BackgroundAlthough fungal infections are relatively rare, they have low detection rates and high mortality rates. The value of metagenomic next-generation sequencing (mNGS) in kidney transplant patients with fungal infections remains insufficiently explored, especially regarding diagnosis and antimicrobial stewardship.MethodsFrom September 2021 to August 2023, 234 kidney transplant patients were enrolled, with detailed data collected on 66 patients suspected of fungal infections. The pathogen detection performance of mNGS and conventional microbiological tests (CMTs) was compared. The impacts of mNGS and CMTs on treatment adjustment were also assessed. Finally, the value of mNGS in detecting donor-derived infections was investigated.ResultsAmong 66 patients, 21 fungal species were identified: 18 species detected by mNGS and 10 by CMTs. The overall positive rate of mNGS was significantly higher than culture (90.67% vs. 26.67%), especially for multiple fungal infections (9vs0). mNGS identified more Candida (26vs12), Pneumocystis jirovecii (14vs0), Aspergillus (10vs4), Mucor (6vs2) organisms compared with CMTs. Donor-derived fungi were identified in 11 (6.7%) patients, including 10 cases of Candida spp. and 1 case of Mucor spp. Anti-infection therapies were adjusted in 28 (24.4%) cases based on mNGS.ConclusionThe mNGS technique showed distinct advantages in detecting fungal infections in kidney transplant patients, facilitating informed anti-infection strategies and enhanced graft protection. Moreover, it provides effective identification of fungal infections originating from donor sources.

Allergic Rhinitis (AR) represents a significant global health challenge with extensive prevalence and profound impacts, necessitating the development of novel therapeutic approaches beyond conventional symptomatic treatment. Emerging research has elucidated the crucial role of nasal microbiota dysbiosis in both the pathogenesis and progression of AR. Although the dominant microbial phyla remain largely consistent, significant changes in microbial abundance, composition, and diversity are often observed. In addition, studies have shown a correlation between changes in nasal microbiota and immune markers such as immunoglobulin E levels, suggesting that microbiota changes can reflect the severity of AR. Therefore, targeted modulation of the aberrant nasal microbiota may offer a promising therapeutic approach for this disease. However, further research is crucial for elucidating the causal relationships between specific microbial characteristics, disease severity, and potential comorbidities. This article summarizes recent studies examining the pathogenic role of nasal microbiota dysbiosis, the differential microbial composition across nasal mucosal sites, and potential therapeutic targets in AR. The ultimate goal is to develop precision medicine-based therapeutic interventions that target the underlying pathophysiological mechanisms of AR through specific modulation of dysbiotic nasal microbiota, thereby potentially preventing disease progression and reducing the risk of associated comorbidities.

Surgical treatments for trigeminal neuralgia are frequently limited by postoperative pain recurrence and unexpected sensory preservation, while the detailed microanatomy of the trigeminal motor root and its anatomical variants remain incompletely understood. To address this gap, we conducted a detailed anatomical study using ultrathin epoxy sheet plastination and three-dimensional reconstruction on 44 trigeminal nerves from 22 human cadavers. Serial sections were prepared, stained, and examined macroscopically and microscopically from the pons to the foramen ovale. We identified 3-7 motor rootlets per side at the pontine origin. Aberrant sensory rootlets and sensory-motor anastomoses were observed in 26.7% of specimens. The motor root consistently coursed inferomedial to the sensory root and trigeminal ganglion within Meckel's cave, whereas aberrant sensory rootlets followed an independent trajectory without joining the motor trunk. The anastomoses formed bridging connections between the sensory and motor roots within the cerebellopontine cistern, and the meningeal layers investing the motor root underwent a transition within Meckel's cave, where the arachnoid mater appeared to form a distinct perineurial sheath. These findings provide a high-resolution microanatomical map of the trigeminal motor root. The documented variants, including aberrant sensory rootlets and intersystem anastomoses, may represent important anatomical substrates for persistent sensation or pain recurrence after surgery. The inferomedial course of the motor root also highlights its vulnerability during percutaneous foramen ovale procedures. Collectively, these data offer anatomical guidance for optimizing surgical planning and intraoperative strategies in microvascular decompression, partial sensory rhizotomy, and percutaneous procedures, potentially contributing to improved outcomes in trigeminal neuralgia surgery.

