Association between colchicine use and the risk of dementia among patients with gout: A nationwide retrospective cohort study.

BACKGROUND: Recent findings suggest a link between gout and the development of dementia. Early treatment with colchicine is recommended as a first-line therapy for gout flares. Animal studies demonstrate that colchicine could induce cognitive impairment. This cohort study aimed to investigate the association between colchicine use and the risk of developing dementia. METHODS: In this nationwide cohort study, we performed comparative analysis on 6147 patients ≥40 years, with gout and colchicine new users against 6147 controls to assess subsequent dementia risk. The colchicine group and the control group (urate lowering therapy group) were matched on the bases of age, sex, index year, and comorbidities. All participants were followed for up to 14 years for a diagnosis of dementia considering medical records were retrospectively checked over this period. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Sensitivity analyses were performed to validate our findings. RESULTS: The adjusted hazard ratio (aHR) of dementia for colchicine users was 1.45 (95% CI = 1.05, 1.99) relative to comparison group after adjusting for sex, age, and comorbidities. Sensitivity analysis aiming to minimize underdiagnosed occult dementia at the time of index year yielded consistent positive association. In higher accumulative dose colchicine group (cumulative defined daily dose [cDDD] >30), the aHR of dementia risk for colchicine users was 1.42 (95% CI = 1.03, 1.97) compared with nonusers. For those duration of colchicine use >30 days, the aHR was 1.53 (95% CI = 1.01-2.32) compared to the nonuser group. CONCLUSIONS: A significant risk of dementia was observed in this study in patients with gout using colchicine at higher cDDD and for a longer period. Further research is needed to elucidate the relationship between colchicine, gout, and dementia.

Concatenated ScaA and TSA56 Surface Antigen Sequences Reflect Genome-Scale Phylogeny of Orientia tsutsugamushi: An Analysis Including Two Genomes from Taiwan.

Orientia tsutsugamushi is an obligate intracellular bacterium associated with trombiculid mites and is the causative agent of scrub typhus, a life-threatening febrile disease. Strain typing of O. tsutsugamushi is based on its immunodominant surface antigen, 56-kDa type-specific antigen (TSA56). However, TSA56 gene sequence-based phylogenetic analysis is only partially congruent with core genome-based phylogenetic analysis. Thus, this study investigated whether concatenated surface antigen sequences, including surface cell antigen (Sca) proteins, can reflect the genome-scale phylogeny of O. tsutsugamushi. Complete genomes were obtained for two common O. tsutsugamushi strains in Taiwan, TW-1 and TW-22, and the core genome/proteome was identified for 11 O. tsutsugamushi strains. Phylogenetic analysis was performed using maximum likelihood (ML) and neighbor-joining (NJ) methods, and the congruence between trees was assessed using a quartet similarity measure. Phylogenetic analysis based on 691 concatenated core protein sequences produced identical tree topologies with ML and NJ methods. Among TSA56 and core Sca proteins (ScaA, ScaC, ScaD, and ScaE), TSA56 trees were most similar to the core protein tree, and ScaA trees were the least similar. However, concatenated ScaA and TSA56 sequences produced trees that were highly similar to the core protein tree, the NJ tree being more similar. Strain-level characterization of O. tsutsugamushi may be improved by coanalyzing ScaA and TSA56 sequences, which are also important targets for their combined immunogenicity.

Renal artery coil embolization as an endovascular approach for establishing a rabbit model of chronic kidney disease.

