A 10-year retrospective study of antibacterial-induced thrombocytopenia in a women and children hospital using China Hospital Pharmacovigilance System and Visual Basic for Applications.

AIMS: We aimed to investigate antibacterial-induced thrombocytopenia using the China Hospital Pharmacovigilance System (CHPS) in conjunction with Visual Basic for Applications (VBA). METHODS: Between September 2011 and December 2022, a 2-phase workflow was employed to identify antibacterial-induced thrombocytopenia, including preliminary screening in phase (I) conducted by CHPS algorithms and causality assessment by trained pharmacists in phase (II) using VBA. The incidence of thrombocytopenia in each antibacterial was calculated, and comparisons were performed between paediatric and adult patients. RESULTS: CHPS algorithms identified 4080 cases from 485 238 admissions (including 223 735 admissions receiving at least 1 antibacterial treatment). After ruling out cases with chemotherapy and abnormal platelet count at admission, 3832 cases were available. Using VBA, pharmacists identified 1039 cases (1246 antibacterial treatments, 28 agents) as potential thrombocytopenia instances (κ = 0.89), with an incidence of 0.46%. All antibacterial treatments correlated temporally with thrombocytopenia. Carbapenems (meropenem 1.77%), glycopeptides (vancomycin 1.55%) and lincosamides (clindamycin 0.44%) were prominent causal groups. The highest incidences of thrombocytopenia in the cephalosporins and penicillins groups were ceftazidime (2.04%) and piperacillin/tazobactam (1.24%), respectively. Among all antibacterial treatments, clindamycin showed the shortest time to onset (TTO), and erythromycin showed the longest TTO. Paediatric patients exhibited a longer TTO (61 vs. 29 h), extended time to nadir (83 vs. 37 h), lower platelet nadir count values (110 vs. 92 × 109/L), and a higher severe case proportion (12.37 vs. 3.86%) when compared with adults. CONCLUSION: Different antibacterial agents exhibit varying incidences of thrombocytopenia, with notable disparities between adults and children in the characteristics of thrombocytopenia.

Changing the spin disorder of two-dimensional magnetic Cr2TiC2Tx to long-range order through noble metal adhesion.

To enhance the use of Cr2TiC2Tx MXene in spin electronics, it is essential to transform its spin-disordered state into a long-range ordered spin state. In this study, first-principles calculations show that Rh layers adhered to the Cr2TiC2Tx surfaces can transform its spin disordered state into a long-range spin order by donating electrons to the O terminations, resulting in Cr2TiC2Tx becoming a single-layer A-type antiferromagnet. As the proportion of F termination increases from 0 to 100%, the exchange coupling constant J1 of the compound escalates from 0.5 to 15.9 meV. Concurrently, the Néel temperature experiences a significant rise from 8 K to 110 K. The analysis of the density of states reveals that the obtained Cr2TiC2Tx exhibits excellent conductivity with O termination and semiconductor characteristics with F termination. These unique features make Cr2TiC2Tx a promising magnetic material for application in spin electronics.

Edge-sharing bi-octahedral diruthenium(IV,IV) compounds containing Ru-Ru bonds chelated and bridged by two carbonate and two oxo groups.

From paddle-wheel starting material Na3Ru2(CO3)4·6H2O, a family of edge-sharing bi-octahedral (ESBO) diruthenium(IV,IV) compounds formulated as Ru2O2(CO3)2(H2O)2L2·nH2O [L = piperazine (1) or 2-methylpiperazine (2), n = 4, and L = 2,2-dimethylpiperazine (3), n = 12] and Ru2O2(CO3)2(OH)4{M(H2O)4}2·nH2O [M = Mg (4), n = 4, and Ni (5), n = 2] were prepared and structurally characterized. The Ru28+ dimer is chelated and bridged by two CO32- and two µ-O in a trans manner, and the Ru-Ru distances fall in the range 2.3808(6)-2.4001(4) Å. Compound 2 shows the shortest Ru-Ru distance for all known ESBO Ru2 compounds reported thus far. Increasing -CH3 groups of terminal piperazine ligands coordinated to the Ru(µ-O)2(µ-O3C)2Ru core, and according to Raman spectra experiments combined with theoretical calculations, the intense bands of compounds 1-3 appearing at ∼360 cm-1 can be assigned to the stretching of Ru-Ru bonds.