BackgroundHearing loss (HL) is the leading cause of disability worldwide, with a particularly severe impact on low- and middle-income countries and causing a huge economic burden. While child HL prevention exists, working-age adults (WAP) struggle to avoid occupational and environmental risks.MethodUsing Global Burden of Disease 2021 data, this study analyzed global HL prevalence trends in the WAP (1992-2021). Analyses included age-standardized prevalence rates (ASPR), estimated annual percentage change, and age-period-cohort (APC) modeling, stratified by gender, age, cause, severity, and Social Demographic Index (SDI).ResultGlobal WAP HL prevalence significantly increased to 524 million in 2021 (a 56.9% increase since 1992), primarily due to population growth and aging. Age period cohort (APC) analysis revealed different patterns: as age increases, risk increases and cyclical effects generally increased (except in low SDI regions). The upward trend of birth cohorts in high to middle SDI countries was worrying. In addition, this study also observed that there was a gender difference in the prevalence trend of HL in WAP (male incidence rate was higher, but female growth was faster), and the patient population was gradually younger. Improved trends from 2017-2021 globally and regionally suggest a potential, albeit unexpected, positive influence of the COVID-19 pandemic on HL prevalence.ConclusionThe global HL burden in the WAP is large and uneven, necessitating targeted interventions focusing on modifiable risks and SDI disparities. Further research is essential to understand the trends observed during the COVID-19 pandemic and to improve prevention strategies.

Objective: To evaluate the effectiveness of integrating the O-AMAS teaching model with problem-based learning (PBL) in instructing medical undergraduates in otolaryngology-head and neck surgery, a specialty that demands rapid clinical decisionmaking and lifelong self-directed learning (SDL) ability. Methods: This study utilized a self-controlled before-and-after trial design to evaluate the effectiveness of traditional teaching techniques in comparison to an innovative strategy that integrates the O-AMAS teaching model with PBL in otolaryngology-head and neck surgery education. Data was collected through in-class and phased tests, a student satisfaction survey evaluating various aspects of the new approach, and the advanced SDL rating scale measuring changes in students' self-directed learning abilities across four dimensions. Statistical analysis used paired sample t-tests. Results: The new teaching model was associated with significantly higher scores in both in-class tests (mean difference = 4.7; Cohen's d = 1.01, 95% CI: 0.77-1.25) and stage tests (mean difference = 4.8; Cohen's d = 0.93, 95% CI: 0.69-1.17), as well as improved total SDL scores (Cohen's d = 0.68, 95% CI: 0.45-0.91), all p < 0.001. Implications for School Health Policy, Practice, and Equity: None. Conclusion: This preliminary evidence suggests that integrating O-AMAS with PBL is a promising approach for otolaryngology education. The observed short-term gains in performance and SDL warrant further evaluation in more rigorous, controlled designs.

Polo-like kinase 1 (PLK1) plays pivotal roles in cell division and cancer pathogenesis, making it a highly coveted therapeutic target for anticancer strategies. This article reports a series of PLK1 inhibitors developed using a structure-based strategy, culminating in the discovery of compound B31, a novel isoform-specific PLK1 inhibitor with excellent kinome selectivity. In vitro, this compound exhibited superior anticancer potency across a broad spectrum of cell lines, particularly against K562, achieving a remarkable IC50 value of 0.08 nM. In a mouse model harboring subcutaneous K562 tumors, oral administration of B31 at dosages of 10 or 20 mg/kg twice weekly exhibited remarkable antileukemic activity. B31 had minimal impact on HEK293T cells and very weak inhibitory activity against the hERG channel. Furthermore, in the acute toxicity test, this compound demonstrated an extraordinary safety profile even at a dosage of 500 mg/kg, highlighting its potential as a novel antileukemic agent.