PURPOSE: This study aimed to investigate the safety and feasibility of renal artery coil embolization for establishing chronic kidney disease (CKD) in rabbits. METHODS: Ten male adult New Zealand rabbits underwent renal artery coil embolization. Initially, the main renal artery on one side was completely embolized, followed by embolization of approximately 2/3 of the primary branches of the contralateral renal artery one week later. Four rabbits were randomly chosen for sacrifice at 4 weeks post-embolization, while the remaining six were sacrificed at 8 weeks post-embolization. The assessment encompassed the animals' general condition, angiography, biochemical parameters, inflammatory markers, and histopathological examination of the kidneys and hearts. RESULTS: Four weeks after embolization, serum creatinine level showed a significant increase (2.4 mg/dL ± 0.6, p = 0.009 vs. baseline), with a subsequent 4.12-fold elevation at 8 weeks post-embolization (4.9 mg/dL ± 1.4, p < 0.001 vs. baseline). Additionally, significant increases in serum blood urea nitrogen, calcium, and potassium ions were observed at 8 weeks post-embolization (58.3 mg/dL ± 19.0, p < 0.001 vs. baseline; 23.1 mg/dL ± 4.4, p < 0.001 vs. baseline; 6.3 mEq/L ± 0.7, p < 0.001 vs. baseline). The completely embolized kidney exhibited notable atrophy, severe fibrosis, and cortical calcification, whereas the contralateral partially embolized kidney displayed compensatory hypertrophy, along with glomerulosclerosis, tubular dilation, tubular casts, and interstitial fibrosis. CONCLUSION: Renal artery coil embolization proved effective and safe for establishing a CKD model in rabbits.

Octenidine exposure was not associated with reduced Octenidine susceptibility of meticillin-resistant Staphylococcus aureus (MRSA) in an extended-care facility in Singapore.

OBJECTIVES: Antiseptics such as chlorhexidine gluconate (CHG) and octenidine dihydrochloride (OCT) are frequently used in hospitals to prevent and control meticillin-resistant Staphylococcus aureus (MRSA) transmission. With increasing prevalence of reduced CHG susceptibility of MRSA, concerns are raised about the possibility of reduced OCT susceptibility. Hence, we evaluated the prevalence of reduced CHG and OCT susceptibility over 3 years and assessed the association between exposure to OCT and MRSA reduced susceptibility to OCT. METHODS: MRSA isolates from inpatients who acquired MRSA in an extended-care facility from 2019 to 2021, were included for antiseptic susceptibility testing. Inpatients were exposed to universal daily CHG bathing from January to September 2019, and universal daily OCT bathing after October 2019. The minimum inhibitory concentrations (MICs) were determined by broth microdilution method. Multivariable logistic regression was used to assess if exposure to OCT bathing was independently associated with reduced OCT susceptibility. RESULTS: Of 186 isolates, 179 (96%) had reduced CHG susceptibility (MIC ≥4 mg/L) whilst 46 (25%) had reduced OCT susceptibility (MIC ≥2 mg/L). OCT reduced susceptibility rates were 26.9%, 13.8% and 14.3% in 2019, 2020 and 2021, respectively. CHG reduced susceptibility rates were 95.4%, 100% and 95.9% in 2019, 2020 and 2021, respectively. OCT exposure was not associated with reduced OCT susceptibility (adjusted odds ratio [aOR] 0.23, 95% confidence interval [CI] 0.08 - 0.75, p 0.014), after adjusting for age, gender, race, sample collection year, days-at-risk in facility, past hospitalisation and previous MRSA in the preceding year. CONCLUSION: The prevalence of reduced OCT susceptibility has remained low, despite universal OCT bathing for extended inpatient care. However, CHG reduced susceptibility rates were high. OCT exposure was not associated with reduced OCT susceptibility in MRSA.

Sublethal effect and detoxifying metabolism of metaflumizone and indoxacarb on the fall armyworm, Spodoptera frugiperda.

The fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith) (Lepidoptera, Noctuidae), is a highly polyphagous invasive pest that damages various crops. Pesticide control is the most common and effective strategy to control FAW. In this study, we evaluated the toxicity of metaflumizone and indoxacarb against third-instar FAW larvae using the insecticide-incorporated artificial diet method under laboratory conditions. Both metaflumizone and indoxacarb exhibited substantial toxicity against FAW, with LC50 values of 2.43 and 14.66 mg/L at 72 h, respectively. The sublethal effects of metaflumizone and indoxacarb on parental and F1 generation FAW were investigated by exposing third-instar larvae to LC10 and LC30 concentrations of these insecticides. Sublethal exposure to these two insecticides significantly shortened adult longevity, extended pupal developmental times and led to reduced pupal weight, pupation rates, and adult fecundity in the treated parental generation and F1 generation at LC10 or LC30 concentrations, in comparison to the control group. The larval developmental times were shortened in the parental generation but prolonged in the F1 generation, after being treated with sublethal concentrations of metaflumizone. Furthermore, larvae exposed to LC10 or LC30 concentrations of indoxacarb exhibited elevated activity levels of cytochrome P450 monooxygenase and glutathione S-transferase, which coincides with the observed synergistic effect of piperonyl butoxide and diethyl maleate. In conclusion, the high toxicity and negative impact of metaflumizone and indoxacarb on FAW provided significant implications for the rational utilization of insecticides against this pest.

