Global incidence trends of early-onset colorectal cancer and related exposures in early-life: an ecological analysis based on the GBD 2019.

Background: The incidence of early-onset colorectal cancer (EOCRC) is increasing globally. This study aims to describe the temporal trends of incidence and explore related risk exposures in early-life at the country level based on the GBD 2019. Methods: Data on the incidence and attributable risk factors of EOCRC were obtained from the GBD 2019. Temporal trends of age-standardized incidence were evaluated by average annual percentage change (AAPC). Early-life exposures were indicated as summary exposure values (SEV) of selected factors, SDI and GDP per capita in previous decades and at ages 0-4, 5-9, 10-14 and 15-19 years. Weighted linear or non-linear regressions were applied to evaluate the ecological aggregate associations of the exposures with incidences of EOCRC. Results: The global age-standardized incidence of EOCRC increased from 3.05 (3.03, 3.07) to 3.85 (3.83, 3.86) per 100,000 during 1990 and 2019. The incidence was higher in countries with high socioeconomic levels, and increased drastically in countries in East Asia and Caribbean, particularly Jamaica, Saudi Arabia and Vietnam. The GDP per capita, SDI, and SEVs of iron deficiency, alcohol use, high body-mass index, and child growth failure in earlier years were more closely related with the incidences of EOCRC in 2019. Exposures at ages 0-4, 5-9, 10-14 and 15-19 years were also associated with the incidences, particularly for the exposures at ages 15-19 years. Conclusion: The global incidence of EOCRC increased during past three decades. The large variations at regional and national level may be related with the distribution of risk exposures in early life.

The short-term effects of Jin's three needles in conjunction with mirror therapy on brain function in patients with upper limb disability following an ischemic stroke were evaluated using ReHo analysis.

BACKGROUND: Jin's three needle (JTN) is a commonly utilized treatment for ischemic stroke in China. Mirror therapy (MT) is also gradually transitioning from treating limb discomfort to restoring motor function in the damaged limb. Investigations into the 2 treatments' mechanisms of action are still ongoing. We used functional magnetic resonance imaging (fMRI) technique in this study to examine the effects of JTN combined with mirror therapy MT on brain function in patients with upper limb dysfunction in ischemic stroke, as well as potential central mechanisms. The goal was to provide a solid evidence-based medical basis to support the continued use of JTN combination MT. METHODS: This study will be a single-blind, randomized, and controlled experiment. Randomization was used to assign 20 patients who met the study's eligibility requirements to the JTN + MT treatment group or the JTN control group. Each intervention will last for 4 weeks, with 6 days of treatment per week. The JTN acupuncture points are 3 temporal acupuncture points on the opposite side of the wounded limb, 3 hand acupuncture points on the injured upper limb, 3 shoulder acupuncture points, Renzhong and Baihui, The (JTN + MT) group simultaneously takes MT for 30 minutes. fMRI of the brain using BOLD and T1-weighted images was done both before and after therapy. Brain areas exhibiting changes in regional homogeneity during the pre and posttreatment periods were analyzed. RESULTS: By the end of the treatment course, Jin three-needle therapy plus MT activated more relevant brain functional regions and increased cerebral blood oxygen perfusion than Jin three-needle therapy alone (P <.05). CONCLUSION: In patients with upper limb impairment following an ischemic stroke, JTN with MT may improve brain function reconstruction in the relevant areas.

Association between spectrum of mycotoxins and semen quality: A cross-sectional study in Beijing, China.