Accurate segmentation of small organs-at-risk (OARs) in computed tomography (CT) images is crucial for radiotherapy treatment planning in head and neck cancer. However, the low soft tissue contrast, small spatial structures, and the limited training data pose significant challenges for automated segmentation methods. This paper proposes prior-driven refinement network (PRNet), a novel deep learning-based approach that leverages the foundation model's general-purpose representations and domain-specific knowledge to tackle these challenges. PRNet builds upon the initial coarse segmentation and refines small organs by utilizing the coarse segmentation as prior knowledge. PRNet inherits its architecture from the Segment Anything Model (SAM) but incorporates a novel prior encoder and mask refinement transformer, enabling the fusion of domain-specific knowledge with SAM's robust representations.The architecture of PRNet is inherited from the Segment Anything Model (SAM), with the addition of the prior encoder and the mask refinement transformer, allowing for the fusion of domain-specific knowledge with SAM's robust representations. Experiments on three public datasets demonstrate PRNet's superior performance, with average Dice scores of 75.14% +/- 12.81%, 76.56% +/- 12.90%, and 82.83 +/- 13.49% respectively. These results represent improvements of 3.61%, 3.64%, and 5.14% over current state-of-the-art methods. Moreover, experiments on four diverse datasets demonstrate PRNet's generalizability across different anatomical regions and imaging modalities, including liver tumors, myocardial pathologies, and thoracic organs. Our proposed method shows potential for improving clinical radiotherapy planning workflows and contributing to more precise treatment delivery in head and neck cancer patients.

Background and objectives: Recent advances in multimodal large language models (MLLMs) have shown promise in medical image interpretation, yet their utility in surgical contexts remains unexplored. This study evaluates six MLLMs’ performance in interpreting diverse imaging modalities for laryngeal cancer surgery. Methods: We analyzed 169 images (X-rays, CT scans, laryngoscopy, and pathology findings) from 50 patients using six state-of-the-art MLLMs. Model performance was assessed across 1084 clinically relevant questions by two independent physicians. Results: Claude 3.5 Sonnet achieves the highest accuracy (79.43%, 95% CI: 77.02%-81.84%). Performance varied significantly across imaging modalities and between commercial and open-source models, with a 19-percentage point gap between the best commercial and open-source solutions. Conclusion: Advanced MLLMs show promising potential as clinical decision support tools in laryngeal cancer surgery, while performance variations suggest the need for specialized model development and clinical workflow integration. Future research should focus on developing specialized MLLMs trained on large-scale multi-center laryngeal cancer datasets.

OBJECTIVES:The thyroid foramen (TF) has an average incidence of 27% in cadaveric studies. Protecting the TF is crucial to reducing intraoperative bleeding and postoperative complications. This study aimed to retrospectively verify the incidence, location, size, and contents of the TF in the living participants, and to use the epoxy sheet plastination technology to reveal the mesoscopic anatomy of the TF and its relationship with surrounding structures. METHODS:Fifty-two living participants and nine embalmed cadavers were enrolled for this study. The incidence, location, and size of the TF were recorded. The cadaveric specimens were prepared as transverse plastinated slices, and the fine configuration of the TF was examined. The study was approved by the Ethics Committees of The First Affiliated Hospital and Anhui Medical University. RESULTS:(1) The incidence of the TF in the living participant was 28.8% and its average size was 6.8 ± 0.8 mm2. (2) The TF was lined with the inner thyroid perichondrium and covered by the outer pericondrium, which was a tendinous fascia-like structure with various origins. (3) The outer thyroid pericondrium was pieced by the transforaminal vessels and contributed to the perivascular fascia in the TF. CONCLUSION:The incidence of the TF in living participants, its mesoscopic anatomy, and relationship with surrounding structures are new contributions that offer a complementary understanding of the TF. Future research perspectives should involve their radiological and surgical expansion to delineate the TF anatomy in various clinical applications. LEVEL OF EVIDENCE:Not applicable.

