Pro-CRISPR PcrIIC1-associated Cas9 system for enhanced bacterial immunity.

The CRISPR system is an adaptive immune system found in prokaryotes that defends host cells against the invasion of foreign DNA1. As part of the ongoing struggle between phages and the bacterial immune system, the CRISPR system has evolved into various types, each with distinct functionalities2. Type II Cas9 is the most extensively studied of these systems and has diverse subtypes. It remains uncertain whether members of this family can evolve additional mechanisms to counter viral invasions3,4. Here we identify 2,062 complete Cas9 loci, predict the structures of their associated proteins and reveal three structural growth trajectories for type II-C Cas9. We found that novel associated genes (NAGs) tended to be present within the loci of larger II-C Cas9s. Further investigation revealed that CbCas9 from Chryseobacterium species contains a novel ß-REC2 domain, and forms a heterotetrameric complex with an NAG-encoded CRISPR-Cas-system-promoting (pro-CRISPR) protein of II-C Cas9 (PcrIIC1). The CbCas9-PcrIIC1 complex exhibits enhanced DNA binding and cleavage activity, broader compatibility for protospacer adjacent motif sequences, increased tolerance for mismatches and improved anti-phage immunity, compared with stand-alone CbCas9. Overall, our work sheds light on the diversity and 'growth evolutionary' trajectories of II-C Cas9 proteins at the structural level, and identifies many NAGs-such as PcrIIC1, which serves as a pro-CRISPR factor to enhance CRISPR-mediated immunity.

Tetramethylpyrazine nitrone delays the aging process of C. elegans by improving mitochondrial function through the AMPK/mTORC1 signaling pathway.

Aging is characterized as the process of functional decline in an organism from adulthood, often marked by a progressive loss of cellular function and systemic deterioration of multiple tissues. Among the numerous molecular, cellular, and systemic hallmarks associated with aging, mitochondrial dysfunction is considered one of the pivotal factors that initiates the aging process. During aging, mitochondria undergo varying degrees of damage, resulting in impaired energy production and disruption of the homeostatic regulation of mitochondrial quality control systems, which in turn affects cellular energy metabolism and results in cellular dysfunction, accelerating the aging process. AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin complex 1 (mTORC1) are two central kinase complexes responsible for sensing intracellular nutrient levels, regulating metabolic homeostasis, modulating aging and play a crucial role in maintaining the homeostatic balance of mitochondria. Our previous studies found that the novel compound tetramethylpyrazine nitrone (TBN) can protect mitochondria via the AMPK/mTOR pathway in many animal models, extending healthy lifespan through the Nrf2 signaling pathway in nematodes. Building upon this foundation, we have posited a reasonable hypothesis, TBN can improve mitochondrial function to delay aging by regulating the AMPK/mTORC1 signaling pathway. This study focuses on the C. elegans, exploring the impact and underlying mechanisms of TBN on aging and mitochondrial function (especially the mitochondrial quality control system) during the aging process. The present studies demonstrated that TBN extends lifespan of wild-type nematodes and is associated with the AMPK/mTORC1 signaling pathway. TBN elevated ATP and NAD+ levels in aging nematodes while orchestrating mitochondrial biogenesis and mitophagy. Moreover, TBN was observed to significantly enhance normal activities during aging in C. elegans, such as mobility and pharyngeal pumping, concurrently impeding lipofuscin accumulation that were closely associated with AMPK and mTORC1. This study not only highlights the delayed effects of TBN on aging but also underscores its potential application in strategies aimed at improving mitochondrial function via the AMPK/mTOR pathway in C. elegans.

Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia.

BACKGROUND: Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine the prevalence of the GAA repeat expansion in FGF14 in Chinese populations presenting late-onset cerebellar ataxia (LOCA) and evaluate the characteristics of tandem repeat inheritance, radiological features and sympathetic nerve involvement. METHODS: GAA-FGF14 repeat expansion was screened in an undiagnosed LOCA cohort (n = 664) and variations in repeat-length were analyzed in families of confirmed GAA-FGF14 ataxia patients. Brain magnetic resonance imaging (MRI) was used to evaluate the radiological feature in GAA-FGF14 ataxia patients. Clinical examinations and sympathetic skin response (SSR) recordings in GAA-FGF14 patients (n = 16) were used to quantify sympathetic nerve involvement. RESULTS: Two unrelated probands (2/664) were identified. Genetic screening for GAA-FGF14 repeat expansion was performed in 39 family members, 16 of whom were genetically diagnosed with GAA-FGF14 ataxia. Familial screening revealed expansion of GAA repeats in maternal transmissions, but contraction upon paternal transmission. Brain MRI showed slight to moderate cerebellar atrophy. SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage. CONCLUSIONS: GAA-FGF14 ataxia was rare among Chinese LOCA cases. Parental gender appears to affect variability in GAA repeat number between generations. Reduced SSR amplitude is a prominent feature in GAA-FGF14 patients, even in the pre-symptomatic stage.