Exposure to mycotoxins is unavoidable in daily life through ingestion, dermal, and inhalation routes. Toxicological studies found that exposure to mycotoxins might affect male reproductive function. However, there is still a lack of population evidence. We aimed to assess the association of individual and joint exposure to spectrum of mycotoxins with semen quality. The present study included 192 participants in Beijing, China. We measured conventional semen parameters and assessed semen quality. Sixty-seven traditional or emerging mycotoxins were determined to describe the spectrum of mycotoxins. The participants were widely exposed to multiple mycotoxins, and nearly half were simultaneously exposed to more than six mycotoxins. After adjusting potential confounders, logistic regression indicated that the number and concentration of plasma mycotoxin were correlated to the risk of low semen quality. Plasma beauvericin and citrinin concentrations were associated with lower semen quality. The least absolute shrinkage and selection operator regression showed similar results to logistic regression. Quantile-based g-computation and Bayesian kernel machine regression models found that the mixture of mycotoxins was harmful to semen quality, especially in sperm motility. In conclusion, both individual and mixture of mycotoxin exposure were correlated with lower semen quality. More regulations and measures should be taken to reduce mycotoxin contamination.

Single-cell transcriptomic analysis identifies downregulated phosphodiesterase 8B as a novel oncogene in IDH-mutant glioma.

Introduction: Glioma, a prevalent and deadly brain tumor, is marked by significant cellular heterogeneity and metabolic alterations. However, the comprehensive cell-of-origin and metabolic landscape in high-grade (Glioblastoma Multiforme, WHO grade IV) and low-grade (Oligoastrocytoma, WHO grade II) gliomas remains elusive. Methods: In this study, we undertook single-cell transcriptome sequencing of these glioma grades to elucidate their cellular and metabolic distinctions. Following the identification of cell types, we compared metabolic pathway activities and gene expressions between high-grade and low-grade gliomas. Results: Notably, astrocytes and oligodendrocyte progenitor cells (OPCs) exhibited the most substantial differences in both metabolic pathways and gene expression, indicative of their distinct origins. The comprehensive analysis identified the most altered metabolic pathways (MCPs) and genes across all cell types, which were further validated against TCGA and CGGA datasets for clinical relevance. Discussion: Crucially, the metabolic enzyme phosphodiesterase 8B (PDE8B) was found to be exclusively expressed and progressively downregulated in astrocytes and OPCs in higher-grade gliomas. This decreased expression identifies PDE8B as a metabolism-related oncogene in IDH-mutant glioma, marking its dual role as both a protective marker for glioma grading and prognosis and as a facilitator in glioma progression.

Correction: Phosphorescent [3 + 2 + 1] coordinated Ir(iii) cyano complexes for achieving efficient phosphors and their application in OLED devices.

[This corrects the article DOI: 10.1039/D1SC01426A.].

Mid-Infrared Photoacoustic Stimulation of Neurons through Vibrational Excitation in Polydimethylsiloxane.

Photoacoustic (PA) emitters are emerging ultrasound sources offering high spatial resolution and ease of miniaturization. Thus far, PA emitters rely on electronic transitions of absorbers embedded in an expansion matrix such as polydimethylsiloxane (PDMS). Here, it is shown that mid-infrared vibrational excitation of C─H bonds in a transparent PDMS film can lead to efficient mid-infrared photoacoustic conversion (MIPA). MIPA shows 37.5 times more efficient than the commonly used PA emitters based on carbon nanotubes embedded in PDMS. Successful neural stimulation through MIPA both in a wide field with a size up to a 100 µm radius and in single-cell precision is achieved. Owing to the low heat conductivity of PDMS, less than a 0.5 °C temperature increase is found on the surface of a PDMS film during successful neural stimulation, suggesting a non-thermal mechanism. MIPA emitters allow repetitive wide-field neural stimulation, opening up opportunities for high-throughput screening of mechano-sensitive ion channels and regulators.

A comparative analysis of different reduced-port laparoscopic surgical procedures after non-curative endoscopic resection for early colorectal cancer.

