Adverse drug events associated with linezolid administration: a real-world pharmacovigilance study from 2004 to 2023 using the FAERS database.

Introduction: Linezolid is an oxazolidinone antibiotic that is active against drug-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis. Real-world studies on the safety of linezolid in large populations are lacking. This study aimed to determine the adverse events associated with linezolid in real-world settings by analyzing data from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: We retrospectively extracted reports on adverse drug events (ADEs) from the FAERS database from the first quarter of 2004 to that of 2023. By using disproportionality analysis including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), along with the multi-item gamma Poisson shrinker (MGPS), we evaluated whether there was a significant association between linezolid and ADE. The time to onset of ADE was further analyzed in the general population and within each age, weight, reporting population, and weight subgroups. Results: A total of 11,176 reports of linezolid as the "primary suspected" drug and 263 significant adverse events of linezolid were identified, including some common adverse events such as thrombocytopenia (n = 1,139, ROR 21.98), anaemia (n = 704, ROR 7.39), and unexpected signals that were not listed on the drug label such as rhabdomyolysis (n = 90, ROR 4.33), and electrocardiogram QT prolonged (n = 73, ROR 4.07). Linezolid-induced adverse reactions involved 27 System Organ Class (SOC). Gender differences existed in ADE signals related to linezolid. The median onset time of all ADEs was 6 days, and most ADEs (n = 3,778) occurred within the first month of linezolid use but some may continue to occur even after a year of treatment (n = 46). Conclusion: This study reports the time to onset of adverse effects in detail at the levels of SOC and specific preferred term (PT). The results of our study provide valuable insights for optimizing the use of linezolid and reducing potential side effects, expected to facilitate the safe use of linezolid in clinical settings.

Dopants Induce Persistent Room Temperature Phosphorescence in Triarylamine Boronate Esters.

Purely organic materials exhibiting room temperature phosphorescence (RTP) are promising candidates for oxygen sensors and information encryption owing to their cost-effective and environmentally friendly nature. Herein, we report a bimolecular RTP system where DTBU acts as the guest and TBBU serves as the host. In contrast to previously reported results, we find that both pure DTBU and TBBU do not exhibit RTP in the solid state even under N2 atmosphere. A DTBU/TBBU system with a low doping ratio (0.1 mol %) exhibits persistent yellowish-green afterglow with a lifetime of 340 ms and is highly sensitive to oxygen. A DTBU/TBBU system with a higher doping ratio (10 mol %) maintains a phosphorescence lifetime of 179 ms under air. Applications of DTBU/TBBU at varied doping ratios in both oxygen sensing and information encryption are demonstrated. We propose that the T1 state of TBBU acts as an energy transfer intermediate between Tn and T1 of DTBU, ultimately leading to the generation of persistent RTP. Overall, this work demonstrates the critical importance of material purity in the design of RTP systems, and how an understanding of host-guest doping enables their photophysical properties to be precisely tuned.

Rreb1 is a key transcription factor in Sertoli cell maturation and function and spermatogenesis in mouse.

Spermatogenesis is a developmental process driven by interactions between germ cells and Sertoli cells. This process depends on appropriate gene expression, which might be regulated by transcription factors. This study focused on Rreb1, a zinc finger transcription factor, and explored its function and molecular mechanisms in spermatogenesis in a mouse model. Our results showed that RREB1 was predominantly expressed in the Sertoli cells of the testis. The decreased expression of RREB1 following injection of siRNA caused impaired Sertoli cell development, which was characterized using a defective blood-testis barrier structure and decreased expression of Sertoli cell functional maturity markers; its essential trigger might be SMAD3 destabilization. The decreased expression of RREB1 in mature Sertoli cells influenced the cell structure and function, which resulted in abnormal spermatogenesis, manifested as oligoasthenoteratozoospermia, and we believe RREB1 plays this role by regulating the transcription of Fshr and Wt1. RREB1 has been reported to activate Fshr transcription, and we demonstrated that the knockdown of Rreb1 caused a reduction in follicle-stimulating hormone receptor (FSHR) in the testis, which could be the cause of the increased sperm malformation. Furthermore, we confirmed that RREB1 directly activates Wt1 promoter activity, and RREB1 downregulation induced the decreased expression of Wt1 and its downstream polarity-associated genes Par6b and E-cadherin, which caused increased germ-cell death and reduced sperm number and motility. In conclusion, RREB1 is a key transcription factor essential for Sertoli cell development and function and is required for normal spermatogenesis.