Spatio-temporal evolution and its policy influencing factors of agricultural land-use efficiency under carbon emission constraint in mainland China.

In the context of the vision to reach peak carbon dioxide emissions before 2030 and achieve carbon neutrality before 2060, Mainland China's agricultural development will face strict carbon constraints. This paper analyzes the agricultural land-use efficiency of Mainland China's agriculture under carbon emission constraint from 1996 to 2020, based on the unexpected super SBM (Slack-based measure)-Undesirable DEA, Malmquist index model, and quartile division-GIS method. The results show that: from 1996 to 2020, the agricultural output value per land and grain output per land show an upward trend, and the agricultural carbon emissions per land of most provinces show an increasing trend and larger emissions. The agricultural land-use efficiency in Mainland China rises first and then decreases, and technological progress is the decisive path to improving the agricultural land-use efficiency in Mainland China. The average MI in the prominent grain-selling area during 1996-2020 was as high as 1.071, which was significantly higher than that in the prominent grain-producing area (1.039) and the balance area (1.030). The improvement of agricultural land-use efficiency is mostly due to technological progress, but the instability of technical input and management in land use. To improve agricultural land-use efficiency in Mainland China, we should pay attention to the precise policy formulation of low-carbon and high-quality development and strengthen government investment in the difference between space resource endowment and development status.

Precisely Activating cGAS-STING Pathway with a Novel Peptide-Based Nanoagonist to Potentiate Immune Checkpoint Blockade Cancer Immunotherapy.

As an essential intracellular immune activation pathway, the cGAS-STING pathway has attracted broad attention in cancer treatment. However, low bioavailability, nonspecificity, and adverse effects of small molecule STING agonists severely limit their therapeutic efficacy and in vivo application. In this study, a peptide-based STING agonist is first proposed, and KLA is screened out to activate the cGAS-STING pathway by promoting mitochondrial DNA (mtDNA) leakage. To precisely activate the cGAS-STING pathway and block the PD-1/PD-L1 pathway, a multi-stimuli activatable peptide nanodrug (MAPN) is developed for the effective delivery of KLA and PD-L1 antagonist peptide (CVR). With rational design, MAPN achieved the site-specific release of KLA and CVR in response to multiple endogenous stimuli, simultaneously activating the cGAS-STING pathway and blocking PD-1/PD-L1 pathway, ultimately initiating robust and durable T cell anti-tumor immunity with a tumor growth inhibition rate of 78% and extending the median survival time of B16F10 tumor-bearing mice to 40 days. Overall, antimicrobial peptides, which can promote mtDNA leakage through damaging mitochondrial membranes, may be potential alternatives for small molecule STING agonists and giving a new insight for the design of novel STING agonists. Furthermore, MAPN presents a universal delivery platform for the effective synergy of multiple peptides.

Convergence Analysis of Novel Fractional-Order Backpropagation Neural Networks With Regularization Terms.

Fractional-order derivatives have the potential to improve the performance of backpropagation (BP) neural networks. Several studies have found that the fractional-order gradient learning methods may not converge to real extreme points. The truncation and the modification of the fractional-order derivative are applied to guarantee convergence to the real extreme point. Nonetheless, the real convergence ability is based on the assumption that the algorithm is convergent, which limits the practicality of the algorithm. In this article, a novel truncated fractional-order BP neural network (TFO-BPNN) and a novel hybrid TFO-BPNN (HTFO-BPNN) are designed to solve the above problem. First, to avoid overfitting, a squared regularization term is introduced into the fractional-order BP neural network. Second, a novel dual cross-entropy cost function is proposed and employed as a loss function for the two neural networks. The penalty parameter helps to adjust the effect of the penalty term and further alleviates the gradient vanishing problem. In terms of convergence, the convergence ability of the two proposed neural networks is first proved. Then, the convergence ability to the real extreme point is further analyzed theoretically. Finally, the simulation results effectively illustrate the feasibility, high accuracy, and good generalization ability of the proposed neural networks. Comparative studies among the proposed neural networks and some related methods further substantiate the superiority of the TFO-BPNN and the HTFO-BPNN.