Introduction: Surgery serves as a salvage procedure for non-curative resection of early-stage colorectal cancer under endoscopy. A standard method for performing additional surgery after endoscopic submucosal dissection (ESD) for early colorectal cancer has yet to be established. Aim: To enhance the understanding of different surgical outcomes by discussing additional treatment strategies following non-complete curative endoscopic resection of early colorectal cancer. Material and methods: This retrospective study included 88 patients who were divided into three groups based on the surgical approach: conventional laparoscopic surgery (CLS), single-incision plus one-port laparoscopic surgery (SILS+1), and three-port laparoscopic surgery combined with natural orifice specimen extraction surgery (three-port NOSES). The study aimed to compare the surgical outcomes, safety, and postoperative recovery among these groups. Results: The SILS+1 and three-port NOSES groups demonstrated comparable safety and efficacy to the CLS group in terms of blood loss, complications, number of lymph node dissections, and length of bowel resection. However, the SILS+1 and three-port NOSES groups had advantages in terms of incision length (7.11 ±0.38, 4.24 ±0.33, 3.16 ±0.22, p < 0.001), postoperative pain (4.000 [3.0,5.0], 3.500 [3.0,4.0], 3.000 [3.0,4.0]; p = 0.003), cosmetic result (4.000 [3.8,5.0], 7.000 [7.0,8.0], 7.000 [7.0,8.0]; p < 0.001), and hospital stay (8.000 [7.0,9.0], 7.000 [6.3,8.0.], 7.000 [6.3,8.0]; p = 0.035). Conclusions: Different strategies of reduced-port laparoscopic surgery have been demonstrated to be effective and safe in additional surgery after non-curative ESD. These techniques have shown reduced pain and increased satisfaction among patients. Reduced-port laparoscopic surgery is expected to become the preferred treatment option for these patients.

Epigenetically associated IGF2BP3 upregulation promotes cell proliferation by regulating E2F1 expression in hepatocellular carcinoma.

RNA-binding proteins (RBPs) are a class of proteins that primarily function by interacting with different types of RNAs and play a critical role in regulating the transcription and translation of cancer-related genes. However, their role in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we analyzed RNA sequencing data and the corresponding clinical information of patients with HCC to screen for prognostic RBPs. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was identified as an independent prognostic factor for liver cancer. It is upregulated in HCC and is associated with a poor prognosis. Elevated IGF2BP3 expression was validated via immunohistochemical analysis using a tissue microarray of patients with HCC. IGF2BP3 knockdown inhibited the proliferation of Hep3B and HepG2 cells, whereas IGF2BP3 overexpression promoted the expansion of HuH-7 and MHCC97H cells. Mechanistically, IGF2BP3 modulates cell proliferation by regulating E2F1 expression. DNA hypomethylation of the IGF2BP3 gene may increase the expression of IGF2BP3, thereby enhancing cell proliferation in HCC. Therefore, IGF2BP3 may act as a novel prognostic biomarker and a potential therapeutic target for HCC.

Prognostic Understanding, Goals of Care, and Quality of Life in Hospitalized Patients with Leukemia or Multiple Myeloma.

Background: Prior studies reveal a lack of illness understanding and prognostic awareness among patients with hematological malignancies. We evaluated prognostic awareness and illness understanding among patients with acute leukemia and multiple myeloma (MM) and measured patient-hematologist discordance. Methods: We prospectively enrolled patients with acute leukemia and MM at Mount Sinai Hospital or Yale New Haven Hospital between August 2015 and February 2020. Patients were administered a survey assessing prognostic awareness, goals of care (GOC), and quality of life. Hematologists completed a similar survey for each patient. We assessed discordance across the cohort of patients and hematologists using the likelihood-ratio chi-square test and within patient-hematologist pairs using the kappa (κ) statistic. Results: We enrolled 185 patients (137 with leukemia and 48 with MM) and 29 hematologists. Among patients, 137 (74%) self-identified as White, 27 (15%) as Black, and 21 (11%) as Hispanic. Across the entire cohort, patients were significantly more optimistic about treatment goals compared with hematologists (p = 0.027). Within patient-hematologist pairs, hematologists were significantly more optimistic than patients with respect to line of treatment (κ = 0.03). For both leukemia and MM cohorts, patients were significantly more likely to respond "don't know" or deferring to a faith-based response with 88 (64%) and 34 (71%), respectively, compared with only 28 (20%) and 11 (23%) of hematologists, respectively. Conclusions: We observed significant discordance regarding prognosis and GOC among patients with hematological malignancies and their hematologists. These data support future interventions to improve prognostic understanding among this patient population to facilitate informed treatment choices.