Optimum timing of lung resection surgery following SARS-CoV-2 infection for non-small cell lung cancer.

BACKGROUND: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on postoperative recovery of non-small cell lung cancer (NSCLC) is need to be understood, thereby informing the optimal timing of surgical decision-making during the COVID-19 pandemic for NSCLC patients. This study reports the postoperative outcomes of surgical NSCLC patients with preoperative SARS-CoV-2 infection. METHOD: This single-center retrospective cohort study included 241 NSCLC patients who underwent lobectomy or sub-lobectomy between December 1, 2022 and February 14, 2023. Surgical outcomes of patients with preoperative SARS-CoV-2 infection (stratified by the time from diagnosis of SARS-CoV-2 infection to surgery) were compared with those without preoperative SARS-CoV-2 infection. The primary outcomes were total postoperative complications and postoperative pulmonary complications (PPCs), the secondary outcomes included operation time, total postoperative drainage and time, length of hospital stay (LOS), 30-day and 90-day postoperative symptoms. RESULTS: This study included 153 (63.5%) patients with preoperative SARS-CoV-2 infection and 88 (36.5%) patients without previous SARS-CoV-2 infection. In patients with a preoperative SARS-CoV-2 diagnosis, the incidence of total postoperative complications (OR, 3.00; 95% CI, 1.12-8.01; p = 0.028) and PPCs (OR, 4.20; 95% CI, 1.11-15.91; p = 0.035) both increased in patients infected having surgery within 2 weeks compared with non-infection before surgery. However, patients who underwent lung resection more than 2 weeks after SARS-CoV-2 diagnosis had a similar risk of postoperative complications and surgical outcomes with those non-infection before surgery. CONCLUSION: This is the first study to provide evidence regarding the optimum timing of lung resection surgery and assessing early outcomes after surgery in NSCLC patients with SARS-CoV-2 infection. Our study documents that the SARS-CoV-2 infection did not complicate surgical procedures for lung cancer, and suggest that lung surgery should be postponed at least 2 weeks after SARS-CoV-2 infection for NSCLC patients.

Core Structure-Oriented Asymmetric α-Allenylic Alkylation of Amino Acid Esters Enabled by Chiral Aldehyde/Palladium Catalysis.

Aiming at the reported chiral synthons leading to manzacidins A and D, here we report a highly efficient catalytic asymmetric α-allenylic alkylation reaction of NH2-unprotected amino acid esters that is promoted by combined chiral aldehyde/palladium catalysis. Fifty examples of unnatural α,α-disubstituted amino acid esters are reported with good-to-excellent yields and stereoselectivities. Based on this methodology, a key intermediate leading to manzacidin C and its other three stereoisomers is prepared accordingly.

Age-dependent changes in the gut microbiota and serum metabolome correlate with renal function and human aging.

Human aging is invariably accompanied by a decline in renal function, a process potentially exacerbated by uremic toxins originating from gut microbes. Based on a registered household Chinese Guangxi longevity cohort (n = 151), we conducted comprehensive profiling of the gut microbiota and serum metabolome of individuals from 22 to 111 years of age and validated the findings in two independent East Asian aging cohorts (Japan aging cohort n = 330, Yunnan aging cohort n = 80), identifying unique age-dependent differences in the microbiota and serum metabolome. We discovered that the influence of the gut microbiota on serum metabolites intensifies with advancing age. Furthermore, mediation analyses unveiled putative causal relationships between the gut microbiota (Escherichia coli, Odoribacter splanchnicus, and Desulfovibrio piger) and serum metabolite markers related to impaired renal function (p-cresol, N-phenylacetylglutamine, 2-oxindole, and 4-aminohippuric acid) and aging. The fecal microbiota transplantation experiment demonstrated that the feces of elderly individuals could influence markers related to impaired renal function in the serum. Our findings reveal novel links between age-dependent alterations in the gut microbiota and serum metabolite markers of impaired renal function, providing novel insights into the effects of microbiota-metabolite interplay on renal function and healthy aging.

