antigen expressions were studied using immunofluorescence staining assay and western blot. RESULTS: Curcumin reduced HCMV immediate early antigen (IEA) and UL83A expressions and IL-6, and TNF-α secretions and recovered cell proliferation to normal level in HCMV infected HELF cells. CONCLUSIONS: Curcumin anti-HCMV effect may possibly be that curcumin concurrently alters host cell microenviroment and inhibits the HCMV antigen expressions. These findings may provide a basic understanding of the curcumin anti-HCMV effect and a novel strategy for further development of curcumin anti-HCMV treatment.

Urinary tract infection following the use of BTK inhibitors: a real-world analysis of post-marketing surveillance data.

BACKGROUND: Emerging case reports have raised awareness of urinary tract infection (UTI) which maybe a potentially serious complication. The present study aimed to summarize the clinical characteristics of patients with BTK inhibitor-related UTI, and the association between BTK inhibitors and UTI events was also assessed by disproportionality analysis. RESEARCH DESIGN AND METHODS: We conducted an observational, retrospective, and pharmacovigilance study using data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Data were retrieved from Quarter 1, 2004 to Quarter 2, 2022. The clinical characteristics of cases were summarized using descriptive statistics. We used the χ2 or Fisher exact methods for the analysis of categorical variables and the Mann-Whitney test or Student's t-text for the comparisons of continuous variables between fatal and non-fatal cases. A p-value less than 0.05 is considered to be statistically significant. Information component (IC) and reporting odds ratio (ROR) were used to evaluate the association. RESULTS: BTK inhibitors were identified as the suspected drug causing UTI in 539 cases. The age of those cases concentrated on 60-89 years (87.83%, data available in 263/539). UTI signals were detected during BTK inhibitors treatment (IC 0.95[0.83-1.08], ROR 1.96[1.80-2.13]). The association between BTK inhibitors and UTI events was shown among all groups but not in the group of age<60 years old. There were no significant differences in age and gender between fatal and non-fatal cases. However, a significant difference in reporting regions was found (p = 0.016), with the highest percentage of reported deaths occurring in Europe (26.15%, p = 0.000). CONCLUSIONS: Our study suggested a safety signal for UTI and BTK inhibitors compared to all other drugs in the database, especially in the elder (age ≥60). Further studies are needed to clarify these results.

Tacrolimus Related Acute Pancreatitis: An Observational, Retrospective, Pharmacovigilance Study.

PURPOSE: Recent case reports have drawn attention to the emergence of acute pancreatitis, a potentially life-threatening complication associated with tacrolimus. This study uses the Food and Drug Administration Adverse Event Reporting System (FAERS) to investigate the risk signal of acute pancreatitis associated with calcineurin inhibitors (CNIs), with a focus on tacrolimus. METHODS: We conducted an observational retrospective pharmacovigilance study utilizing the FAERS database, encompassing data from its inception to the third quarter of 2023. The assessment of the association between CNIs and acute pancreatitis was carried out using the Information Component (IC) and Reporting Odds Ratio (ROR). Logistic regression analysis was employed to elucidate factors contributing to fatal outcomes. All analyses were performed using R version 3.2.5. FINDING: We identified 221 cases of acute pancreatitis linked to CNIs. The median age of individuals experiencing acute pancreatitis induced by tacrolimus was 43, with a predominant occurrence among male patients. Our study showed a significant association between CNIs and acute pancreatitis (ROR 1.82 [1.60-2.08], IC 0.85 [3.66-3.92]). Comparing tacrolimus and cyclosporine, the signal for tacrolimus seemed to be higher. Further analysis revealed that, with the exception of patients aged 60 and above, the signal for tacrolimus remained stable. Contrastingly, the signal for cyclosporine was unstable and limited to the male group and individuals aged less than 20 years. In cases of CNIs-related acute pancreatitis, the mortality rate was 31.67% (70/221 cases). Logistic regression analysis indicated that a younger age acts as a protective factor for death due to CNIs-related acute pancreatitis (OR 0.943, 95% CI 0.915-0.972, P = 0.000). IMPLICATIONS: Our study has identified a safety signal for tacrolimus in relation to acute pancreatitis. Additionally, we observed advanced age as a significant risk factor for tacrolimus-related acute pancreatitis, leading to mortality. Given the widespread use of tacrolimus, it is crucial for healthcare providers to be vigilant and informed about the potential association with acute pancreatitis.

Comparison of four criteria for potentially inappropriate medications in older patients with newly diagnosed non-small cell lung cancer.

BACKGROUND: Potentially inappropriate medication (PIM) use is a common problem among older patients. This study aimed to compare the prevalence of PIMs in older patients with newly diagnosed non-small cell lung cancer (NSCLC), and to identify the correlates of PIMs. RESEARCH DESIGN AND METHODS: A secondary analysis of a prospective cohort study was conducted. Patients were enrolled from January 2014 to December 2020 and information were extracted from patients' electronic medical records (EMRs). We evaluated the PIMs using four different PIM criteria. The concordance among the four PIM criteria was calculated using kappa tests. The possible risk factors associated with PIMs were analyzed by multivariate logistic regression. RESULTS: The prevalence of at least one PIM identified by the four criteria ranged from 25.1% to 48.2% among 514 patients. There was moderate consistency between the GO-PIM scale and the AGS/Beers criteria, while poor consistency with the other criteria (the STOPP criteria and the Chinese criteria). Polypharmacy was found to be significantly associated with the occurrence of PIMs in all criteria (p < 0.001). CONCLUSIONS: Our results showed a high prevalence of PIMs in older patients with NSCLC, which was significantly associated with polypharmacy, and the consistency across the four criteria was poor-to-moderate.

Formaldehyde aggravates airway inflammation through induction of glycolysis in an experimental model of asthma exacerbated by lipopolysaccharide.

Formaldehyde (FA) exposure has been reported to induce or aggravate allergic asthma. Infection is also a potential risk factor for the onset and aggravation of asthma. However, no study has addressed the effects of FA exposure on asthmatic patients with respiratory infection. FA is ubiquitous in environment and respiratory infections are common in clinics. Therefore, it is necessary to explore whether FA exposure leads to the further worsening of symptoms in asthma patients with existing respiratory infection. In the present study, ovalbumin (OVA) was used to establish the murine asthma model. Lipopolysaccharide (LPS) was intratracheal administrated to mimic asthma with respiratory infection. The mice were exposed to 0.5 mg/m3 FA. FA exposure did not induce a significant aggravation on OVA induced allergic asthma. However, the lung function of specific airway resistance (sRaw), histological changes and cytokines production were greatly aggravated by FA exposure in OVA/LPS induced murine asthma model. Monocyte-derived macrophages (MDMs) were isolated from asthmatic patients. Exposure of MDMs to FA and LPS resulted in increased TNF-α, IL-6, IL-1ß, and nitric oxide (NO) production. Lactate produciton and lactate dehydrogenase A (LDHA) expression were found to be upregulated by FA in OVA/LPS induced asthmatic mice and LPS stimulated MDMs. Furthermore, glycolysis inhibitor 2-Deoxy-d-glucose attenuated FA and LPS induced TNF-α, IL-6, IL-1ß, and NO production. We conclude that FA exposure can lead to the aggravation of allergic asthma with infection through induction of glycolysis. This study could offer some new insight into how FA promotes asthma development.