Pseudomonas aeruginosa bloodstream infections carry mortality rates exceeding 60%, with escalating antibiotic resistance dramatically limiting therapeutic options. The type III secretion system (T3SS), a virulence apparatus delivering cytotoxic effectors via PcrV-dependent translocation pores, represents a therapeutic target. Here, we developed a monoclonal antibody (5C8) targeting the central domain (H106-D173) of PcrV, which regulates translocation pore size. 5C8 demonstrated sub-nanomolar affinity (KD = 0.32 nM) via biolayer interferometry and broad neutralization efficacy against clinical isolates (IC50: 0.32-1.47 μg/mL). In murine bloodstream infection models, 5C8 conferred improved survival against cytotoxic (exoU+) and invasive (exoS+) strains (P < 0.01 vs controls), reducing bacterial loads in lungs/kidneys by 1.5-log10 colony-forming unit (P < 0.01) and suppressing interleukin-6 levels by 60-82% (P < 0.01). Mechanistic studies revealed 5C8's dual action: blocking effector release (ExoU/ExoT reduced by 41-88% via liquid chromatography-mass spectrometry) and constricting T3SS pores below 1.2 nm (carbohydrate exclusion assay). Molecular docking identified D125/K129/Y145 as critical binding residues, validated by alanine scanning and mutant construction. Humanized Hu5C8 retained potency (KD = 0.55 nM) with extended half-life (t1/2 = 91.26 h) through Fc receptor engineering. As an inhibitor targeting the pore size-determining domain of PcrV, 5C8 disrupts virulence through a novel dual mechanism, providing a paradigm-shifting strategy against multidrug-resistant P. aeruginosa, bridging a critical gap in sepsis management.

Chronic inflammation impedes the healing of diabetic ulcers (DUs), while P-glycoprotein (P-gp)-mediated drug efflux reduces the efficacy of conventional drug formulations. In this study, a novel liposome-mediated hyaluronic acid (HA) microneedle patch (E-Lipo@A-HMN) was developed for enhanced DUs healing via the transdermal delivery of Acetyl-11-keto-β-boswellic acid (AKBA) and β-elemene (ELE). The findings demonstrate that liposomal encapsulation enhances the solubility and bioavailability of ELE, and HA microneedles improve skin penetration and enable controlled drug release by providing a biodegradable, biocompatible scaffold that improves skin penetration and enables controlled drug release. Furthermore, our treatment protocol could effectively attenuate inflammation and promote fibroblast proliferation, collagen deposition and angiogenesis by inhibiting P-gp expression, enhancing intracellular drug accumulation and downregulating the PI3K/AKT/NF-κB signaling pathway. Compared to conventional therapies, E-Lipo@A-HMN exhibits better therapeutic performance, demonstrating enhanced anti-inflammatory activity and accelerated wound repair. Moreover, the treatment protocol displays an excellent biosafety profile. It offers a novel, safe, and effective therapeutic strategy for treating DUs with significant potential for clinical application.

Invasive candidiasis, primarily caused by Candida albicans , represents the most common fungal disease among hospitalized patients and poses a significant threat to human health. Intrinsic or acquired immunosuppression serves as a critical risk factor predisposing individuals to this disease, while simultaneously reducing the efficacy of conventional antifungal therapies and worsening clinical outcomes. Given the central role of immune dysfunction in the pathogenesis of invasive candidiasis, immunotherapeutic strategies hold substantial promise. We targeted dectin-1, the primary pattern recognition receptor for β-1,3-glucan, by engineering XJ104, a bispecific T-cell engager that fuses dectin-1 to the light chains of an anti-CD3 monoclonal antibody. This construct is designed to bridge Candida β-1,3-glucan with CD3 on T cells, thereby inducing anti- Candida immunity. Our results demonstrate that XJ104 exhibits high specificity for β-1,3-glucan and activates effector cells in a Candida -dependent manner in vitro . In murine models, XJ104 enhances Th1 and Th17 responses and confers significant protection against both C. albicans and non-albicans infections. Crucially, CD3 + T-cell depletion and cytokine neutralization abolished this protection, confirming the T-cell-dependent protective efficacy of XJ104. These results establish that enhancing the endogenous T-cell function represents an effective strategy against invasive candidiasis. In conclusion, our study presents a novel therapeutic approach that bridges T cells and Candida pathogens, promoting robust Candida -specific immunity and controlling invasive infections caused by Candida spp . These findings underscore the potential of XJ104 as a clinically promising immunotherapy for the treatment of invasive candidiasis.