Improved Diagnostic Accuracy of Multi-Slice Spiral CT Combined with MRI in Colon Cancer Patients with Ileus: A Comparative Study.

Background: Colon cancer is a common malignant tumor that often leads to intestinal obstruction, resulting in significant morbidity and mortality. Early and accurate diagnosis of colon cancer and associated ileus is crucial for timely treatment and improved patient outcomes. Various diagnostic methods, including MSCT and MRI, are currently used in clinical practice. However, the optimal imaging approach for accurate diagnosis remains uncertain. Objective: To study the value and accuracy of multi-slice spiral CT (MSCT) combined with magnetic resonance imaging (MRI) in diagnosing colon cancer obstruction. Methods: A retrospective analysis was performed on 100 cases of colon cancer and ileus patients admitted to the Hai'an Hospital of Chinese Medicine from January 2019 to July 2020. The cases were randomly divided into control and experimental groups, with 50 cases in each. The control group was diagnosed with MSCT, and the experimental group was diagnosed with MRI based on the control group. The positive and negative detection rates, test accuracy, sensitivity, and specificity were compared between the 2 groups. The area under the curve (AUC), quality of life (QOL) score, and mental status scale in non-psychiatric settings (MSSNS) score were calculated with the receiver operator characteristic curve (ROC) and compared between the 2 groups. Results: The test accuracy, positive detection rate, negative detection rate, test specificity, sensitivity, and AUC of the experimental group were significantly higher than those of the control group, and the results were statistically significant (P < .05). There was no significant difference in the QOL and the MSSNS scores between the 2 groups (P > .05). Conclusion: MSCT combined with MRI has a high application value in diagnosing colon cancer obstruction patients, and can significantly improve the test's accuracy, specificity and sensitivity.

Causal relationship between gut microbiota and functional outcomes after ischemic stroke: A comprehensive Mendelian randomization study.

AIMS: To investigate the association of the genetic predisposition of specific gut microbiotas with the clinical outcome of ischemic stroke. METHODS: We leveraged publicly available genome-wide association study (GWAS) data to perform Mendelian randomization (MR) analysis. The gut microbiota-related GWAS data from 18,340 individuals from the international consortium MiBioGen was used. The summary data for functional outcomes after ischemic stroke was obtained from the Genetics of Ischemic Stroke Functional Outcome (GISCOME) network meta-analysis. The primary outcomes were judged by the modified Rankin Scale (mRS). The principal analyses were conducted using the inverse-variance weighted (IVW) MR method. The Cochran's Q test, weighted median, MR-Egger regression, leave-one-SNP-out analysis, MR-Pleiotropy Residual Sum, and Outlier methods were adopted as sensitivity analyses. Furthermore, we performed bi-directional MR analysis and the MR Steiger directionality test to examine the direction of the causal relations. RESULTS: The results demonstrated that the genetic predisposition of genus Lactococcus, genus Ruminococcaceae NK4A214 group, family Peptostreptococcaceae, and genus Odoribacter was positively associated with favorable functional outcome after ischemic stroke. Genus Collinsella, genus Ruminococcaceae UCG005, genus Akkermansia, genus Eubacterium oxidoreducens group, and family Verrucomicrobiaceae were identified to be associated with worse functional outcomes after ischemic stroke. Our results showed no evidence of heterogeneity, directional pleiotropic effects, or collider bias, and the sensitivity of our analysis was acceptable. CONCLUSION: The genetic predisposition of different gut microbiotas was associated with the clinical outcome of ischemic stroke. Microbiota adjustment was a promising method to improve the clinical outcome of ischemic stroke.

Electrochemical Trifluoromethylation and Sulfonylation of N-Allylamides: Synthesis of Oxazoline Derivatives.

We report a new method for the synthesis of trifluoromethylated and sulfonylated oxazolines by electrochemical radical cascade cyclizations of N-allylamides with sodium trifluoromethanesulfinate or sulfonylhydrazines. This protocol provides a green and useful strategy to synthesize trifluoromethylated and sulfonylated oxazolines with a broad substrate scope under ambient conditions.