Effects of the thiol methyltransferase inhibitor DCMB on the pharmacokinetics and metabolism of vicagrel in rats.

P2Y12 receptor inhibitors are commonly used in clinical antiplatelet therapy, typically alongside other medications. Vicagrel, a promising P2Y12 receptor inhibitor, has submitted a new drug marketing application to the U.S. FDA. Its primary metabolites and some metabolic pathways are identical to those of clopidogrel. The aim of this study was to investigate the effects of the thiol methyltransferase inhibitor ({plus minus})-2,3-dichloro-α-methylbenzylamine (DCMB) on the metabolism and pharmacokinetics of vicagrel. In vitro incubation with human and rat liver microsomes revealed that DCMB significantly inhibited the methylation of vicagrel's thiol metabolite M15-1. Rats were orally administered 6 mg/kg [14C]vicagrel (100 µCi/kg) 1 h after peritoneal injection with or without DCMB (80 mg/kg). Compared to the control group, the plasma of DCMB-pretreated rats exhibited C max decrease and T max delay for all vicagrel-related substances, the methylation product of the thiol metabolite (M9-2) and the derivatization product of the active thiol metabolite (MP-M15-2). However, no significant changes in AUC or t 1/2 were observed. DCMB had negligible effect on the total radiological recovery of vicagrel within 72 h, although the rate of vicagrel excretion slowed down within 48 h. DCMB had a negligible impact on the metabolic pathway of vicagrel. Overall, the present study found that DCMB did not significantly affect the total exposure, metabolic pathways, metabolite profiles, or total excretion rates of vicagrel-related metabolites in rats, but led to C max decrease, T max delay, and slower excretion rate within 48 h. Significance Statement This study used LC-MS/MS combined with radiolabeling technology to investigate the effects of the TMT inhibitor DCMB on the absorption, metabolism and excretion of vicagrel in rats. This work helps to better understand the in vivo metabolism of active thiol metabolites of P2Y12 inhibitors such as clopidogrel and vicagrel, etc.

Independent Configuration and Reprogramming of Porous Characters in Macroporous Hydrogel Enabled by the Orthogonal Dynamic Network.

Macroporous hydrogels have attracted much attention in both industry and academia, where the morphological characteristics of pores are essential. Despite significant improvements on regulating porous structures, the independent configuration and reprogramming of porosity and pore size still remain challenging owing to the lack of a chemical design to decouple the mechanism for adjusting each characteristic. Here, we report a strategy to adaptively control porous features relying on an orthogonal dynamic network. Disulfide bonds are employed to relax polymer chains during freezing via UV irradiation, thus, generating pores in hydrogels. On such a basis, the porosity is continuously switched from 0 to 75% by controlling network relaxation ratios. Subsequently, the pore size is further reversibly manipulated through the association or dissociation of dynamic metallic coordination. As a result, the porosity and pore size achieved independent configurations. Meanwhile, the dynamic nature of the network makes it possible to reprogram the porous character of a prepared hydrogel. Beyond these, the photopatterning of pores represents the capability to regulate the third feature. Our strategy provides an effective way to arbitrarily manipulate porous morphologies, which can inspire the design of future functional porous materials.

Blood-Catalyzed Polymerization Creates Conductive Polymer in Live Zebrafish.

Conducting polymers are of great interest in bioimaging, bio-interfaces, and bioelectronics for their biocompatibility and the unique combination of optical, electrical, and mechanical properties. They are typically prepared outside through traditional organic synthesis and delivered into the biological systems. The ability to call for the polymerization ingredients available inside the living systems to generate conducting polymers in vivo will offer new venues in future biomedical applications. This study is the first report of in vivo synthesis of an n-doped conducting polymer (n-PBDF) within live zebrafish embryos, achieved through whole blood catalyzed polymerization of 3,7-dihydrobenzo[1,2-b:4,5-b']difuran-2,6-dione (BDF). Prior to this, the efficacy of such a polymerization was rigorously established through a sequence of in vitro experiments involving Hemin, Hemoproteins (Hemoglobin, Myoglobin, and Cytochrome C), red blood cells, and the whole blood. Ultimately, in cellulo formed n-PBDF within cultured primary neurons demonstrated enhanced bio-interfaces and led to more effective light-induced neural activation than the prefabricated polymer. This underscores the potential advantages of synthesizing conducting polymers directly in living systems for biomedical applications.