Mal de Meleda.

This case report describes diffuse waxy palmoplantar hyperkeratosis in a symmetrically well-demarcated "gloves and socks" distribution with nail dystrophy.

Epidemiology of Murine Typhus in Taiwan from 2013 to 2020.

Murine typhus is a flea-borne disease caused by Rickettsia typhi infection. The disease is a notifiable infectious disease in Taiwan. Specimens from suspected cases are required to be sent to the Taiwan Centers for Disease Control and Prevention for laboratory diagnosis. In this study, 204 cases of murine typhus were identified by bacterial isolation, real-time polymerase chain reaction, or indirect immunofluorescence assay between 2013 and 2020. The average incidence rate was 0.11/100,000 person-years (95% CI: 0.08-0.13). Murine typhus occurred throughout the year, but it was most prevalent in summer (May to August). The majority of patients were males (75%), residents of Kaohsiung city (31%), and worked in agriculture, forestry, fishing, and animal husbandry (27%). Fever was the most common symptom, present in 95.6% of patients, followed by headache (41%), myalgia (33%), and liver dysfunction (33%). Only 13% of patients had a rash. Up to 80% of cases were among hospitalized patients, and 43% of patients developed severe manifestations. Serological assays also indicated coinfection events. Seven patients showed a 4-fold increase in antibody titers against Orientia tsutsugamushi (N = 2), Coxiella burnetii (n = 2), and Leptospira (N = 3). In conclusion, murine typhus is an endemic and important zoonotic rickettsial disease in Taiwan that cannot be ignored. Further epidemiological surveillance and clinical characteristics should be continuously investigated to prevent and control murine typhus.

Artificial Modulation and Rewiring of Cell Cycle Progression Using Synthetic Circuits in Fission Yeast.

Cell cycle control is a central aspect of the biology of proliferating eukaryotic cells. However, progression through the cell cycle relies on a highly complex network, making it difficult to unravel the core design principles underlying the mechanisms that sustain cell proliferation and the ways in which they interact with other cellular pathways. In this context, the use of a synthetic approach to simplify the cell cycle network in unicellular genetic models such as fission yeast has opened the door to studying the biology of proliferating cells from unique perspectives. Here, we provide a series of methods based on a minimal cell cycle module in the fission yeast Schizosaccharomyces pombe that allows for an unprecedented artificial control of cell cycle events, enabling the rewiring and remodeling of cell cycle progression.

Ipsilateral lower limb motor performance and its association with gait after stroke.

BACKGROUND AND PURPOSE: Motor deficits of the ipsilateral lower limb could occur after stroke and may be associated with walking performance. This study aimed to determine whether the accuracy and movement path of targeted movement in the ipsilateral lower limb would be impaired in the chronic stage of stroke and whether this impairment would contribution to gait. METHODS: Twenty adults with chronic stroke and 20 age-matched controls went through Mini Mental Status Examination (MMSE), and a series of sensorimotor tests. The targeted movement tasks were to place the big toe ipsilateral to the lesion at an external visual target (EXT) or a proprioceptive target (PRO, contralateral big toe) with eyes open (EO) or closed (EC) in a seated position. A motion analysis system was used to obtain the data for the calculation of error distance, deviation from a straight path, and peak toe-height during the targeted movement tasks and gait velocity, step length, step width and step length symmetry of the lower limb ipsilateral to the brain lesion during walking. RESULTS: The stroke group had significantly lower MMSE and poorer visual acuity on the ipsilateral side, but did not differ in age or other sensorimotor functions when compared to the controls. For the targeted movement performance, only the deviation in PRO-EC showed significant between-group differences (p = 0.02). Toe-height in both EXT-EO and in PRO-EO was a significant predictor of step length (R2 = 0.294, p = 0.026) and step length symmetry (R2 = 0.359, p = 0.014), respectively. DISCUSSION AND CONCLUSIONS: The performance of ipsilateral lower limb targeted movement could be impaired after stroke and was associated with step length and its symmetry. The training of ipsilateral targeted movement with unseen proprioceptive target may be considered in stroke rehabilitation.