Annulation Reaction of Quinoxalin-2(1H)-ones Initiated by Electrochemical Decarboxylation of N-Arylglycines.

A new methodology for the synthesis of tetrahydroimidazo[1,5-a]quinoxalin-4(5H)-ones has been accomplished through annulation of quinoxalin-2(1H)-ones initiated by electrochemical decarboxylation of N-arylglycines catalyzed by ferrocene. With a pair of oxidative and reductive processes occurring among the substrates and intermediates instead of on the electrodes, the electricity consumption was decreased.

[Surgical Safety of Elderly Hospitalized Patients Stratified by Age in General Surgery].

Objective To compare the surgical safety of elderly hospitalized patients in different age groups undergoing general surgery,and provide references for preoperative evaluation and treatment decision-making.Methods The inpatients ≥ 60 years old in the department of general surgery were selected from a national multi-center survey conducted from January to June in 2015 and from January to June in 2016.The patient characteristics and postoperative outcomes were described,and the risk factors for adverse postoperative outcomes of patients in different age groups were explored.Results The elderly patients (≥75 years old) accounted for 17.33%.The non-elderly patient (< 75 years old) group and the elderly patient (≥75 years old) group had significant differences in the proportions of patients with three or more chronical diseases (13.18% vs.5.36%,P<0.001),emergency surgery (16.64% vs.7.62%,P<0.001),American Society of Anesthesiologists score≥3 (48.68% vs.27.28%,P<0.001),and postoperative return to the intensive care unit(33.64% vs.12.00%,P<0.001).The occurrence of postoperative infectious complications showed no significant difference between the two age groups (7.29% vs.6.40%,P=0.410),while severe complications differed between the two groups (6.51% vs.2.60%,P<0.001).Besides,emergency surgery was a common independent risk factor for the two age groups.Conclusions Advanced age is not a contraindication to surgery of elderly patients.With consideration to patient's physical conditions and available surgical resources,elderly patients can still benefit from surgery.

Tetramethylpyrazine nitrone TBN extends the lifespan of C. elegans by activating the Nrf2/SKN-1 signaling pathway.

SKN-1, the ortholog of mammalian Nrf2 proteins, is a transcription factor that plays an important role in oxidative stress resistance and longevity. Similar to other defense systems, the Nrf2-mediated stress response is compromised in aging and neurodegenerative diseases. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a derivative of tetramethylpyrazine armed with a potent free radical-scavenging nitrone moiety, exerted multifunctional neuroprotection in neurological and other diseases. However, the ability of TBN to extend a healthy lifespan and its underlying mechanisms of action are not yet clear. C. elegans have become a popular animal model in aging research. Herein, we demonstrate that TBN can extend the lifespan, promote age-associated health indicators, and restore mitochondrial function in C. elegans. TBN also significantly reduced ROS levels and superoxide accumulation in C. elegans. We show that TBN-mediated lifespan extension is SKN-1dependent. The present study provides valuable insights into the mechanisms by which TBN inhibits aging via the Nrf2/SKN-1 pathway in C. elegans.

Hydropyridylation of α,ß-Unsaturated Esters through Electroreduction of 4-Cyanopyridine.

A mild and highly efficient method for the hydropyridylation of α,ß-unsaturated esters has been developed. This protocol provides the products smoothly with a wide substrate scope in an undivided cell under ambient conditions. Moreover, studies showed that the scope could be extended to other unsaturated compounds, including enones and aldehydes.

Synthesis of Antimicrobial Benzo[1,2,4]triazoloazepinium Salts and Tetrahydronaphtho[1,2-e][1,2,4]triazines by Polar [3+ + 2] and [4 + 2]-Cycloaddition Reactions.