The value of total tumor diameter in unilateral multifocal papillary thyroid carcinoma: a propensity score matching analysis.

Background: Tumor multifocality is frequently observed in papillary thyroid carcinoma (PTC). However, the maximum tumor diameter (MTD), currently utilized in various staging schemes, might not accurately indicate the level of aggressiveness exhibited by multifocal tumors. We aimed to investigate the relationship between total tumor diameter (TTD) and clinicopathological features of papillary thyroid carcinoma. Methods: Retrospective data analysis was done on 1936 individuals who underwent complete thyroidectomy for PTC. Patients were classified into subgroups according to unilateral multifocality, central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM). The relationships of clinicopathological features among these groups were analyzed. Results: Unilateral multifocality was observed in 117 patients. The clinicopathological features of the unilateral multifocal PTC were similar to the unifocal PTC with approximate TTD. The unilateral multifocality played no independent role in CLNM and LLNM. Moreover, the efficiency of TTD in predicting CLNM and LLNM was significantly higher than that of MTD. Conclusion: In the case of unilateral multifocal PTC, TTD is a more accurate indicator of the biological characteristics of the tumor than MTD.

Photocatalyzed Borylcyclopropanation of Alkenes with a (Diborylmethyl)iodide Reagent.

Cyclopropane skeletons play a prominent role in the development of organic synthesis and pharmaceutical chemistry. Herein, we report the design and synthesis of a stable, multifunctional (diborylmethyl)iodide reagent (CHI(Bpin)2 ) for the photoinduced cyclopropanation of alkenes, providing an array of 1,2-substituted cyclopropylboronates in good yields. This α-haloboronic ester can be readily synthesized on a multigram scale from commercially available starting materials. Furthermore, the protocol displays high chemo- and diastereoselectivity, excellent functional-group tolerance, and allows for late-stage borylcyclopropanation of complex molecules. Mechanistic studies reveal that the borylcyclopropanation proceeds through a radical addition/polar cyclization pathway mediated by the photocatalyst fac-Ir(ppy)3 and visible light.

Asymmetric α-Allylation of N-Unprotected Amino Acid Esters with 1,3-Disubstituted Allyl Acetates Enabled by Chiral-Aldehyde/Palladium Catalysis.

A chiral aldehyde/palladium catalysis-enabled asymmetric α-allylation of NH2-unprotected amino acid esters with 1,3-disubstituted allyl acetates is described in this work. With the utilization of different chiral phosphine ligands, both the anti- and syn-selective allylation reactions are achieved enantioselectively. A series of α,α-disubstituted amino acid esters bearing two adjacent chiral centers are produced in moderate-to-excellent yields, diastereoselectivities, and enantioselectivities.

Chiral aldehyde catalysis enables direct asymmetric α-substitution reaction of N-unprotected amino acids with halohydrocarbons.

The direct catalytic α-hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to α,α-disubstituted non-proteinogenic α-amino acid compounds. However, all the reported methodologies depend on N-protected amino acids as starting materials. Herein, we report on three highly efficient aldehyde-catalyzed direct α-hydrocarbylations of N-unprotected amino acid esters with aryl-, allyl-, and benzyl halides. By promoting a simple chiral BINOL-aldehyde catalyst or combining catalysts of a chiral aldehyde and Lewis acid ZnCl2, the asymmetric α-arylation, α-allylation, and α-benzylation of amino acid esters with the corresponding halohydrocarbons proceed smoothly, producing α,α-disubstituted α-amino acids in moderate-to-high yields and good-to-excellent enantioselectivities. The asymmetric α-arylation reaction can be applied in the formal synthesis of the clinical candidate compound (+)-AG-041R. Based on the results given by control experiments, three reaction models are proposed to illustrate the stereoselective-control outcomes.