Introduction Candida albicans is a commensal fungus that colonizes most healthy individuals’ skin and mucosal surfaces but can also cause life-threatening invasive infections, particularly in immunocompromised patients. Despite antifungal treatment availability, drug resistance is increasing, and mortality rates remain unacceptably high. Heat shock protein Ssa1, a conserved member of the Hsp70 family in yeast, is a novel invasin that binds to host cell cadherins, induces host cell endocytosis, and enables C. albicans to cause maximal damage to host cells and induces disseminated and oropharyngeal disease. Result Here we discovered a mouse monoclonal antibody (mAb 13F4) that targeting C. albicans Ssa1 with high affinity (EC 50 = 39.78 ng/mL). mAb 13F4 prevented C. albicans from adhering to and invading human epithelial cells, displayed antifungal activity, and synergized with fluconazole in proof of concept in vivo studies. mAb 13F4 significantly prolonged the survival rate of the hematogenous disseminated candidiasis mice to 75%. We constructed a mAb 13F4 three-dimensional structure using homology modeling methods and found that the antigen-binding fragment (Fab) interacts with the Ssa1 N-terminus. Discussion These results suggest that blocking Ssa1 cell surface function may effectively control invasive C. albicans infections and provide a potential new treatment strategy for invasive fungal infections.

We designed and developed a novel DNA topoisomerase I inhibitor MF-6, which was a more potent cytotoxin and a more potent inducer of immunogenic cell death compared with DXd. To utilize MF-6's ability to induce antitumor immunity, a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) trastuzumab-L6 that included a cleavable linker and MF-6 was developed. Different from traditional cytotoxic ADC, the antitumor activity of trastuzumab-L6 was assessed by inducing tumor cell immunogenic cell death, activating dendritic cells and cytotoxic CD8+ T cells to acquire durable adaptive immune memory. Tumor cells treated with trastuzumab-L6 were committed to immunogenic cell death, with upregulation of damage-associated molecular patterns and antigen presentation molecules. In a syngeneic tumor model with a mouse cell line that expressed human HER2, immunocompetent mice showed greater antitumor efficacy compared with nude mice. The trastuzumab-L6-cured immunocompetent mice acquired adaptive antitumor memory and rejected subsequent tumor cell challenge. The trastuzumab-L6 efficacy was abrogated when cytotoxic CD8+ T cells were depleted and enhanced when regulatory CD4+ T cells were depleted. The combination of trastuzumab-L6 with immune checkpoint inhibitors significantly increased antitumor efficacy. Enhanced T cell infiltration, dendritic cell activation, and decreased type M2 macrophages in tumor post trastuzumab-L6 administration confirmed the immune-activating responses. In conclusion, trastuzumab-L6 was considered to be an immunostimulatory agent, rather than a traditional cytotoxic ADC, and its antitumor efficacy was enhanced when combined with an anti-PD-L1 and anti-CTLA-4 antibody, which suggested a potential therapeutic strategy.

Staphylococcus aureus is a major human pathogen associated with high mortality rates. The extensive use of antibiotics is associated with the rise of drug resistance, and exotoxins are not targeted by antibiotics. Therefore, monoclonal antibody (mAb) therapy has emerged as a promising solution to solve the clinical problems caused by refractory S aureus. Recent research suggests that the synergistic effects of several cytotoxins, including bicomponent toxins, are critical to the pathogenesis of S aureus. By comparing the amino acid sequences, researchers found that α-toxin and bicomponent toxins have high homology. Therefore, we aimed to screen an antibody, designated an all-in-one mAb, that could neutralize α-toxin and bicomponent toxins through hybridoma fusion. We found that this mAb has a significant pharmacodynamic effect within in vivo mouse models and in vitro experiments.