TIM22 and TIM29 inhibit HBV replication by up-regulating SRSF1 expression.

Hepatitis B virus (HBV) infection is a serious global health problem. After the viruses infect the human body, the host can respond to the virus infection by coordinating various cellular responses, in which mitochondria play an important role. Evidence has shown that mitochondrial proteins are involved in host antiviral responses. In this study, we found that the overexpression of TIM22 and TIM29, the members of the inner membrane translocase TIM22 complex, significantly reduced the level of intracellular HBV DNA and RNA and secreted HBV surface antigens and E antigen. The effects of TIM22 and TIM29 on HBV replication and transcription is attributed to the reduction of core promoter activity mediated by the increased expression of SRSF1 which acts as a suppressor of HBV replication. This study provides new evidence for the critical role of mitochondria in the resistance of HBV infection and new targets for the development of treatment against HBV infection.

A longitudinal epidemiology study of fluoroquinolone-nonsusceptible Klebsiella pneumoniae reveals an increasing prevalence of qnrB and qnrS in Taiwan.

BACKGROUND: Our objective was to investigate the prevalence of plasmid-mediated quinolone resistance (PMQR) genes in fluoroquinolone-nonsusceptible Klebsiella pneumoniae (FQNSKP) in Taiwan, 1999-2022. METHODS: A total of 938 FQNSKP isolates were identified from 1966 isolates. The presence of PMQR and virulence genes, antimicrobial susceptibility, capsular types, and PMQR-plasmid transferability were determined. RESULTS: An increasing number of PMQR-containing FQNSKP isolates were observed over the study period. Our results showed that 69.0% (647 isolates) of FQNSKP isolates contained at least one PMQR gene, and 40.6%, 37.0%, and 33.9% of FQNSKP carried aac(6')-Ib-cr, qnrB, and qnrS, respectively. None of FQNSKP carried qepA and qnrC. The most common combination of PMQR genes was aac(6')-Ib-cr and qnrB (12.3%). The presence of PMQR genes is strongly related to resistance to aminoglycoside, cephalosporin, tetracycline, and sulfamethoxazole/trimethoprim in FQNSKP. The capsular serotype K64 is the most common serotype we tested in both the non-PMQR and PMQR FQNSKP isolates, while K20 showed a higher prevalence in PMQR isolates. The magA and peg-344 genes showed a significantly higher prevalence rate in non-PMQR isolates than in PMQR isolates. Eleven isolates that carried the PMQR and carbapenemase genes were identified; however, three successful transconjugants showed that the PMQR and carbapenemase genes were not located on the same plasmid. CONCLUSIONS: Our results indicated an increasing prevalence of PMQR genes, especially qnrB and qnrS, in FQNSKP in Taiwan. Moreover, the distribution of PMQR genes was associated with capsular serotypes and antimicrobial resistance gene and virulence gene distribution in FQNSKP.

Diastereodivergent α-Homoallylation of Cyclic Enones.

α,ß-Unsaturated carbonyls are essential structural motifs for nucleophiles of disease-related proteins. Methods for stereoselective functionalizations at the α-position include the Morita-Baylis-Hillman, Negishi, Sonogashira, Stille, and Rauhut-Currier reactions. Described here is a method for the diastereodivergent α-homoallylation of cyclic enones via a sequence of conjugate addition, aldol condensation, and diastereoselective [3,3]-sigmatropic rearrangement. Mechanistic investigations revealed that the [3,3]-sigmatropic rearrangement proceeds with transfer of chirality. These inspire a photocatalyzed olefin isomerization of the aldol condensation product leading to a highly diastereoselective [3,3]-sigmatropic rearrangement to furnish the α-homoallylation of cyclic enones. Importantly, this photocatalyzed olefin isomerization/diastereoselective [3,3]-sigmatropic rearrangement reaction sequence permits a full stereocontrol of the exo-ß-position featuring an allyl group as a synthetic functional handle.