Neuroimmune modulating and energy supporting nanozyme-mimic scaffold synergistically promotes axon regeneration after spinal cord injury.

Spinal cord injury (SCI) represents a profound central nervous system affliction, resulting in irreversibly compromised daily activities and disabilities. SCI involves excessive inflammatory responses, which are characterized by the existence of high levels of proinflammatory M1 macrophages, and neuronal mitochondrial energy deficit, exacerbating secondary damage and impeding axon regeneration. This study delves into the mechanistic intricacies of SCI, offering insights from the perspectives of neuroimmune regulation and mitochondrial function, leading to a pro-fibrotic macrophage phenotype and energy-supplying deficit. To address these challenges, we developed a smart scaffold incorporating enzyme mimicry nanoparticle-ceriumoxide (COPs) into nanofibers (NS@COP), which aims to pioneer a targeted neuroimmune repair strategy, rescuing CGRP receptor on macrophage and concurrently remodeling mitochondrial function. Our findings indicate that the integrated COPs restore the responsiveness of pro-inflammatory macrophages to calcitonin gene-related peptide (CGRP) signal by up-regulating receptor activity modifying protein 1 (RAMP1), a vital component of the CGRP receptor. This promotes macrophage fate commitment to an anti-inflammatory pro-resolution M2 phenotype, then alleviating glial scar formation. In addition, NS@COP implantation also protected neuronal mitochondrial function. Collectively, our results suggest that the strategy of integrating nanozyme COP nanoparticles into a nanofiber scaffold provides a promising therapeutic candidate for spinal cord trauma via rational regulation of neuroimmune communication and mitochondrial function.

Open-ICL: Open-Set Modulation Classification via Incremental Contrastive Learning.

Open-set modulation classification (OMC) of signals is a challenging task for handling "unknown" modulation types that are not included in the training dataset. This article proposes an incremental contrastive learning method for OMC, called Open-ICL, to accurately identify unknown modulation types of signals. First, a dual-path 1-D network (DONet) with a classification path (CLP) and a contrast path (COP) is designed to learn discriminative signal features cooperatively. In the COP, the deep features of the input signal are compared with the semantic feature centers (SFCs) of known classes calculated from the network, to infer its signal novelty. An unknown signal bank (USB) is defined to store unknown signals, and a novel moving intersection algorithm (MIA) is proposed to dynamically select reliable unknown signals for the USB. The "unknown" instances, together with SFCs, are continuously optimized and updated, facilitating the process of incremental learning. Furthermore, a dynamic adaptive threshold (DAT) strategy is proposed to enable Open-ICL to adaptively learn changing signal distributions. Extensive experiments are performed on two benchmark datasets, and the results demonstrate the effectiveness of Open-ICL for OMC.

A gel plaster in the form of nipple cover: A comfortable and safe transdermal delivery method for mammary hyperplasia.

Hyperplasia of mammary glands (HMG) is considered a precancerous condition with a risk of malignant transformation, highlighting the necessity of proactive treatment in the early stages. Transdermal drug delivery offers significant advantages such as painlessness, absence of first-pass effect, and good patient compliance. However, the unique structure of the breast requires transdermal formulations for treating mammary hyperplasia to exhibit higher levels of safety and comfort. We have formulated an ancient topical formula called 'Muxiang Bing,' comprising traditional Chinese medicines Aucklandiae Radix (AR) and Rehmanniae Radix (RR), for the treatment of HMG. This formula has been transformed into a gel paster in the form of nipple cover for trans-nipple-areola delivery. In our investigations, we observed that the optimal formulation of the Muxiang gel plaster demonstrated enhanced permeation facilitated by AR's effect on RR. Furthermore, pre-treatment with the Muxiang gel plaster improved mammary tissue morphology, hormone levels, oxidative stress, aberrant cell proliferation, and damage in rat models, thus preventing and ameliorating mammary hyperplasia. The Muxiang gel plaster exhibited low skin irritability in rats, and long-term use did not cause harm to their internal organs or blood cells, indicating its safety and efficacy.