Background Talaromycosis is an invasive endemic mycosis caused by the dimorphic fungus Talaromyces marneffei (T. marneffei, TM). It mainly affects immunodeficient patients, especially HIV-infected individuals, which causes significant morbidity and mortality. Culture-based diagnosis takes a long turnaround time with low sensitivity, leading to treatment delay. In this study, we aimed to evaluate the performance of Metagenomic Next-Generation Sequencing (mNGS) for the rapid diagnosis of talaromycosis in HIV-infected patients. Methods Retrospectively analysis was conducted in HIV-infected cases at Changsha First Hospital (China) from January 2021 to March 2022. Patients who underwent routine microbiological examination and mNGS testing in parallel were enrolled. The clinical final diagnosis was used as a reference standard, and cases were classified into the TM group (60 cases) and the non-TM group (148 cases). The clinical performances of mNGS were compared with culture and serum Galactomannan (GM). The mixed infections detected by mNGS were analyzed. The impact of mNGS detection on treatment was also investigated. Results The sensitivity of mNGS test reached 98.3% (95% CI, 89.8-99.9), which was significantly higher than culture (66.7% [95% CI, 53.2-77.9], P < 0.001) and serum GM (83.3% [95% CI, 71.0-91.2], P < 0.05). The specificity of 98.6% (95% CI, 94.7-99.7) was similar to culture (100.0% [95% CI, 96.8-100.0], P = 0.156), and superior to serum GM (91.9% [95% CI, 85.9-95.5], P < 0.05). In bronchoalveolar lavage fluid (BALF) samples, the positive rate of mNGS was 97.6%, which was significantly higher than culture (28.6%, P <0.001). mNGS has excellent performance in the identification of mixed infection in TM group patients. Cytomegalovirus, Epstein-Barr virus and Pneumocystis jirovecii were the most common concurrent pathogens. In summary, 60.0% (36/60) patients were added or adjusted to antimicrobial therapy after mNGS test. Conclusion mNGS is a powerful technique with high specificity and sensitivity for the rapid diagnosis of talaromycosis. mNGS of BALF samples may be a good option for early identification of T. marneffei in HIV-infected individuals with manifestations of infection. Moreover, mNGS shows excellent performance in mixed infection, which benefits timely treatment and potential mortality reduction.

近年来,临床上多重耐药革兰阴性菌引起感染的死亡率居高不下.β-内酰胺酶是革兰阴性菌对多种β-内酰胺类抗生素耐药的主要原因.目前,治疗耐药革兰阴性菌感染的抗菌药物研发遭遇瓶颈,21世纪以来未见基于新靶点的小分子药物上市.近年来,新药研发机构逐渐聚焦于开发β-内酰胺酶抑制剂,旨在通过克服β-内酰胺酶介导的耐药性提高现有抗菌药物的临床疗效.头孢他啶-阿维巴坦在临床上的成功应用,使β-内酰胺类抗生素/β-内酰胺酶抑制剂复方制剂成为最有望解决临床多重耐药革兰阴性菌感染的策略.本文对近年来有关β-内酰胺类抗生素/β-内酰胺酶抑制剂复方制剂的相关研究和临床应用进展进行综述,并对未来β-内酰胺酶抑制剂复方制剂的研究方向进行了展望.

自1989年抑制HIV-1感染的CD4-Fc融合蛋白被首次报道以来,Fc融合蛋白的治疗性应用在医药学领域引起广泛关注.Fc融合蛋白由功能分子和免疫球蛋白的Fc结构域组成,不仅具有蛋白的生物学功能且兼具抗体的特性,如在体内具有长半衰期、诱导抗体依赖细胞介导的细胞毒性效应(antibody-dependent cell-mediated cytotoxicity,ADCC)等.通过对Fc结构域进行糖基化、脱酰胺化、氨基酸定点突变改造,还可增强或减弱其介导的ADCC等效应,用于临床疾病的诊断与治疗.另外,Fc融合蛋白在多个非临床领域也有广泛应用.本文对重组Fc融合蛋白的结构特征和药理学特性、临床药物开发及其在非临床领域中的应用与发展进行综述.