Fine mapping and analysis of candidate genes for qBT2 and qBT7.2 locus controlling bolting time in radish (Raphanus sativus L.).

KEY MESSAGE: Two major QTLs for bolting time in radish were mapped to chromosome 02 and 07 in a 0.37 Mb and 0. 52 Mb interval, RsFLC1 and RsFLC2 is the critical genes. Radish (Raphanus sativus L.) is an important vegetable crop of Cruciferae. The premature bolting and flowering reduces the yield and quality of the fleshy root of radish. However, the molecular mechanism underlying bolting and flowering in radish remains unknown. In YZH (early bolting) × XHT (late bolting) F2 population, a high-density genetic linkage map was constructed with genetic distance of 2497.74 cM and an average interval of 2.31 cM. A total of nine QTLs for bolting time and two QTLs for flowering time were detected. Three QTLs associated with bolting time in radish were identified by QTL-seq using radish GDE (early bolting) × GDL (late bolting) F2 population. Fine mapping narrowed down qBT2 and qBT7.2 to an 0.37 Mb and 0.52 Mb region on chromosome 02 and 07, respectively. RNA-seq and qRT-PCR analysis showed that RsFLC1 and RsFLC2 were the candidate gene for qBT7.2 and qBT2 locus, respectively. Subcellular localization exhibited that RsFLC1 and RsFLC2 were mainly expressed in the nucleus. A 1856-bp insertion in the first intron of RsFLC1 was responsible for bolting time. Overexpression of RsFLC2 in Arabidopsis was significantly delayed flowering. These findings will provide new insights into the exploring the molecular mechanism of late bolting and promote the marker-assisted selection for breeding late-bolting varieties in radish.

A novel mucosal bivalent vaccine of EV-A71/EV-D68 adjuvanted with polysaccharides from Ganoderma lucidum protects mice against EV-A71 and EV-D68 lethal challenge.

BACKGROUND: Human enteroviruses A71 (EV-A71) and D68 (EV-D68) are the suspected causative agents of hand-foot-and-mouth disease, aseptic meningitis, encephalitis, acute flaccid myelitis, and acute flaccid paralysis in children. Until now, no cure nor mucosal vaccine existed for EV-A71 and EV-D68. Novel mucosal bivalent vaccines are highly important for preventing EV-A71 and EV-D68 infections. METHODS: In this study, formalin-inactivated EV-A71 and EV-D68 were used as antigens, while PS-G, a polysaccharide from Ganoderma lucidum, was used as an adjuvant. Natural polysaccharides have the characteristics of intrinsic immunomodulation, biocompatibility, low toxicity, and safety. Mice were immunized intranasally with PBS, EV-A71, EV-D68, or EV-A71 + EV-D68, with or without PS-G as an adjuvant. RESULTS: The EV-A71 + EV-D68 bivalent vaccine generated considerable EV-A71- and EV-D68-specific IgG and IgA titres in the sera, nasal washes, saliva, bronchoalveolar lavage fluid, and feces. These antibodies neutralized EV-D68 and EV-A71 infectivity. They also cross-neutralized infections by different EV-D68 and EV-A71 sub-genotypes. Furthermore, compared with the PBS group, EV-A71 + EV-D68 + PS-G-vaccinated mice exhibited an increased number of EV-D68- and EV-A71-specific IgA- and IgG-producing cells. In addition, T-cell proliferative responses, and IFN-γ and IL-17 secretion in the spleen were substantially induced when PS-G was used as an adjuvant with EV-A71 + EV-D68. Finally, in vivo challenge experiments demonstrated that the immune sera induced by EV-A71 + EV-D68 + PS-G conferred protection in neonate mice against lethal EV-A71 and EV-D68 challenges as indicated by the increased survival rate and decreased clinical score and viral RNA tissue expression. Taken together, all EV-A71/EV-D68 + PS-G-immunized mice developed potent specific humoral, mucosal, and cellular immune responses to EV-D68 and EV-A71 and were protected against them. CONCLUSIONS: These findings demonstrated that PS-G can be used as a potential adjuvant for EV-A71 and EV-D68 bivalent mucosal vaccines. Our results provide useful information for the further preclinical and clinical development of a mucosal bivalent enterovirus vaccine against both EV-A71 and EV-D68 infections.