Factor XIa (FXIa) has emerged as a promising target for novel anticoagulant development since inhibiting it can reduce thrombosis without significant bleeding risks. Despite a few FXIa inhibitors entering clinical trials, none have been approved for the market yet. Here, we present highly selective and orally bioavailable FXIa inhibitors derived from compound 1, 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one. Structure-activity relationship studies led to the discovery of promising 1-(pyridin-2-ylmethyl)pyridin-2(1H)-one-based FXIa inhibitors 37, 39b, 43, and 46b, which exhibited enhanced FXIa potency and selectivity compared to asundexian, an FXIa inhibitor in phase III clinical trials. Their anticoagulant activity was also comparable to or greater than that of asundexian. Compound 43 significantly reduced thrombosis in both FeCl3-induced mouse and rabbit arterial thrombosis models, demonstrating superior efficacy compared to asundexian. Importantly, 43 did not increase bleeding risks and exhibited a favorable safety profile in mice, suggesting its potential as a promising FXIa inhibitor for the treatment of thrombosis.

The active sites of numerous metalloproteins feature two metal ion cofactors-either identical or distinct-that are positioned in close proximity, typically around 3.8 Å apart. This two-metal-ion catalytic mechanism (TCM) endows these enzymes with a remarkable catalytic efficiency. Enzymes employing TCM play vital biological roles in both humans and pathogenic organisms, with some identified as validated therapeutic targets. Various rational drug design approaches, including nucleoside analogs, prodrugs, metal-binding group design, bioisosteres, pharmacophore modeling, scaffold hopping, tautomerism, and structure-based drug design, have been successfully applied to several enzymes with TCMs, thus yielding the development and approval of many small-molecule drugs for the treatment of several diseases, including certain catastrophic illnesses, such as hepatitis C infection, coronavirus disease 2019, and acquired immune deficiency syndrome. Additionally, drug repurposing has proven to be a critical strategy in the development of therapeutics targeting TCM enzymes. This article reviews the significant achievements in design and development of small-molecule drugs targeting several enzymes with TCMs, including RNA-dependent RNA polymerase, HIV-1 integrase, influenza virus cap-dependent endonuclease, and phosphodiesterase, hoping to offer valuable insights and guidance to facilitate future drug discovery efforts focused on these enzymes and related molecular targets.

INTRODUCTION:Polo-like kinases (PLKs) have five isoforms, all of which play crucial roles in cell cycle and cell proliferation, offering opportunities for drug design and treatment of cancers and other related diseases. Notably, PLK1 and PLK4 have been extensively investigated as cancer drug targets. One distinctive feature of PLKs is the presence of a unique polo-box domain (PBD), which regulates kinase activity and subcellular localization. This provides possibilities for specifically targeting PLKs. AREA COVERED:This article provides an overview of the roles of PLKs in various cancers and related diseases, as well as the drug development involving PLKs, with a particular focus on PLK1 and PLK4. It summarizes the PLK1 and PLK4 inhibitors that have been disclosed in patents or literature (from 2018 - present), which were sourced from SciFinder and WIPO database. EXPERT OPINION:After two decades of drug development on PLKs, several drugs progressed into clinical trials for the treatment of many cancers; however, none of them has been approved yet. Further elucidating the mechanisms of PLKs and identifying and developing highly selective ATP-competitive inhibitors, highly potent drug-like PBD inhibitors, degraders, etc. may provide new opportunities for cancer therapy and the treatment for several nononcologic diseases. PLKs inhibition-based combination therapies can be another helpful strategy.