Novel annulated azaheterocycles of benzo[1,2,4]triazoloazepine and tetrahydronaphtho[1,2-e][1,2,4]triazine derivatives have been synthesized. Treatment of 2-diazenyl-1,2,3,4-tetrahydronaphthalen-2-yl acetates with BF3·Et2O generates 1-aza-2-azoniaallenium cation intermediates (or azocarbenium ions), which are intercepted by nitriles via cascade polar [3+ + 2]-cycloaddition/rearrangement reactions to afford benzo[1,2,4]triazoloazepinium salts. These literature unprecedented fused tricycle compounds have been shown to exhibit antimicrobial activity against Gram-positive Staphylococcus aureus with in silico docking studies, suggesting that they may exhibit their antibiotic activity through inhibition of DNA gyrase. Additionally, when ethyl 2-(1-acetoxy-1,2,3,4-tetrahydronaphthalen-2-yl)diazene-1-carboxylate is employed, the reaction with BF3·Et2O produces 1,2-diaza-1,3-diene, which reacts with nitriles via a diaza-Diels-Alder reaction with inverse electron demand, leading to ethyl tetrahydronaphtho[1,2-e][1,2,4]triazine carboxylates. The DFT calculation has been performed to further prove the D-A reaction speculation.

Formicincola oecophyllae gen. nov. sp. nov., a novel member of the family Acetobacteraceae isolated from the weaver ant Oecophylla smaragdina.

In this study, a novel bacterium designated F3b2T was isolated from the gut sample of weaver ant Oecophylla smaragdina and characterised. Strain F3b2T was a Gram-negative, aerobic, non-motile, ovoid-shaped bacterium and grows optimally at 28-30 °C. Its major respiratory quinone is ubiquinone 10 (Q-10) and the major fatty acids are C18:1 ω7c, C19:0 cyclo ω8c and C16:0, representing 85% of the total fatty acids. The 16S rRNA gene sequence of strain F3b2T was highest in similarity to that of Oecophyllibacter saccharovorans DSM106907T and Swingsia samuieinsis NBRC 107927T at 94.35% and 91.96%, respectively. A 16S rRNA gene-based phylogenetic analysis and a core genes-based phylogenomic analysis placed strain F3b2T in a distinct lineage in the family Acetobacteraceae. The phylogenetic placement was supported by lower than species delineation threshold average nucleotide identity (ANI) (≤ 70.2%), in silico DNA-DNA hybridization (DDH) (≤ 39.5%) and average amino acid identity (AAI) (≤ 63.5%) values between strain F3b2T and closest neighbours. These overall genome relatedness indices also supported the assignment of strain F3b2T to a novel genus within Acetobacteraceae. The genome of strain F3b2T was 1.96 Mb with 60.4% G + C DNA content. Based on these results, strain F3b2T represented a novel taxon of Acetobacteraceae, for which we proposed the name Formicincola oecophyllae gen. nov. sp. nov., and strain F3b2T (= LMG 30590T = DSM 106908T = NBRC 113640T = KCTC 62951T) as the type strain.

A Hierarchical Approach for Traffic Sign Recognition Based on Shape Detection and Image Classification.

In recent years, the development of self-driving cars and their inclusion in our daily life has rapidly transformed from an idea into a reality. One of the main issues that autonomous vehicles must face is the problem of traffic sign detection and recognition. Most works focusing on this problem utilize a two-phase approach. However, a fast-moving car has to quickly detect the sign as seen by humans and recognize the image it contains. In this paper, we chose to utilize two different solutions to solve tasks of detection and classification separately and compare the results of our method with a novel state-of-the-art detector, YOLOv5. Our approach utilizes the Mask R-CNN deep learning model in the first phase, which aims to detect traffic signs based on their shapes. The second phase uses the Xception model for the task of traffic sign classification. The dataset used in this work is a manually collected dataset of 11,074 Taiwanese traffic signs collected using mobile phone cameras and a GoPro camera mounted inside a car. It consists of 23 classes divided into 3 subclasses based on their shape. The conducted experiments utilized both versions of the dataset, class-based and shape-based. The experimental result shows that the precision, recall and mAP can be significantly improved for our proposed approach.

[Patterns of Perioperative Blood Transfusion in Patients with Blood Loss during Major Cardiac Surgery].

Objective To investigate the patterns of perioperative blood transfusion in patients with blood loss during major cardiac surgery,so as to provide data reference for rational and standardized blood use.Methods The adult patients(aged 18 years or above)who underwent vascular surgery,coronary artery bypass grafting surgery,heart valve surgery or surgery for congenital heart disease in a national multicenter(four large hospitals)survey in China,2015-2016 were included in this study.We described their baseline characteristics,postoperative outcomes,and in particular,bleeding and patterns of perioperative blood transfusion(autologous and allogeneic,the latter including red blood cells,plasma,and platelet,or a combination of these components).Results Autologous blood transfusion in operation accounted for the highest proportion(58.84%)in patients undergoing heart valve surgery.The patients undergoing vascular surgery had the largest autologous blood transfusion volume(722 ml)and the highest intraoperative transfusion proportion of allogeneic blood(53.28%),especially that of platelet(39.34%).Compared with the transfusion of red blood cells,the transfusion of other blood components showed concentrated time distribution,and the proportion of plasma transfusion was the highest one day post operation.With the increase in bleeding volume,combined transfusion presented increased proportion and became the dominant transfusion pattern.Conclusions The blood transfusion patterns varied significantly depending on different types of cardiac surgery,different perioperative stages,and different bleeding volumes.It is necessary to formulate the targeted transfusion practice scheme on the basis of understanding the current situation,so as to make better use of blood resources and improve the safety of transfusion.