Fused-Ring Pyrrole-Based Near-Infrared Emissive Organic RTP Material for Persistent Afterglow Bioimaging.

Organic near-infrared room temperature phosphorescence (RTP) materials offer remarkable advantages in bioimaging due to their characteristic time scales and background noise elimination. However, developing near-infrared RTP materials for deep tissue imaging still faces challenges since the small band gap may increase the non-radiative decay, resulting in weak emission and short phosphorescence lifetime. In this study, fused-ring pyrrole-based structures were employed as the guest molecules for the construction of long wavelength emissive RTP materials. Compared to the decrease of the singlet energy level, the triplet energy level showed a more effectively decrease with the increase of the conjugation of the substituent groups. Moreover, the sufficient conjugation of fused ring structures in the guest molecule suppresses the non-radiative decay of triplet excitons. Therefore, a near-infrared RTP material (764 nm) was achieved for deep penetration bioimaging. Tumor cell membrane is used to coat RTP nanoparticles (NPs) to avoid decreasing the RTP performance compared to traditional coating by amphiphilic surfactants. RTP NPs with tumor-targeting properties show favorable phosphorescent properties, superior stability, and excellent biocompatibility. These NPs are applied for time-resolved luminescence imaging to eliminate background interference with excellent tissue penetration. This study provides a practical solution to prepare long-wavelength and long-lifetime organic RTP materials and their applications in bioimaging.

Potential interactions between triazole antifungal agents and lorlatinib based on ultra-performance liquid chromatography-tandem mass spectrometry in rat plasma.

AIM: Our study is to investigate the effects of triazole antifungal drugs on the pharmacokinetics of lorlatinib in rats. METHODS: The samples were precipitated with methanol. Chromatographic separation was performed on a ultra-performance liquid chromatography (UPLC) system using a BEH C18 column. The mobile phase consisted of 0.1% formic acid water and methanol. Lorlatinib and crizotinib (internal standard) were detected in multiple reaction monitoring mode. The fragment ions were 407.3-228.07 for lorlatinib and m/z 450.3-260.0 for crizotinib. Lorlatinib and different triazole antifungal drugs were given to Sprague Dawley rats by gavage, and blood was collected from the tail vein at a certain time point. The validated UPLC-MS/MS method was applied to a drug interaction study of ketoconazole, voriconazole, itraconazole, and posaconazole with lorlatinib in rats. RESULTS: Ketoconazole and voriconazole significantly inhibited lorlatinib metabolism. When administration with ketoconazole and voriconazole, the area under the curve from time zero to infinity of lorlatinib increased by 49.0% and 104.3%, respectively; the clearance decreased by 40.0% and 40.0%, respectively. While itraconazole and posaconazole did not affect lorlatinib pharmacokinetics. CONCLUSION: The UPLC-MS/MS-based assay is helpful to further understand the pharmacokinetics of lorlatinib in rats, and confirmed the findings that the combination of lorlatinib with CYP3A inhibitors should be avoided as predicted by our pre-clinical studies.

Assessing safety concerns of interstitial lung disease associated with antibody-drug conjugates: a real-world pharmacovigilance evaluation of the FDA adverse event reporting system.