Achieving White-Light Emission Using Organic Persistent Room Temperature Phosphorescence.

Artificial lighting currently consumes approximately one-fifth of global electricity production. Organic emitters with white persistent RTP have potential for applications in energy-efficient lighting technologies, due to their ability to harvest both singlet and triplet excitons. Compared to heavy metal phosphorescent materials, they have significant advantages in cost, processability, and reduced toxicity. Phosphorescence efficiency can be improved by introducing heteroatoms, heavy atoms, or by incorporating luminophores within a rigid matrix. White-light emission can be achieved by tuning the ratio of fluorescence to phosphorescence intensity or by pure phosphorescence with a broad emission spectrum. This review summarizes recent advances in the design of purely organic RTP materials with white-light emission, describing single-component and host-guest systems. White phosphorescent carbon dots and representative applications of white-light RTP materials are also introduced.

Perioperative and oncological outcomes of uniportal versus three-port thoracoscopic segmentectomy for lung cancer: a propensity score matching analysis.

Background: With an increasing amount of small nodules being detected, segmentectomy has recently received a great deal of attention. We have previously reported the feasibility and safety of uniportal segmentectomy. This study aims to further compare the perioperative and oncological outcomes of uniportal and three-port thoracoscopic segmentectomy in lung cancer patients. Methods: Patients undergoing thoracoscopic segmentectomy for lung cancer from January 2014 to March 2021 were enrolled. Clinical data were collected from the Western China Lung Cancer Database, a prospectively maintained database at the Department of Thoracic Surgery, West China Hospital. Propensity score matching (PSM) was used to reduce the heterogeneity in baseline characteristics. Perioperative outcomes, 1-, 3-, and 5-year overall survival (OS), and progression-free survival (PFS) were compared. Results: Of the 10,063 lung cancer patients who underwent thoracoscopic lung resection, 2,630 patients receiving segmentectomy were selected (uniportal: 400; three-port: 2,230). After matching, similar results were found between the 2 groups (uniportal: 400; three-port: 1,200) regarding the number of lymph nodes harvested, the length of postoperative hospital stays, chest tube drainage volume, and postoperative complication rate. The mean follow-up duration was 27 months. Uniportal regimen showed similar 1- (100% vs. 99.9%, P=0.36), 3- (100% vs. 90.4%, P=0.20), 5-year OS (97.7% vs. 99.4%, P=0.78), as well as PFS, with the three-port regimen. Conclusions: Uniportal video-assisted thoracoscopic segmentectomy is proven to be safe and feasible, and the perioperative outcomes and oncological results were similar between the uniportal and three-port regimens.

The Radical Anion and Dianion of Benzo[3,4]cyclobuta[1,2-b]phenazine.

We present the reduction of two azaacenes (a benzo-[3,4]cyclobuta[1,2-b]phenazine and a benzo[3,4]cyclobuta[1,2-b]naphtho[2,3-i]phenazine derivative), featuring a single cyclobutadiene unit, to their radical anions and dianions. The reduced species were produced using potassium naphthalenide in the presence of 18-crown-6 in THF. Crystal structures of the reduced representatives were obtained and their optoelectronic properties evaluated. Charging these 4n Hückel systems gives dianionic 4n + 2 π-electron systems with increased antiaromaticity, according to NICS(1.7)zz calculations, featuring unusually red-shifted absorption spectra.

Chiral aldehyde-nickel dual catalysis enables asymmetric α-propargylation of amino acids and stereodivergent synthesis of NP25302.

The combined catalytic systems derived from organocatalysts and transition metals exhibit powerful activation and stereoselective-control abilities in asymmetric catalysis. This work describes a highly efficient chiral aldehyde-nickel dual catalytic system and its application for the direct asymmetric α-propargylation reaction of amino acid esters with propargylic alcohol derivatives. Various structural diversity α,α-disubstituted non-proteinogenic α-amino acid esters are produced in good-to-excellent yields and enantioselectivities. Furthermore, a stereodivergent synthesis of natural product NP25302 is achieved, and a reasonable reaction mechanism is proposed to illustrate the observed stereoselectivity based on the results of control experiments, nonlinear effect investigation, and HRMS detection.