[Inhibitory Effects of Nicotinamide on Streptococcus mutans Growth and Biofilm Formation].

Objective: To explore the effects of nicotinamide (NAM) on the growth, biofilm formation and exopolysaccharides (EPS) production of Streptococcus mutans. Methods: The minimum inhibitory concentration (MIC) of NAM on S. mutanswas determined by the planktonic bacterial susceptibility assay. The NAM mass concentrations were set as 1/2 MIC, 1/4 MIC and 1/8 MIC for hree separate treatment groups. Culture medium without NAM was used in the negative control group and culture medium containing 0.1 mg/mL NaF was used for the positive control group (except for the scanning electron microscopy). The growth curves of S. mutans under different NAM concentrations were drawn. Crystal violet assay and anthrone-sulfuric acid method were used to explore the effects of NAM on S. mutans biofilm formation and water-insoluble EPS production, respectively. The morphology and structure of S. mutansplanktons and biofilms after NAM treatment were observed by scanning electron microscopy. Results: The MIC of NAM on S. mutans was 32 µg/µL. After 16 µg/µL (1/2 MIC), 8 µg/µL (1/4 MIC) and 4 µg/µL (1/8 MIC) NAM treatments, S. mutans growth and biofilm formation were inhibited, with the 16 µg/µL NAM group displaying the most significant inhibitory effects. The synthesis of EPS decreased significantly in the 16 µg/µL and 8 µg/µL NAM groups in comparison with that of the negative control group (P<0.05). Under scanning electron microscope, the cell length of S. mutans was shortened, the cell width was extended, and the length/width ratio was decreased, showing significant difference when comparing the 16 µg/µL and 8 µg/µL NAM groups with the negative control group (P<0.05). Conclusion: Under the influence of NAM at certain concenrations, the growth, biofilm formation, and EPS synthesis of S. mutanswere inhibited.

[frtR Gene Affects Acid Production and Demineralization Ability of Streptococcus mutans].

Objective: To study the effect of the frtR gene of TetR family on the acid production ability of Streptococcus mutans( S. mutans) and the bacteria's ability to induce tooth demineralization . Methods: The growth of two strains of S. mutans UA159, Δ frtR, the frtR gene in-frame deletion strain, and Δ frtR/pDL278- frtR, the complement strain, was examined. The structure of biofilm was observed by laser scanning confocal microscopy (LSCM). The quantitative determination of water-insoluble extracellular polysaccharide (EPS) in the bacterial biofilms was done by anthrone-sulfuric acid method. The acid production capacity of S. mutans was measured by glycolytic pH drop. The demineralization-inducing ability of the strains on bovine teeth was determined by transverse microradiography (TMR). Results: The growth curves of the strains showed that frtR did not affect the growth of S. mutans. According to the findings of LSCM observation, frtR did not affect the biofilm formation. According to the findings of the anthrone-sulfuric acid method, frtR did not have any significant impact on the EPS synthesis of S. mutans. The results of the glycolytic pH drop assay showed that the deletion of frtR delayed the rate of acid production by S. mutans when sucrose was the only carbon source. In addition, according to the TMR results, knocking out frtR reduced the depth and amount of demineralization induced by S. mutans on the surface of bovine teeth. Conclusion: The deletion of frtR can weaken the acid production ability and the demineralization ability of S. mutans.

[Research progress on pesticide residues of Angelicae Sinensis Radix].