BACKGROUND: Antibody-drug conjugates have revolutionized cancer therapy due to their selectivity and efficacy. However, concerns have been raised regarding the potential effects of trastuzumab deruxtecan in interstitial lung diseases. AIM: This study aimed to investigate the safety signals and time to onset of antibody-drug conjugates induced interstitial lung disease. METHOD: We utilized the FDA Adverse Event Reporting System database (2004-2022) to identify interstitial lung disease safety signals in 13 FDA-approved antibody-drug conjugates. Disproportionality analysis was conducted to estimate the reporting odds ratios for interstitial lung disease. RESULTS: Seven antibody-drug conjugates exhibited safety signals of interstitial lung disease: trastuzumab deruxtecan [reporting odds ratio, ROR (95% confidence intervals, CI) = 64.15 (57.07-72.10)], enfortumab vedotin [ROR (95% CI) = 5.24 (3.25-8.43)], trastuzumab emtansine [ROR (95% CI) = 3.62 (2.90-4.53)], brentuximab vedotin [ROR (95% CI) = 3.22 (2.49-4.17)], polatuzumab vedotin [ROR (95% CI) = 2.56 (1.59-4.12)], gemtuzumab ozogamicin [ROR (95% CI) = 2.53 (1.70-3.78)], and inotuzumab ozogamicin [ROR (95% CI) = 2.33 (1.21-4.49)]. Five antibody-drug conjugates with limited reports were excluded from further analysis: belantamab mafodotin, loncastuximab tesirine, mirvetuximab sorafenib, tisotumab vedotin, and moxetumomab pasudotox. Japan and the United States were the primary reporting countries. CONCLUSION: This real-world study highlights high safety signals of interstitial lung disease associated with antibody-drug conjugates. Clinicians should be aware of these safety concerns and risk factors and implement early identification measures for their patients. Future research should prioritize comprehensively exploring the relationship between antibody-drug conjugates and lung diseases.

Novel research and future prospects of artificial intelligence in cancer diagnosis and treatment.

Research into the potential benefits of artificial intelligence for comprehending the intricate biology of cancer has grown as a result of the widespread use of deep learning and machine learning in the healthcare sector and the availability of highly specialized cancer datasets. Here, we review new artificial intelligence approaches and how they are being used in oncology. We describe how artificial intelligence might be used in the detection, prognosis, and administration of cancer treatments and introduce the use of the latest large language models such as ChatGPT in oncology clinics. We highlight artificial intelligence applications for omics data types, and we offer perspectives on how the various data types might be combined to create decision-support tools. We also evaluate the present constraints and challenges to applying artificial intelligence in precision oncology. Finally, we discuss how current challenges may be surmounted to make artificial intelligence useful in clinical settings in the future.

A Markov model-based cost-effectiveness analysis comparing zanubrutinib to ibrutinib for treating relapsed and refractory chronic lymphocytic leukemia.

OBJECTIVE: This article examined the cost-effectiveness of zanubrutinib and ibrutinib for managing relapsed and refractory chronic lymphocytic leukemia from the viewpoint of payers in China and the US. METHODS: Markov models were employed to conduct comparisons. Baseline characteristics and clinical data were extracted from the ALPINE study. The cost-effectiveness outcome indicators encompassed cost, quality-adjusted life years, and the incremental cost-effectiveness ratio. RESULTS: The Markov model analysis revealed that the zanubrutinib group incurred an incremental cost per patient of $-24,586.53 compared to the ibrutinib group. The zanubrutinib group exhibited an incremental utility per capita of 0.28 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio of $-88,068.16 per quality-adjusted life year, which is lower than the payment threshold in China. The willingness-to-pay value in China for 2022 was three times the country's gross domestic product per capita. In the US, patients in the zanubrutinib group experienced per capita incremental costs of $-79,421.56, per capita incremental utility of 0.28 quality-adjusted life years, and an incremental cost-effectiveness ratio of $-284,485.45 per quality-adjusted life year. CONCLUSION: For Chinese payers, zanubrutinib exhibited superior cost-effectiveness compared to ibrutinib. Zanubrutinib proved to be a more affordable option for US payers when considering the payment threshold.