Background Infection is an important cause of death after kidney transplant surgery. Although fungal infections are relatively rare, they have low detection rates and high mortality rates. The value of metagenomic next-generation sequencing (mNGS) in kidney transplant patients with fungal infections remains to be studied, especially in diagnosis and to guide the use of antibiotics. Methods From September 2021 to August 2023, a total of 234 patients after kidney transplantation were enrolled, and data of 66 patients with suspected fungal infections were collected. The pathogen detection performance of mNGS and conventional microbiological tests (CMTs) were compared. The impacts of mNGS and CMTs on treatment adjustment were also assessed. Finally, we explored the value of mNGS in donor-derived infections. Results A total of 21 fungal species were detected in the 66 patients, of which 18 species of fungus were detected by mNGS and 10 species of fungus were detected by CMTs. mNGS was significantly higher than culture in total positive rate (90.67% vs. 26.67%), especially for multiple fungal infections (9vs0). mNGS identified more candida (26vs12), pneumocystis jirovecii (14vs0), aspergillus (10vs4), mucor (6vs2) organisms compared with CMTs. Fungi from donors were identified in 11(6.7%) patients, including 10 cases of Candida spp. and 1 case of Mucor spp. The anti-infection therapies were adjusted in 28 (24.4%) cases by mNGS. Conclusion The mNGS technique showed distinct advantages in detecting fungal infections in kidney transplant patients, which can guide anti-infection strategies and protect grafts. In addition, it has a good identification value for fungal infections from donor sources.

Thrombo-inflammation is closely associated with a few severe cardiovascular and infectious diseases. Factor XIIa (FXIIa) in the intrinsic coagulation pathway plays a pivotal role in the development of thrombo-inflammation and its inhibition has emerged as a potential therapeutic approach for thrombo-inflammatory disorders. Nonetheless, as of now, few small-molecule FXIIa inhibitors have demonstrated notable effectiveness against thrombo-inflammation, with none progressing into clinical stages. Herein, we present potent, covalent, reversible, and selective small-molecule FXIIa inhibitors such as 4a and 4j obtained through structure-based drug design. Compounds 4a and 4j showed significant anticoagulation and substantial anti-inflammatory effects in vitro, coupled with exceptional plasma stability. Furthermore, in carrageenan-induced thrombosis models, 4a and 4j demonstrated remarkable dual antithrombotic and anti-inflammatory activity when administered orally. Compound 4j exhibited a favorable safety profile without obvious tissue toxicity in mice, suggesting its potential as an oral therapeutic option for thrombo-inflammation.

BackgroundPulmonary hypertension (PH) in patients with end-stage renal disease (ESRD) has a high incidence rate and mortality and its early identification is critical. However, whether a combination of clinical, electrocardiographic, and echocardiographic parameters can predict the occurrence of PH in patients with ESRD remains to be elucidated. Herein, we evaluated the predictive value of the combined score of these parameters.MethodsData from 370 patients with newly diagnosed ESRD who underwent routine echocardiography and electrocardiography between May 2016 and May 2017 were retrospectively evaluated. The incidence of PH during a 60-month follow-up period was investigated. Twenty-one patients were excluded due to incomplete data among other reasons. Finally, 349 patients were included in the analysis, of whom, 158 (45%) developed PH.ResultsAnalysis of electrocardiogram reports suggested that a corrected Q-T interval (QTc) of >438.5 ms was associated with PH. Echocardiographic reports suggest that left atrial diameter (LAD), interventricular septum thickness in end-diastole (IVSd), stroke volume (SV), and pericardial effusion are also associated with PH development. Results of multivariate Cox analysis showed that LAD >3.785 cm, IVSd >1.165 cm, SV >79.5 ml, QTc >438.5 ms, and pericardial effusion were independent predictors of PH in patients with ESRD. The incidence of new-onset PH increased significantly with increasing composite scores, that is, the sum of risk scores determined using hazard ratios.ConclusionsA total score that includes a combination of parameters such as LAD >3.785 cm, IVSd>1.165 cm, SV >79.5 ml, QTc >438.5 ms, and pericardial effusion can help describe the risk of new-onset PH.