Tailoring local electron density and molecular oxygen activation behavior via potassium/halogen co-tuned graphitic carbon nitride for enhanced photocatalytic activity.

Graphite carbon nitride (g-C3N4) is a promising photocatalyst,but its inadequate reactive sites, weak visible light responsiveness, and sluggish separation of photogenerated carriers hamperthe improvement of photodegradation efficiency. In this work, potassium (K) and halogen atoms co-modified g-C3N4 photocatalysts (CN-KX, X = F, Cl, Br, I) were constructed to adjust the electrical and band structure for enhanced generation of reactive oxygen species. Through an integration of theoretical calculation and experimental exploration, the doping sites of halogen atoms as well as the evolution of crystal, band, and electronic structures were investigated. The results show that a covalent bond is formed between the F atom and the C atom, substitution of the N atom occurs with a Cl atom, and doping of Br, I, or K atoms takes place at the interstitial site. CN-KX photocatalysts exhibits lower band gap, faster photogenerated electron migration, and enhanced photocatalytic activity. Specifically, the CN-KI photocatalyst exhibits the highest photodegradation efficiency because of its smaller interplanar spacing, formation of the midgap state, and adjustable local electron density. Equally, the doping of I atom not only provides a stable adsorption site for oxygen (O2) but also facilitates electron transfer, promoting the production of superoxide radicals (O2-) and contributing to the process of photodegradation.

Long-term follow-up of eltrombopag treatment for patients with cyclosporin A refractory/relapsed transfusion-dependent non-severe aplastic anemia: A report from a single center in China.

INTRODUCTION: Aplastic anemia (AA) is characterized by bone marrow failure and cytopenia. Eltrombopag (ELT) is effective and safe for treating refractory/relapsed AA; however, reports on the long-term outcomes of transfusion-dependent non-severe AA (TD-NSAA) are limited. METHODS: Patients with TD-NSAA refractory to immunosuppressive therapy (IST) or relapsed after IST, treated with ELT alone, and followed up for at least 12 months were retrospectively enrolled. The baseline characteristics of patients, efficacy and adverse effects of ELT, and relapse and clone evolution rates after ELT were documented. RESULTS: Of the 55 patients with TD-NSAA included, 24 (43.6%) were men. Median age at diagnosis was 46 (19-80) years. Twenty-four patients had relapsed TD-NSAA , and 31 patients had refractory TD-NSAA. During the median follow-up period of 28 (12-48) months, the overall and complete response rates at 3, 6, and 12 months of ELT treatment were 38.2%, 60.0%, and 52.7% and 9.1%, 14.6%, and 9.1%, respectively. After a median follow-up of 28 (12-48) months, 21.2% (7/33) of patients experienced relapse, with a median duration from ELT treatment to relapse of 14 (6-45) months. CONCLUSION: ELT was effective in patients with relapsed/refractory TD-NSAA, with tolerable adverse effects.

The Value of Magnetic Resonance Imaging in Assessing Immediate Efficacy After Microwave Ablation of Lung Malignancies.