Background Candida albicans infections are particularly prevalent in immunocompromised patients. Even with appropriate treatment with current antifungal drugs, the mortality rate of invasive candidiasis remains high. Many positive results have been achieved in the current vaccine development. There are also issues such as the vaccine’s protective effect is not persistent. Considering the functionality and cost of the vaccine, it is important to develop safe and efficient new vaccines with long-term effects. In this paper, an antifungal nanovaccine with Polyethyleneimine (PEI) as adjuvant was constructed, which could elicit more effective and long-term immunity via stimulating B cells to differentiate into long-lived plasma cells. Materials and Methods Hsp90-CTD is an important target for protective antibodies during disseminated candidiasis. Hsp90-CTD was used as the antigen, then introduced SDS to “charge” the protein and added PEI to form the nanovaccine. Dynamic light scattering and transmission electron microscope were conducted to identify the size distribution, zeta potential, and morphology of nanovaccine. The antibody titers in mice immunized with the nanovaccine were measured by ELISA. The activation and maturation of long-lived plasma cells in bone marrow by nanovaccine were also investigated via flow cytometry. Finally, the kidney of mice infected with Candida albicans was stained with H&E and PAS to evaluate the protective effect of antibody in serum produced by immunized mice. Results Nanoparticles (NP) formed by Hsp90-CTD and PEI are small, uniform, and stable. NP had an average size of 116.2 nm with a PDI of 0.13. After immunizing mice with the nanovaccine, it was found that the nano-group produced antibodies faster and for a longer time. After 12 months of immunization, mice still had high and low levels of antibodies in their bodies. Results showed that the nanovaccine could promote the differentiation of B cells into long-lived plasma cells and maintain the long-term existence of antibodies in vivo. After immunization, the antibodies in mice could protect the mice infected by C. albicans. Conclusion As an adjuvant, PEI can promote the differentiation of B cells into long-lived plasma cells to maintain long-term antibodies in vivo. This strategy can be adapted for the future design of vaccines.

Recently, Cryptococcus and non-albicans Candida (NAC) have emerged as health-threatening pathogens for clinical fungal infections. Due to their increased resistance to existing antifungal drugs, novel antifungals are urgently needed. In this study, we evaluated the antifungal effect of VT-1161 and its comparators itraconazole and fluconazole against common fluconazole-sensitive or -resistant Cryptococcus and NAC strains. The tested strains were obtained from Chinese patients by the Invasive Fungal Infection Group within the past 2 years. The minimum inhibitory concentrations (MICs) of VT-1161 and other triazoles were measured according to the Clinical and Laboratory Standards Institute (CLSI) M27-Ed4 guidelines. We found that VT-1161 exhibited strong in vitro activity against Cryptococcus spp.. VT-1161 (geometric mean MIC = 0.024 μg/mL) was 21.7-fold and 104.5-fold more potent than itraconazole and fluconazole, respectively. Against the seven Cryptococcus neoformans isolates with higher fluconazole MICs (≥8 μg/mL based on the MIC90 value of this azole), VT-1161 maintained potent activities, with MICs ranging between 0.031 and 0.5 μg/mL. For NAC spp., VT-1161 (geometric mean MIC = 0.099 μg/mL) was 6.0-fold and 11.4-fold more effective than itraconazole and fluconazole, respectively. There is a positive correlation of the MICs between VT-1161 and itraconazole/fluconazole. The MIC values of VT-1161 against Candida glabrata and Candida tropicalis were significantly lower than those of fluconazole, whereas for Candida parapsilosis the differences in the MIC values between VT-1161 and fluconazole were not statistically significant. The results showed that tetrazole VT-1161 might be a promising candidate for treating Cryptococcus and NAC infections.