The treatment of HIV-1/AIDS has achieved great success, partly owing to the clinical applications of HIV-1 integrase (IN) strand transfer inhibitors (INSTIs). After briefly introducing HIV-1/AIDS and its treatment, this chapter discusses the medical applications and limitations of five US Food and Drug Administration–approved INSTIs for the treatment of HIV/AIDS and preexposure prophylaxis for HIV-1. The development of authentic HIV-1 IN inhibitors, which include two main categories, INSTIs and IN-LEDGF/p75 allosteric inhibitors, is then reviewed. Pharmacophore and binding modes of INSTIs are provided, which are helpful for designing and identifying better novel INSTIs that may overcome the emergence of resistance to marketed INSTIs.

Bacterial proliferation and the disordered extracellular matrix (ECM) at the wound site are the major reasons for delayed healing and abnormal scarring. The development of new multifunctional dressing materials that can effectively prevent scar formation without delaying wound healing remains a challenge. In this study, we construct a verteporfin-loaded biodegradable hydrogel (VP-gel) using hyaluronic acid and thiol-terminated 4-arm polyethylene glycol (PEG). The injectable VP-gel sustainably releases small doses of verteporfin in the wound microenvironment that generates reactive oxygen species (ROS) under red light irradiation to kill bacteria efficiently. Importantly, the sustained release of VP could also regulate TGF-β family-induced cellular responses and the downstream signaling molecule Smad2 in fibroblasts to reduce myofibroblast differentiation, promoting ECM reconstruction and scarless wound healing. Immunohistochemical examination of wound healing and histomorphology in a mouse full-thickness wound model demonstrates excellent acceleration effects of VP-gel for infected wound healing. Therefore, VP-gel with anti-scarring and antibacterial activity, as well as enhanced infection wound healing ability shows great potential in the clinical treatment of scar healing for infected wounds.

Fibrotic kidney injury from hepatocarcinogenesis seriously impacts treatment effect. Astragaloside IV (AS-IV), an extract of Astragalus membranaceus, has several pharmacological activities, which are useful in the treatment of edema and fibrosis. Nrf2/HO-1 is a key antioxidant stress pathway and help treatment of kidney injury. Smad3 phosphorylation is implicated in hepatocarcinogenesis. Our previous study clarified that Smad3 is differentially regulated by different phosphorylated forms of Smad3 on hepatocarcinogenesis. Therefore, we investigated the contribution of AS-IV on the therapy of kidney fibrosis from hepatocarcinogenesis. And the focus was on whether the phosphorylation of Smad3 and the regulation of Nrf2/HO-1 pathway were involved during AS-IV therapy and whether there is an effect of Nrf2 knockout on the phosphorylation of Smad3. We performed TGF-β1 stimulation on HK-2 cells and intervened with AS-IV. Furtherly, we investigated renal injury of AS-IV on Nrf2 knockout mice during hepatocarcinogenesis and its mechanism of action. On the one hand, in vitro results showed that AS-IV reduced the ROS and α-SMA expression of HK-2 by promoting the expression pSmad3C/p21 of and Nrf2/HO-1 and suppressed the expression of pSmad3L/PAI-1. On the other hand, the in vivo results of histopathological features, serological biomarkers, and oxidative damage indicators showed that Nrf2 knockout aggravated renal injury. Besides, Nrf2 deletion decreased the nephroprotective effect of AS-IV by suppressing the pSmad3C/p21 pathway and promoting the pSmad3L/PAI-1 pathway. The experimental results were as we suspected. And we identify for the first time that Nrf2 deficiency increases renal fibrosis from hepatocarcinogenesis and attenuates the therapeutic effects of AS-IV via regulating pSmad3C/3L signal pathway.