Stent fracture after transjugular intrahepatic portosystemic shunt placement using the bare metal stent/stent-graft combination technique.

BACKGROUND: A transjugular intrahepatic portosystemic shunt (TIPS) is widely placed to treat portal hypertension. Because the Viatorr® stent (W. L. Gore and Associates, Flagstaff, AZ, United States) is not available in all hospitals in China, the bare metal stent (BMS)/stent-graft combination technique is still popular for TIPS construction. Stent fracture is a complication after TIPS placement using this technique, with limited available literature focusing on it. AIM: To assess the incidence of stent fracture after TIPS placement using the BMS/ stent-graft combination technique and to identify the risk factors for stent fracture. We proposed technique modifications to improve the clinical results of TIPS placement with the BMS/stent-graft combination technique. METHODS: We retrospectively analyzed the computed tomography (CT) data of all patients with portal hypertension who underwent the TIPS procedure between June 2011 and December 2021 in a single center. Patients implanted with the BMS/stent graft and had follow-up imaging data available were included. We identified patients with stent fracture and analyzed their characteristics. Multivariable logistic regression was applied to identify the potential predictors of stent fracture. RESULTS: Of the 68 included patients, stent fracture occurred in seven (10.3%) patients. Based on CT images, the stent fractures were categorized into three types. Our study consisted of four (57.1%) type I fractures, one (14.3%) type II fracture, one (14.3%) type IIIa fracture, and one (14.3%) type IIIb fracture. After adjusting for covariates, multivariable logistic regression revealed that the risk factors for stent fracture were the implantation of a greater number of stents [adjusted odds ratio (aOR) = 22.2, 95% confidence interval (CI): 1.2-415.4, P = 0.038] and a larger proximal sagittal stent bending angle (aOR = 1.1, 95%CI: 1.0-1.3, P = 0.020). CONCLUSION: Stent fracture occurred in approximately 10% of patients with portal hypertension who underwent TIPS with the BMS/stent-graft combination technique. The number of implanted stents and stent bending angle at the inferior vena cava end were predictors of stent fracture, which suggests that the incidence of stent fracture could potentially be reduced by procedural modifications.

Single-cell and spatial architecture of primary liver cancer.

Primary liver cancer (PLC) poses a leading threat to human health, and its treatment options are limited. Meanwhile, the investigation of homogeneity and heterogeneity among PLCs remains challenging. Here, using single-cell RNA sequencing, spatial transcriptomic and bulk multi-omics, we elaborated a molecular architecture of 3 PLC types, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC). Taking a high-resolution perspective, our observations revealed that CHC cells exhibit internally discordant phenotypes, whereas ICC and HCC exhibit distinct tumor-specific features. Specifically, ICC was found to be the primary source of cancer-associated fibroblasts, while HCC exhibited disrupted metabolism and greater individual heterogeneity of T cells. We further revealed a diversity of intermediate-state cells residing in the tumor-peritumor junctional zone, including a congregation of CPE+ intermediate-state endothelial cells (ECs), which harbored the molecular characteristics of tumor-associated ECs and normal ECs. This architecture offers insights into molecular characteristics of PLC microenvironment, and hints that the tumor-peritumor junctional zone could serve as a targeted region for precise therapeutical strategies.