The general law of plasma proteome alterations occurring in the lifetime of Chinese individuals reveals the importance of immunity.

BACKGROUND: Aging is characterized by a continuous loss of protein homeostasis. A closer examination of peripheral blood, which houses proteins from nearly all tissues and cells, helped identify several biomarkers and other aspects of aging biology. To further explore the general law of aging and identify key time nodes and associated aging biology, we collected 97 plasma samples from 253 healthy individuals aged 0-100 years without adverse outcomes to conduct nano-Ultra High Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (nano-UHPLC-MS/MS) and weighted gene co-expression network analysis (WGCNA). RESULTS: Through biological processes and key biological pathways identified in discrete age group modules, our analyses highlighted a strong correlation between alterations in the immune system and aging process. We also identified hub genes associated with distinct age groups that revealed alterations not only in protein expression but also in signaling cascade. Among them, hub genes from age groups of 0-20 years old and 71-100 years old are mostly involved in infectious diseases and the immune system. In addition, CDC5L and HMGB2 were the key transcription factors (TFs) regulating genes expression in people aged between 51-60 and 71-100 years of age. They were shown to not only be independent but also mutually regulate certain hub gene expressions. CONCLUSIONS: This study reveals that the plasma proteome undergoes a complex alteration over the lifetime of a human. In this process, the immune system is crucial throughout the lifespan of a human being. However, the underlying mechanism(s) regulating differential protein expressions at distinct ages remains to be elucidated.

The Radical Anion, Dianion and Electron Transport Properties of Tetraiodotetraazapentacene.

Tetraiodotetraazapentacene I4 TAP, the last missing derivative in the series of halogenated silylated tetraazapentacenes, was synthesized via condensation chemistry from a TIPS-ethynylated diaminobenzothiadiazol in three steps. Single and double reduction furnished its air-stable monoanion and relatively air-stable dianion, both of which were characterized by crystallography. All three species are structurally and spectroscopically compared to non-halogenated TAP and Br4 TAP. I4 TAP is an n-channel material in thin-film transistors with average electron mobilities exceeding 1 cm2 (Vs)-1 .

Clinical features and molecular epidemiology of carbapenem-resistant Enterobacterales infection in children. / å„¿ç«¥ç¢³é’éœ‰çƒ¯ç±»è€è¯è‚ æ†èŒç›®ç»†èŒæ„ŸæŸ“çš„ä¸´åºŠç‰¹å¾åŠåˆ†å­æµè¡Œç ”ç©¶.

OBJECTIVES: To study the clinical features of children with carbapenem-resistant Enterobacterales (CRE) infection and the molecular characteristics of isolated strains. METHODS: A retrospective analysis was performed on the clinical data and infection status of the children who were hospitalized in Guangdong Provincial People's Hospital from January 2018 to June 2021. A total of 1 098 non-repetitive strains of Enterobacterales were obtained. Drug sensitivity test, PCR amplification, and resistance-related gene sequencing were performed for 66 isolated CRE strains to observe molecular epidemiology. RESULTS: Among the 1 098 strains of Enterobacterales, the detection rate of CRE was 6.01% (66/1 098). The 66 CRE strains were isolated from 66 children, among whom there were 37 boys (56%) and 29 girls (44%), with an age of 2 days to 14 years. Among these 66 children, 16 (24%) had an age of <1 month, 28 (42%) had an age of 1-12 months, 11 (17%) had an age of 12-36 months, and 11 (17%) had an age of >36 months. The children with CRE were mainly distributed in the department of neonatology (38 children, 58%) and the pediatric intensive care unit (17 children, 26%). The top three types of specimens with CRE detection were respiratory specimens (48%), midstream urine specimens (21%), and blood specimens (17%). The CRE strains were mainly Klebsiella pneumoniae (45 strains, 68%), Escherichia coli (12 strains, 18%), and Enterobacter cloacae (6 strains, 9%), with high resistance to carbapenems (such as imipenem and ertapenem), penicillin, and cephalosporins, slightly high resistance to commonly used antibiotics, and relatively low resistance to amikacin (14%), levofloxacin (23%), and tobramycin (33%). The carbapenemase genotypes of Klebsiella pneumoniae strains were mainly blaNDM (20 strains, 44%), blaIMP (10 strains, 22%), and blaKPC (5 strains, 11%), and the carbapenemase genotypes of Escherichia coli strains were mainly blaNDM (10 strains, 83%). After sequencing, there were 24 blaNDM-1 strains, 6 blaNDM-5 strains, 5 blaIMP-4 strains, and 3 blaKPC-2 strains, and some genotypes were not identified. CONCLUSIONS: There is a high incidence rate of CRE infection among children, mainly those aged 1-12 months. CRE generally has high resistance to antibacterial drugs, and metalloenzymes are the main type of carbapenemases for CRE strains in children.