Sepsis is a common life-threatening disease in the intensive care unit (ICU) that is usually treated empirically without pathogen identification. As a non-invasive and high-throughput technology, plasma microbial cell-free DNA (mcfDNA) sequencing can detect unknown pathogens independent of previous clinical or laboratory information. In this study, a total of 199 cases suspected of bloodstream infection (BSI) from January 2020 to June 2020 were collected, and potential pathogens were detected by simultaneous blood culture and plasma mcfDNA sequencing. Other clinical microbiological assays were performed within 7 days of plasma mcfDNA sequencing, including smear, culture of samples taken from relevant infected sites, and β-D-glucan/galactomannan (BDG/GM) tests, among others. The diagnoses were classified as sepsis [94 (47.2%)], non-sepsis [87 (43.7%)], and non-infectious disease [18 (9.0%)]. The sensitivity and specificity of plasma mcfDNA sequencing for diagnosing sepsis were 68.1 and 63.2%, respectively, which were significantly better than those of blood culture, especially for the common bacteria that cause hospital-acquired infection, namely, Acinetobacter baumannii (p < 0.01) and Klebsiella pneumoniae (p < 0.01), and DNA viruses (plasma mcfDNA sequencing only, p < 0.01). However, there was no significant difference in the rate of positivity between plasma mcfDNA sequencing and blood culture for antibiotic-non-exposed cases (43.6 vs. 30.9%, p = 0.17). In the non-sepsis group, 44.8% of cases (13/29) detected only by plasma mcfDNA sequencing showed infections in other parts of the body, such as lower respiratory infection (LRI), intra-abdominal infection (IAI) and central nervous system infection (CNSI). For some common pathogens (not including anaerobes), turnaround time (TAT) 3 (TAT from the initiation of blood sample processing by nucleic acid extraction to the completion of sequencing analysis) was longer than TAT1 (TAT from blood culture bottles in Virtuo to off Virtuo). With disease progression, significant dynamic changes in microbial species were clearly detected by plasma mcfDNA sequencing.

Recent decades have seen a significant increase in invasive fungal infections, resulting in unacceptably high mortality rates. Anidulafungin (AN) is the newest echinocandin and appears to have several advantages over existing antifungals. However, its poor water solubility and burdensome route of administration (i.e., repeated, long-term intravenous infusions) have limited its practical use. The objective of this study was to develop anidulafungin-loaded Human Serum Albumin (HSA) nanoparticles (NP) so as to increase both its solubility and antifungal efficacy. HSA was reduced using SDS and DTT, allowing liberation of free thiols to form the intermolecular disulfide network and nanoassembly. Reduced HSA was then added to MES buffer (0.1 M, pH 4.8) and magnetically stirred at 350 rpm and 25°C with AN (m/m 50:1) for 2 h to form nanoparticles (AN NP). We next performed routine antifungal susceptibility testing of Candida strains (n = 31) using Clinical and Laboratory Standards Institute (CLSI) methodologies. Finally, the in vivo efficacy of both AN and AN NP was investigated in a murine model of invasive infection by one of the most common fungal species—C. albicans. The results indicated that our carrier formulations successfully improved the water solubility of AN and encapsulated AN, with the latter having a particle size of 29 ± 1.5 nm with Polymer dispersity index (PDI) equaling 0.173 ± 0.039. In vitro AN NP testing revealed a stronger effect against Candida species (n = 31), with Minimum Inhibitory Concentration (MIC) values 4- to 32-fold lower than AN alone. In mice infected with Candida and having invasive candidiasis, we found that AN NP prolonged survival time (P < 0.005) and reduced fungal burden in kidneys compared to equivalent concentrations of free drug (P < 0.0001). In conclusion, the anidulafungin nanoparticles developed here have the potential to improve drug administration and therapeutic outcomes for individuals suffering from fungal diseases.