Emerging trends in clinical research on Janus kinase inhibitors for atopic dermatitis treatment.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects millions of people worldwide, characterized by immune function imbalance and impaired epidermal barrier function. It is a complex disorder that involves multiple pathogenic pathways, including the JAK/STAT signaling pathway, which plays a critical role in regulating immune and inflammatory responses. The therapeutic potential of Janus kinase inhibitors (JAKi) in the management of atopic dermatitis (AD) has garnered significant interest in recent years. AD is a chronic inflammatory skin condition characterized by impaired epidermal barrier function and immune function imbalance, and its pathogenesis is closely associated with dysregulated JAK/signal transducer and activator of transcription (STAT) signaling pathways. JAKi offer a novel therapeutic approach by selectively inhibiting JAK enzymes, thereby blocking downstream STAT signaling and preventing the expression of cytokines involved in AD pathogenesis. This review will focus on several JAKi including tofacitinib, baricitinib, ruxolitinib and upadacitinib, and provide a comprehensive overview of the latest research on the application of JAKi in AD treatment, including its mechanism of action, clinical trial results and safety profile.

MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway.

The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8+ effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3+ macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies.

A 24-year longitudinal study of Klebsiella pneumoniae isolated from patients with bacteraemia and urinary tract infections reveals the association between capsular serotypes, antibiotic resistance, and virulence gene distribution.

Longitudinal studies on the variations of phenotypic and genotypic characteristics of K. pneumoniae across two decades are rare. We aimed to determine the antimicrobial susceptibility and virulence factors for K. pneumoniae isolated from patients with bacteraemia or urinary tract infection (UTI) from 1999 to 2022. A total of 699 and 1,267 K. pneumoniae isolates were isolated from bacteraemia and UTI patients, respectively, and their susceptibility to twenty antibiotics was determined; PCR was used to identify capsular serotypes and virulence-associated genes. K64 and K1 serotypes were most frequently observed in UTI and bacteraemia, respectively, with an increasing frequency of K20, K47, and K64 observed in recent years. entB and wabG predominated across all isolates and serotypes; the least frequent virulence gene was htrA. Most isolates were susceptible to carbapenems, amikacin, tigecycline, and colistin, with the exception of K20, K47, and K64 where resistance was widespread. The highest average number of virulence genes was observed in K1, followed by K2, K20, and K5 isolates, which suggest their contribution to the high virulence of K1. In conclusion, we found that the distribution of antimicrobial susceptibility, virulence gene profiles, and capsular types of K. pneumoniae over two decades were associated with their clinical source.

Evaluation of NG-Test CARBA 5 version 2, Cepheid Xpert Carba-R, and carbapenem inactivation methods in comparison to whole-genome sequencing for the identification of carbapenemases in non-fermenting Gram-negative bacilli.

NG-Test CARBA 5 (NG-Biotech) is a rapid in vitro multiplex immunoassay for the phenotypic detection and differentiation of the "big five" carbapenemase families (KPC, OXA-48-like, VIM, IMP, and NDM). Version 2 of this assay was evaluated alongside the Xpert Carba-R assay (Cepheid, Inc.), the modified carbapenem inactivation method (mCIM), and the CIMTris assay, with a collection of carbapenem-resistant non-fermenting Gram-negative bacilli comprising 138 Pseudomonas aeruginosa and 97 Acinetobacter baumannii isolates. Whole-genome sequencing (WGS) was used as the reference standard. For P. aeruginosa, NG-Test CARBA 5 produced an overall percentage agreement (OPA) with WGS of 97.1%, compared with 92.8% forXpert Carba-R and 90.6% for mCIM. For A. baumannii, as OXA-type carbapenemases (non-OXA-48) are not included, both the NG-Test CARBA 5 and Xpert Carba-R only had an OPA of 6.2%, while the CIMTris performed well with an OPA of 99.0%. The majority of A. baumannii isolates (95.9%) tested falsely positive for IMP on NG-Test CARBA 5; no IMP genes were found on WGS. No clear cause was found for this phenomenon; a cross-reacting protein antigen unique to A. baumannii is a possible culprit. NG-Test CARBA 5 performed well for carbapenemase detection in P. aeruginosa. However, results from A. baumannii isolates should be interpreted with caution.