Abnormalities of serum lipid metabolism in patients with acute paraquat poisoning caused by ferroptosis.

As the mechanism of paraquat (PQ) poisoning is still not fully elucidated, and no specific treatment has been developed in medical practice, the management of PQ poisoning continues to present a medical challenge. In this study, the objective was to investigate the early metabolic changes in serum metabolism and identify the key metabolic pathways involved in patients with PQ poisoning. Quantitative analysis was conducted to determine the relevant metabolites. Additionally, experiments were carried out in both plasma and cell to elucidate the mechanisms underlying metabolic disorder and cell death in PQ poisoning. The study found that polyunsaturated fatty acids (PUFAs) and their metabolites, such as arachidonic acid (AA) and hydroxy eicosatetraenoic acids (HETEs), were significantly increased by non-enzymatic oxidative reaction. Reactive oxygen species (ROS) production increased rapidly at 2 h after PQ poisoning, followed by an increase in PUFAs at 12 h, and intracellular glutathione, cysteine (Cys), and Fe2+ at 24 h. However, at 36 h later, intracellular glutathione and Cys decreased, HETEs increased, and the expression of SLC7A11 and glutathione peroxidase 4 (GPX4) decreased. Ultrastructural examination revealed the absence of mitochondrial cristae. Deferoxamine was found to alleviate lipid oxidation, and increase the viability of PQ toxic cells in the low dose. In conclusion, unsaturated fatty acids metabolism was the key metabolic pathways in PQ poisoning. PQ caused cell death through the induction of ferroptosis. Inhibition of ferroptosis could be a novel strategy for the treatment of PQ poisoning.

Bolt-connected prefabricated cross-shaped I-steel tower crane foundation.

Traditional tower cranes cannot meet the sustainable development goals as they use the cast-in-place concrete foundation, with large size, long construction period, and demolition after construction, resulting in waste of resources and high costs. This paper proposes a bolt-connected prefabricated cross-shaped I-steel tower crane foundation. It offers significant advantages in terms of convenient connection, low amortization cost and recyclability. The split connection point of the foundation is determined through the force analysis of the I-steel. With the ratio of the fixed cross-sectional area to the web height-to-thickness ratio (i.e. total cost) being constant, the inertia moment and bending stiffness of the I-steel are optimized using modern optimization design methods with the ratio of the web plate area to the total section area of the I-steel as the design variable, yielding the ideal strength and stiffness of the I-steel section.

A family of edge-sharing bi-octahedral diruthenium(III,III) compounds containing Ru-Ru single bonds.

From paddlewheel starting reactants Ru2(R'CO2)4+, a family of edge-sharing bi-octahedral (ESBO) diruthenium(III,III) compounds has been prepared, formulated as Ru2(µ-O2CR')2(µ-OR)2(η-L)2 (1-10) [R' = CH3, R = CH3, L = acac (1), tfac (2); R' = CH3, R = CH2CH3, L = hfac (3); R' = CH2CH3, R = CH3, L = acac (4), tfac (5); R' = CH2CH3, R = CH2CH3, L = hfac (6); R' = CH2Cl, R = CH3, L = tfac (7); R' = CH2Cl, R = CH2CH3, L = hfac (8); R' = C6H5, R = CH3, L = tfac (9); and R' = H, R = CH3, L = acac (10); here, acac, tfac and hfac represent acetylacetone, trifluoroacetylacetone and hexafluoroacetylacetone, respectively]. Compounds 1-10 have a similar ESBO coordination geometry of the Ru(µ-O2CR')2(µ-OR)2Ru core with a Ru-Ru center chelated and bridged by two µ-O2CR' and two µ-OR in a trans manner, and each Ru center is also coordinated with a η2-L bidentate ligand. The Ru-Ru distances fall in the range of 2.4560(9)-2.4771(4) Å. The investigation of the electronic spectra and vibrational frequencies as well as theoretical studies with density functional theory (DFT) reveal that compounds 1-10 are ESBO bimetallic species of d5-d5 valence electron counts showing a σ2π2δ2δ*2π*2 electronic configuration. Varying -CH3 to -CF3 groups on the η2-L bidentate ligands coordinating to the Ru(µ-O2CR')2(µ-OR)2Ru core, and according to Raman spectrum measurements combined with theoretical calculations, the intense bands of compounds 1-10 appearing at ∼345 cm-1 in the small-wavenumber region can be assigned to the stretching of the Ru-Ru single bond.