Candida parapsilosis complex is one of the most common non- albicans Candida species that cause candidemia, especially invasive candidiasis. The purpose of this study was to evaluate the antifungal susceptibilities of both colonized and invasive clinical C. parapsilosis complex isolates to 10 drugs: amphotericin (AMB), anidulafungin (AFG), caspofungin (CAS), micafungin (MFG), fluconazole (FLZ), voriconazole (VRZ), itraconazole (ITZ), posaconazole (POZ), 5-flucytosine (FCY), and isaconazole (ISA). In total, 884 C. parapsilosis species complex isolates were gathered between January 2005 and December 2020. C. parapsilosis , Candida metapsilosis , and Candida orthopsilosis accounted for 86.3, 8.1, and 5.5% of the cryptic species, respectively. The resistance/non-wild-type rate of bloodstream C. parapsilosis to the drugs was 3.5%, of C. metapsilosis to AFG and CAS was 7.7%, and of C. orthopsilosis to FLZ and VRZ was 15% and to CAS, MFG, and POZ was 5%. The geometric mean (GM) minimum inhibitory concentrations (MICs) of non-bloodstream C. parapsilosis for CAS (0.555 mg/L), MFG (0.853 mg/L), FLZ (0.816 mg/L), VRZ (0.017 mg/L), ITZ (0.076 mg/L), and POZ (0.042 mg/L) were significantly higher than those of bloodstream C. parapsilosis , for which the GM MICs were 0.464, 0.745, 0.704, 0.015, 0.061, and 0.033 mg/L, respectively ( P < 0.05). The MIC distribution of the bloodstream C. parapsilosis strains collected from 2019 to 2020 for VRZ, POZ, and ITZ were 0.018, 0.040, and 0.073 mg/L, significantly higher than those from 2005 to 2018, which were 0.013, 0.028, and 0.052 mg/L ( P < 0.05). Additionally, MIC distributions of C. parapsilosis with FLZ and the distributions of C. orthopsilosis with ITZ and POZ might be higher than those in Clinical and Laboratory Standards Institute studies. Furthermore, a total of 143 C. parapsilosis complex isolates showed great susceptibility to ISA. Overall, antifungal treatment of the non-bloodstream C. parapsilosis complex isolates should be managed and improved. The clinicians are suggested to pay more attention on azoles usage for the C. parapsilosis complex isolates. In addition, establishing the epidemiological cutoff values (ECVs) for azoles used in Eastern China may offer better guidance for clinical treatments. Although ISA acts on the same target as other azoles, it may be used as an alternative therapy for cases caused by FLZ- or VRZ-resistant C. parapsilosis complex strains.

目的 了解2019年上海市东方医院(南院)菌株分布和抗菌药物敏感性.方法 用纸片扩散法(K-B法)测量抗菌药物抑菌圈直径,梅里埃自动化仪器检测最低抑菌浓度(MIC),按照美国临床实验室标准化协会(CLSI)指南M1002020版和美国食品和药物管理局(FDA)标准判断结果,用WHONET 5.6软件对本院分离细菌耐药性进行统计分析.结果 分离非重复菌株共1510株,革兰阳性菌(G+菌)487株,占32.25％;革兰阴性菌(G-菌)1023株,占67.75％.耐甲氧西林凝固酶阴性葡萄球菌(MRCNS)和耐甲氧西林金黄色葡萄球菌(MRSA)检出率分别为80.0％和54.1％.发现1株利奈唑胺耐药的粪肠球菌.β溶血链球菌以无乳链球菌为主,占77.1％,而无乳链球菌对青霉素96.3％敏感.肺炎链球菌均来自成年人的痰液,50％对青霉素敏感.大肠埃希菌和肺炎克雷伯菌超广谱β内酰胺酶(ESBLs)阳性率分别为52.6％和61.0％.耐碳青霉烯类肺炎克雷伯菌、大肠埃希菌、鲍曼不动杆菌和铜绿假单胞菌检出率分别为53.1％,2.2％,91.1％和38.1％.结论 本院细菌耐药率高,应加强及重视细菌耐药监测.