PURPOSE: To investigate the imaging performance and parametric analysis of magnetic resonance imaging (MRI) immediately after microwave ablation (MWA) of lung malignancies. MATERIALS AND METHODS: We retrospectively analyzed the MRI performance immediately after MWA of 34 cases of lung malignancies. The ablation zone parameters of lung malignancies were measured, including the long diameter (L), short diameter (S), and safety margin of the ablation zone on plain computed tomography (CT), T1-weighted imaging (T1WI), and T2-weighted imaging (T2WI) after MWA. The study calculated the tumor volume (V0), the ablation zone volume (V1), and the ratio of V0 to V1 (V%). Statistical differences between the parameters were analyzed. RESULTS: The ablation area of the lesion exhibited central low signal and peripheral high signal on T2WI, central high signal and peripheral equal or high signal on T1WI, and circumferential enhancement in the periphery. The safety margin measured on T2WI was greater than that measured on plain CT and T1WI. On plain CT, the L, S, and V1 were smaller in the effective treatment group than in the ineffective treatment group (P<0.05). On T1WI, the V% and safety margin were greater in the effective treatment group than in the ineffective treatment group (P=0.009 and P=0.016, respectively). CONCLUSIONS: MRI may be a new, valuable method to assess immediate efficacy after MWA for lung malignancies using the ablation zone parameters V% on T1WI and safety margin on T2WI.

Nanopore-based targeted next-generation sequencing of tissue samples for tuberculosis diagnosis.

Objective: Diagnosing tuberculosis (TB) can be particularly challenging in the absence of sputum for pulmonary tuberculosis cases and extrapulmonary TB (EPTB). This study evaluated the utility of nanopore-based targeted next-generation sequencing (tNGS) for diagnosing TB in tissue samples, and compared its efficacy with other established diagnostic methods. Methods: A total of 110 tissue samples from clinical cases were examined. The sensitivity and specificity of tNGS were benchmarked against a range of existing diagnostic approaches including hematoxylin and eosin (HE) staining in conjunction with acid-fast bacilli (AFB) detection, HE staining combined with PCR, HE staining paired with immunohistochemistry (IHC) using anti-MPT64, and the Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF) assay. Results: The sensitivity and specificity of tNGS were 88.2 and 94.1%, respectively. The respective sensitivities for HE staining combined with AFB, HE staining combined with PCR, HE staining combined with IHC using anti-MPT64, and Xpert MTB/RIF were 30.1, 49.5, 47.3, and 59.1%. The specificities for these methods were 82.4, 88.2, 94.1, and 94.1%, respectively. Analysis of drug resistance based on tNGS results indicated that 10 of 93 TB patients (10.75%) had potential drug resistance. Conclusion: Targeted next-generation sequencing achieved higher accuracy than other established diagnostic methods, and can play a crucial role in the rapid and accurate diagnosis of TB, including drug-resistant TB.

Development of an effective meropenem/KPC-2 inhibitor combination to combat infections caused by carbapenem-resistant K. pneumoniae.

The global public health threat of bacterial antibiotic resistance continues to escalate and necessitates the implementation of urgent measures to expand our arsenal of antimicrobial drugs. In this study, we identified a benzoxaborane compound, namely 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2178), which can effectively inhibit the catalytic activity of the Klebsiella pneumoniae carbapenemase (KPC-2) enzyme. The efficacy of AN2718 as an inhibitor for the KPC-2 enzyme was verified through various assays, including enzyme activity assays and isothermal titration calorimetry. Results of multiple biochemical assays, minimum inhibitory concentration assay, and time-killing assay also showed that binding of AN2718 to KPC-2 enabled the restoration of the bactericidal effect of meropenem. The survival rate of mice infected by carbapenem-resistant, high-virulence strains increased significantly upon treatment with this agent. Most importantly, the meropenem and AN2718 combination is effective on KPC-2 mutations such as KPC-33 that were clinically evolved and exhibited resistance to ceftazidime-avibactam upon the clinical uses of this drug for a couple of years. Comprehensive safety tests both in vitro and in vivo, such as cytotoxicity, haemolytic activity, and cytochrome P450 inhibition assays demonstrated that AN2718 was safe for clinical use. These promising data indicate that AN2718 has a high potential for being approved for the treatment of drug resistant bacterial infections, including those caused by the Ceftazidime-Avibactam resistant strains. To conclude, the compound AN2718 can be regarded as a valuable addition to the current antimicrobial armamentarium and a promising tool to combat antimicrobial resistance.