Integrated Manufacturing of Suspended and Aligned Nanofibrous Scaffold for Structural Maturation and Synchronous Contraction of HiPSC-Derived Cardiomyocytes.

Electrospun nanofiber constructs represent a promising alternative for mimicking the natural extracellular matrix in vitro and have significant potential for cardiac patch applications. While the effect of fiber orientation on the morphological structure of cardiomyocytes has been investigated, fibers only provide contact guidance without accounting for substrate stiffness due to their deposition on rigid substrates (e.g., glass or polystyrene). This paper introduces an in situ fabrication method for suspended and well aligned nanofibrous scaffolds via roller electrospinning, providing an anisotropic microenvironment with reduced stiffness for cardiac tissue engineering. A fiber surface modification strategy, utilizing oxygen plasma treatment combined with sodium dodecyl sulfate solution, was proposed to maintain the hydrophilicity of polycaprolactone (PCL) fibers, promoting cellular adhesion. Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), cultured on aligned fibers, exhibited an elongated morphology with extension along the fiber axis. In comparison to Petri dishes and suspended random fiber scaffolds, hiPSC-CMs on suspended aligned fiber scaffolds demonstrated enhanced sarcomere organization, spontaneous synchronous contraction, and gene expression indicative of maturation. This work demonstrates the suspended and aligned nano-fibrous scaffold provides a more realistic biomimetic environment for hiPSC-CMs, which promoted further research on the inducing effect of fiber scaffolds on hiPSC-CMs microstructure and gene-level expression.

Development of UPLC-MS/MS method for the determination of colistin in plasma and kidney and its application in pharmacokinetics.

Recently, the frequent emergence of multidrug-resistant gram-negative bacterial infections has forced colistin to be used as one of the last-line options for the treatment of these infections. This study aimed to establish and validate a simple, rapid, and reliable method for the quantitative determination of colistin in plasma and kidney homogenates by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of colistin sulfate in rats and the relationship between renal accumulation and time of administration in rats were estimated by measuring plasma and renal colistin concentrations. The colistin in the sample was precipitated by acetonitrile, followed by extraction with nitrogen blow-drying and reconstitution. The chromatographic separation of analytes was conducted on an C18 column using a mobile phase consisting of 0.1% aqueous formic acid and acetonitrile. Polymyxin B was used as an internal standard (IS). Colistin and IS were monitored in positive ion mode with the following mass transition pairs: m/z 585.6→m/z 101.4 for colistin A，m/z 578.6→m/z 101.4 for colistin B and m/z 595.6→m/z 227.2 for IS, respectively. The established method expressed good linearity in 50 - 20000 ng·mL-1 of colistin, with the lower limit of quantification (LLOQ) of 50 ng·mL-1. Methodology validations, including accuracy, precision, matrix effect, recovery, stability, and dilution integrity met the US Food and Drug Administration (FDA) acceptance criteria for bioanalytical method validation. Noncompartmental pharmacokinetic parameters were obtained by the statistical moment theory. The estimates for the terminal half-life (t1/2), the peak time (Tmax), the peak concentration (Cmax), the area under the plasma concentration-time curve (AUC0-t), the volume of distribution (V), the total body clearance (CL) and the mean residence time (MRT0-t) were calculated to be 2.53 ± 1.6 h, 2.17 ± 1.57 h, 2913.01 ± 644.89 ng·mL-1, 15153.46 ± 3599.81 h·ng·mL-1, 0.98 ± 0.56 L·kg-1, 0.28 ± 0.09 L·h-1·kg-1 and 4.07 ± 1.13 h, respectively. And the concentrations of colistin in rat kidney tissue after continuous administration for 1, 3, 5, 7 days were 1.49 ± 0.35 µg·g-1, 2.88 ± 0.74 µg·g-1, 3.40 ± 0.25 µg·g-1 and 4.33 ± 0.63 µg·g-1, respectively. The established method provided a convenient, rapid, stable, sensitive, accurate way for the determination of colistin concentration, which has been successfully used for the pharmacokinetic analysis of colistin sulfate in rat and to explore the relationship between the renal accumulation of colistin and the duration of dosing.