Case Report: Reversible Hyperglycemia Following Rapamycin Treatment for Atypical Choroid Plexus Papilloma in an Infant.

In this study, atypical choroid plexus papilloma was treated with high-dose rapamycin for 17 days preoperatively in an infant. Rapamycin significantly reduced the blood supply to the tumor while reducing the tumor volume, and most of the tumor was resected successfully. However, the infant developed hyperglycemia related to the rapamycin dose, which was effectively controlled by adjusting the dose and applying insulin.

Catalytic asymmetric Tsuji-Trost α-benzylation reaction of N-unprotected amino acids and benzyl alcohol derivatives.

Catalytic asymmetric Tsuji-Trost benzylation is a promising strategy for the preparation of chiral benzylic compounds. However, only a few such transformations with both good yields and enantioselectivities have been achieved since this reaction was first reported in 1992, and its use in current organic synthesis is restricted. In this work, we use N-unprotected amino acid esters as nucleophiles in reactions with benzyl alcohol derivatives. A ternary catalyst comprising a chiral aldehyde, a palladium species, and a Lewis acid is used to promote the reaction. Both mono- and polycyclic benzyl alcohols are excellent benzylation reagents. Various unnatural optically active α-benzyl amino acids are produced in good-to-excellent yields and with good-to-excellent enantioselectivities. This catalytic asymmetric method is used for the formal synthesis of two somatostatin mimetics and the proposed structure of natural product hypoestestatin 1. A mechanism that plausibly explains the stereoselective control is proposed.

TMPRSS12 Functions in Meiosis and Spermiogenesis and Is Required for Male Fertility in Mice.

Serine proteases are involved in many physiological activities as initiators of proteolytic cascades, and some members have been reported to play roles in male reproduction. Transmembrane serine protease 12 (TMPRSS12) has been shown to regulate sperm motility and uterotubal junction migration in mice, but its role in the testis remains unknown. In this study, we verified that TMPRSS12 was expressed in the spermatocytes and spermatids of testis and the acrosome of sperm. Mice deficient in Tmprss12 exhibited male sterility. In meiosis, TMPRSS12 was demonstrated to regulate synapsis and double-strand break repair; spermatocytes of Tmprss12 -/- mice underwent impaired meiosis and subsequent apoptosis, resulting in reduced sperm counts. During spermiogenesis, TMPRSS12 was found to function in the development of mitochondria; abnormal mitochondrial structure in Tmprss12 -/- sperm led to reduced availability of ATP, impacting sperm motility. The differential protein expression profiles of testes in Tmprss12 -/- and wild-type mice and further molecule identification revealed potential targets of TMPRSS12 related to meiosis and mitochondrial function. Besides, TMPRSS12 was also found to be involved in a series of sperm functions, including capacitation, acrosome reaction and sperm-egg interaction. These data imply that TMPRSS12 plays a role in multiple aspects of male reproduction.