An outbreak of an unknown infectious pneumonia has recently occurred in Wuhan, China [1]. The pathogen of the disease was quickly identified as a novel coronavirus (SARS-CoV-2, severe acute respiratory syndrome coronavirus 2),andthediseasewasnamedcoronavirusinfectiondisease-19 (COVID-19) [2]. According to theNewCoronavirus Pneumonia Diagnosis Program (5th edition) published by the National HealthCommissionofChina[3],clinicalmanifestationsconsist of four categories: mild, moderate, severe, and critical. To address the social spread of the virus, Dongxihu Fangcang Hospital, which aims to provide centralized treatment and isolation of COVID-19, was built for patients who were confirmed to have themild type of COVID-19. Hospital equipment usually consists of a series of compartments with different medical or technical support functions, with the ability to deliver early treatment. The mild type patients of COVID-19 can recover shortly after appropriate clinical intervention.Inaddition,virusexclusionafterstandardtreatmentis an important factor indetermining theprognosis ofCOVID-19. Routine blood test was inspected among patients in the Dongxihu Fangcang Hospital. This is the most readily available, efficient, and economic method of examination. Blood analysis examined lymphocytes (LYM), platelets (PLT), the neutrophil-to-lymphocyte ratio (NLR), the lymphocyte-to-monocyte ratio (LMR), the platelet-toneutrophil ratio (PNR), and the platelet-to-lymphocyte ratio (PLR). These blood cell counts and ratios are valuable in understanding the systemic inflammatory response. Researches have shown that NLR has a certain value in evaluating in-hospital mortality, poor clinical outcomes, and severity of COVID-19 [4, 5]. However, it has been rarely reported if these laboratory indicators were correlated with viral expression in COVID19 patients. The aim of this study is to retrospectively analyze clinical data of mild COVID-19 patients treated in the Dongxihu Fangcang Hospital. This studywas conducted in order to identify a simple and effective indicator to assess the correlation between viral exclusion in mild COVID-19 patients and simple laboratory indicators. In this way, it may be possible to perform diagnostic risk stratification and graded treatment of COVID-19 patients. All cases were taken from mild COVID-19 patients in the Dongxihu Fangcang Hospital, which is one of the designated hospitals for the COVID-19 issued by local authorities. When the situation in the epidemic area is stable, the Fangcang hospital was closed on March 8, 2020. The patients with negative nucleic acid will be discharged, and the patients with suspected or positive nucleic acid will be transferred to other hospitals for further treatment. By the time of hospital closure, the median length of stay was 22 days. Nucleic acid test results of the patients before admission were all positive for SARS-CoV-2. A total of 289 samples were included in this study. Excluding patients Chi Zhu, Siyuan Yu and Huangwei Zhao contributed equally to this work and should be considered co-first authors.

Candida and Cryptococcus are the main pathogens of clinical fungal infection associated with high morbidity and mortality. SHR8008 (in fact, this is the only official name in China and it is called VT-1161 by FDA) is a novel tetrazole agent that selectively inhibits fungal CYP51A compared to mammalian cytochrome P450 enzymes to achieve a better antifungal effect. The in vitro activities of SHR8008 and its comparators itraconazole and fluconazole were determined in 127 Candida and 50 Cryptococcus strains isolated from Chinese patients in the last 2 years by Invasive Fungal Infection Group. The MICs of SHR8008 and other triazoles were measured by the Clinical and Laboratory Standards Institute guidelines M27-E4. For Candida spp., SHR8008 (geometric mean MIC=0.078 μg/mL) was 6.5-fold and 11.2-fold more potent than itraconazole and fluconazole, respectively. There is a good correlation of MICs between SHR8008 and itraconazole/fluconazole. The MIC values of SHR8008 against Candida glabrata and Candida tropicalis were significantly lower than those of fluconazole, while for Candida albicans and Candida parapsilosis , the differences between SHR8008 and fluconazole were not statistically significant, either. For Cryptococcus spp., SHR8008 (geometric mean MIC=0.024 μg/mL) was 21.7-fold and 104.5-fold more potent than itraconazole and fluconazole, respectively. Against the seven Cryptococcus neoformans isolates with elevated fluconazole MICs (≥8μg/mL based on the MIC90 value for this azole), SHR8008 maintained potent activity, with MICs ranging between 0.031 and 0.5 μg/mL. The results showed that tetrazole SHR8008 was more promising in the treatment of Candida and Cryptococcus infection than itraconazole and fluconazole.