Post-marketing safety concerns with nirmatrelvir: A disproportionality analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System.

AIMS: Nirmatrelvir is an antiviral drug with a novel mechanism of action, targeting the 3-CL protease, and is used in the treatment of COVID-19. However, the potential side effects have not yet been fully studied. The aim of this study was to identify potential safety signals of nirmatrelvir by analysing post-marketing safety data based on the largest publicly available worldwide pharmacovigilance database. METHODS: We analysed nirmatrelvir adverse events to identify and characterize relevant safety signals based on the FDA Adverse Event Reporting System database in 2022. The case/non-case approach was used to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for adverse events (AEs) that numbered 4 or more. RESULTS: A total of 26 846 cases were included. Disease recurrence (ROR [95% CI] = 413.2 [395.6-431.59]), dysgeusia (ROR [95% CI] = 110.84 [106.04-115.85]), anosmia (ROR [95% CI] = 15.21 [12.76-18.11]), ageusia (ROR [95% CI] = 9.80 [8.50-11.3]) and urticaria (ROR [95% CI] = 1.91 [1.69-2.17]) were the main safety signals. In addition, abdominal pain upper and skin toxicity were two specific safety signals of nirmatrelvir. In the pregnant population, there was a significant increased ROR for life-threatening conditions (ROR [95% CI] = 8.00 [1.77-36.20]). CONCLUSIONS: Our study identified that the main and specific safety signals of nirmatrelvir were disease recurrence, dysgeusia, abdominal pain upper and skin toxicity. Clinicians and pharmacists should be vigilant of these AEs, although differentiating between COVID-19 symptoms and AEs can be challenging. Notably, a potential safety concern of nirmatrelvir should be a warning based on a small number of events in the pregnant population. However, the available data are insufficient, and further continued pharmacovigilance and surveillance is needed to fully understand this issue.

Dissolving microneedle patches-mediated percutaneous delivery of tetramethylpyrazine for rheumatoid arthritis treatment.

Recently, transdermal treatment of rheumatoid arthritis (RA) has received increasing attention due to the advantages of improving patient compliance and avoiding gastrointestinal side effects. However, the stratum corneum (SC) barrier limits the transdermal delivery of most substances. Therefore, we constructed tetramethylpyrazine-loaded dissolving microneedle patches (TMP-DMNPs) and investigated its anti-rheumatoid arthritis effect. The cone-shaped dissolving microneedle patch had complete, neatly arranged needles and great mechanical strength. It could effectively penetrate the stratum corneum when applied to the skin. In vitro transdermal experiment showed that DMNPs could significantly promote the transdermal penetration of TMP compared with TMP-cream. The needles were completely dissolved within 18 min and the applied skin recovered completely within 3 h. The excipients and blank DMNP had good safety and biocompatibility to human rheumatoid arthritis fibroblast synovial cells. To compare the therapeutic effects, the animal model was established. The experiments of paw swelling, histopathology and X-ray examination showed that dissolving microneedles significantly alleviated paw condition, reduced the serum concentrations of proinflammatory cytokines, and inhibited synovial tissue damage in AIA rats. These results indicate that the DMNPs we prepared can deliver TMP safely, effectively and conveniently, providing a basis for the percutaneous treatment of RA.