The demand for Angelicae Sinensis Radix, the dry root of Angelica sinensis, has been increasing year by year. However, the continuous cropping obstacles, frequent occurrence of pests and diseases, overuse of chemical pesticides, excessive pesticide residues and other problems in Angelicae Sinensis Radix production have attracted much attention. In this paper, we summarized the common diseases and pests attacking Angelica sinensis as well as the detection methods and characteristics of pesticide residues in Angelicae Sinensis Radix from 2002 to 2021. Additionally, we compared the limit standards of pesticide residues in Angelicae Sinensis Radix in and out of China and put forward suggestions for the high-quality and green development of Angelicae Sinensis Radix industry conside-ring the existing problems. The pesticide residues in Angelicae Sinensis Radix have been changing from organochlorines to organophosphorus pesticides. In recent years, some organophosphorus pesticides such as phorate, phoxim, isofenphos-methyl, phorate-sulfoxide, fenamiphos, isocarbophos, omethoate, and triazophos in Angelicae Sinensis Radix have seriously exceeded the standards. The detection methods of pesticide residues has evolved from chromatography to high performance chromatography-mass spectrometry, gas chromatography-mass spectrometry(GC-MS), and liquid chromatography-mass spectrometry(LC-MS), and some new detection techniques such as immunoassay have also been applied. Pesticide residues have become a primary factor that restricting the development of Angelicae Sinensis Radix industry. Therefore, moderate application of pesticides, establishment of ecological planting system, and strict limit standards of pesticide residues are necessary to solve the pesticide residue problem.

Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. METHODS: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing. FINDINGS: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. INTERPRETATION: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). FUNDING: Novartis Pharmaceuticals.

Colonization With Fluoroquinolone-Resistant Enterobacterales Decreases the Effectiveness of Fluoroquinolone Prophylaxis in Hematopoietic Cell Transplant Recipients.

BACKGROUND: Levofloxacin prophylaxis is recommended to prevent gram-negative bloodstream infections (BSIs) in patients with prolonged chemotherapy-induced neutropenia. However, increasing fluoroquinolone resistance may decrease the effectiveness of this approach. METHODS: We assessed the prevalence of colonization with fluoroquinolone-resistant Enterobacterales (FQRE) among patients admitted for hematopoietic cell transplantation (HCT) from November 2016 to August 2019 and compared the risk of gram-negative BSI between FQRE-colonized and noncolonized patients. All patients received levofloxacin prophylaxis during neutropenia. Stool samples were collected upon admission for HCT and weekly thereafter until recovery from neutropenia, and underwent selective culture for FQRE. All isolates were identified and underwent antimicrobial susceptibility testing by broth microdilution. FQRE isolates also underwent whole-genome sequencing. RESULTS: Fifty-four of 234 (23%) patients were colonized with FQRE prior to HCT, including 30 of 119 (25%) allogeneic and 24 of 115 (21%) autologous HCT recipients. Recent antibacterial use was associated with FQRE colonization (P = .048). Ninety-one percent of colonizing FQRE isolates were Escherichia coli and 29% produced extended-spectrum ß-lactamases. Seventeen (31%) FQRE-colonized patients developed gram-negative BSI despite levofloxacin prophylaxis, compared to only 2 of 180 (1.1%) patients who were not colonized with FQRE on admission (P < .001). Of the 17 gram-negative BSIs in FQRE-colonized patients, 15 (88%) were caused by FQRE isolates that were genetically identical to the colonizing strain. CONCLUSIONS: Nearly one-third of HCT recipients with pretransplant FQRE colonization developed gram-negative BSI while receiving levofloxacin prophylaxis, and infections were typically caused by their colonizing strains. In contrast, levofloxacin prophylaxis was highly effective in patients not initially colonized with FQRE.

Efficient Electron Transfer from Electron-Sponge Polyoxometalate to Single-Metal Site Metal-Organic Frameworks for Highly Selective Electroreduction of Carbon Dioxide.

In this work, by combining the superiority of polyoxometalates (POMs) and catalytic single-metal site Co of metalloporphyrin, a series of mixed-valence POM-based metal-organic frameworks (MOFs) composites is synthesized by a post-modification method. The electron-transfer property of POM@PCN-222(Co) composite is significantly enhanced owing to the directional electron-transfer from POM to single-metal site Co in PCN-222(Co). In particular, H-POM@PCN-222(Co) gives a high Faradaic efficiency of 96.2% for electroreduction of CO2 into CO and good stability over 10 h. DFT calculations confirm that the directional electron transfer, which accelerates the multi-electron transfer from the electrode to active single-metal site Co, enriches the electron density of the Co center, and ultimately reduces the energy of the rate-determining step, thus increasing the catalytic activity of CO2 reduction reaction (CO2 RR). This work therefore suggests some new insight for the design of efficient electrocatalysts for CO2 RR.