Candida albicans is a common fungal pathogen in humans that colonizes the skin and mucosal surfaces of the majority healthy individuals. How C. albicans disseminates into the bloodstream and causes life-threatening systemic infections in immunocompromised patients remains unclear. Plasminogen system activation can degrade a variety of structural proteins in vivo and is involved in several homeostatic processes. Here, for the first time, we characterized that C. albicans could capture and "subvert" host plasminogen to invade host epithelial cell surface barriers through cell-wall localized Eno1 protein. We found that the "subverted" plasminogen system plays an important role in development of invasive infection caused by C. albicans in mice. Base on this finding, we discovered a mouse monoclonal antibody (mAb) 12D9 targeting C. albicans Eno1, with high affinity to the 254FYKDGKYDL262 motif in α-helices 6, β-sheet 6 (H6S6) loop and direct blocking activity for C. albicans capture host plasminogen. mAb 12D9 could prevent C. albicans from invading human epithelial and endothelial cells, and displayed antifungal activity and synergistic effect with anidulafungin or fluconazole in proof-of-concept in vivo studies, suggesting that blocking the function of cell surface Eno1 was effective for controlling invasive infection caused by Candida spp. In summary, our study provides the evidence of C. albicans invading host by "subverting" plasminogen system, suggesting a potential novel treatment strategy for invasive fungal infections.

目的 慢性肺曲霉病发病隐蔽易被其基础疾病掩盖不易诊断,如不及时积极治疗病死率高.指南建议将曲霉IgG抗体检测作为诊断慢性肺曲霉病的关键指标.但是目前大多数曲霉IgG抗体临床数据来自欧洲国家,中国人的曲霉特异性IgG抗体的生物参考区间仍有待确定.因此本研究的目的是建立适合本实验室的曲霉IgG抗体的生物参考区间.方法 随机选取2019年10月至12月在本院进行健康体检的成年人,收集血清,采用丹娜曲霉IgG抗体检测试剂盒(酶联免疫法)进行测定,测定结果 依据美国临床实验室标准化协会(CLSI)EP28-A3c的方法,用SPSS 25.0软件进行统计分析,建立本实验室的生物参考区间.结果 最终纳入291名患者健康个体,中位年龄37岁(19岁～82岁),其中男141名,中位年龄38岁(19岁～82岁),女150名,中位年龄38岁(20岁～78岁).男性和女性健康成年人血清曲霉IgG抗体水平分别为20.579(43.618)AU/mL 28.387(48.158)AU/mL,差异有统计学意义(P=0.011),因此依据男女性别差异分别建立参考区间.最终,曲霉IgG抗体水平参考区间为男性<111.405 AU/mL,女性<181.888 AU/mL.结论 根据不同性别初步建立了该实验室血清中曲霉IgG抗体的生物学参考区间,为临床的相关疾病诊断提供了参考标准.

Background: The increased prevalence of carbapenem-resistant K. pneumoniae (CRKP) poses a great threat worldwide. Early identification of CRKP in patients is paramount. Moreover, fully understanding the risk factors affecting clinical outcome and actively providing targeted treatment can improve the cure rate of patients with CRKP. Therefore, our study aimed to describe the clinical characteristics and identify the risk factors affecting clinical outcomes in patients with CRKP. Material/Methods: From January 2016 to September 2017, CRKP strains and clinical data from 97 hospitalized patients were collected. We first performed an antibiotic susceptibility test on CRKP strains using the Kirby-Bauer disc agar diffusion method. Logistic regression analysis was then performed to analyze risk factors. Results: According to clinical outcome, among the 97 CRKP patients, 67 were in the effective group and 30 patients were in the noneffective group. Risk factors found to correlate with poor clinical outcome in patients with CRKP included ICU admission, arteriovenous catheterization, indwelling gastric tube, indwelling urethral catheter, tracheal intubation, mechanical ventilation, hypoproteinemia, and exposure to carbapenems. Multivariate analysis showed that hypoproteinemia (OR: 2.83, p=0.042), presence of an indwelling gastric tube (OR: 4.54, p=0.005), and exposure to carbapenems (OR: 2.77, p=0.045) negatively affected clinical outcome in patients with CRKP. Conclusions: Adverse risk factors correlated with poor clinical outcomes in patients with CRKP were determined. This could be of help in identifying high-risk patients with whom clinicians should take extra precautions and adjust therapeutic strategy to supplement conventional basic treatment with additional measures.