Clinical, radiological, and laboratory features of HIV-negative pulmonary cryptococcosis with regard to serum lateral flow assay.

Introduction: Cryptococcosis is the second most common invasive yeast infection in China. Pulmonary cryptococcosis (PC) is difficult to diagnose due to the lack of specific clinical features and the limitation of diagnostic techniques. Although lateral flow assay was very useful in diagnosing cryptococcal infection, quite a few patients with PC presented negative serum lateral flow assay (sLFA). Methods: We conducted a retrospective study of HIV-negative patients who were diagnosed with PC in our hospital over the past decade to explore the potential relationship between the clinical profiles and sLFA in PC. Results: In total, 112 patients with sLFA tested were enrolled in this study, of which 58.93% were male. The positivity rate of sLFA for PC was 91.07%. The extent of pulmonary lesions was positively correlated with sLFA grade (Spearman r = 0.268, p < 0.01). Solitary nodule (SN) and pneumonia were the most common imaging findings in PC with negative and positive sLFA respectively. Among 65 symptomatic PC patients, 14 presented with fever and had higher hypersensitive C-reactive protein (hsCRP) level and more extensive pulmonary involvement (Mann-Whitney U test, p < 0.05) than those without fever. Symptomatic PC patients were more likely to have positive results of sLFA (Mann-Whitney U test, p = 0.05) compared against asymptomatic ones. Discussion: In conclusion, negative sLFA cannot exclude PC in patients with a solitary nodule in lung. Positive sLFA is more reliable in diagnosing PC in symptomatic patients with diffused lesions in lung who generally experience a more severe systemic inflammatory reaction.

Advances in TRPV6 inhibitors for tumors by targeted therapies: Macromolecular proteins, synthetic small molecule compounds, and natural compounds.

TRPV6, a Ca2+-selective member of the transient receptor potential vanilloid (TRPV) family, plays a key role in extracellular calcium transport, calcium ion reuptake, and maintenance of a local low calcium environment. An increasing number of studies have shown that TRPV6 is involved in the regulation of various diseases. Notably, overexpression of TRPV6 is closely related to the occurrence of various cancers. Research confirmed that knocking down TRPV6 could effectively reduce the proliferation and invasiveness of tumors by mainly mediating the calcium signaling pathway. Hence, TRPV6 has become a promising new drug target for numerous tumor treatments. However, the development of TRPV6 inhibitors is still in the early stage, and the existing TRPV6 inhibitors have poor selectivity and off-target effects. In this review, we focus on summarizing and describing the structure characters, and mechanisms of existing TRPV6 inhibitors to provide new ideas and directions for the development of novel TRPV6 inhibitors.

A Fetus with Maternal Uniparental Disomy on Chromosome 20: Case Report with Genetic Analysis and Prenatal Diagnosis.

BACKGROUND: A fetus with increased copy number of chromosome 20 was identified by NIPT. Here we utilize several genetic tests and analyses to illuminate the etiology of such aneuploidy. METHODS: Amniotic fluid cells were extracted from pregnant woman and sent for karyotype and chromosomal microarray analysis (CMA). Trio pedigree analysis was conducted with Chromosome Analysis Suite and uniparental disomy (UPD)-tool software. RESULTS: CMA identified consistent results, which were 2 regions of homozygosity: arr[GRCh37]20p12.2q11.1 (11265096_26266313)hmz and arr[GRCh37]20q11.21q13.2(29510306_54430467)hmz. The trio pedigree analysis discovered that the fetal chromosome 20 was the entire maternal UPD mosaic with isodisomy and heterodisomy. CONCLUSIONS: When a large segment of chromosome is homozygous, appropriate genetic tests are required to find the potential mechanisms for UPD formation.

Performance of Cryptococcal Antigen Lateral Flow Assay in Bronchoalveolar Lavage Fluid in HIV-Negative Patients.

OBJECTIVE: We presented the performance of cryptococcal antigen lateral flow assay test using bronchoalveolar lavage fluid (BALF) samples in the HIV-negative Chinese population. METHODS: From January 2019 to June 2022, cryptococcal antigen was detected in both serum and BALF samples from 113 patients with suspected pulmonary cryptococcosis. RESULTS: 49 patients were finally diagnosed with pulmonary cryptococcosis. The sensitivity of cryptococcal antigen lateral flow assay test in serum and BALF specimens from confirmed cases was 90.0% and 96.0%, respectively, and the specificity was 87.3% and 95.5%, respectively. When the diameter of the lung lesion was less than 15 mm, the antigen positivity rate of BALF was higher than that of serum. Moreover, the result of the cryptococcal antigen test was associated with the lymphocytes count of BALF. CONCLUSION: Our data demonstrate that cryptococcal antigen Lateral Flow Assay for BALF specimens might contribute to the early diagnosis of pulmonary cryptococcosis.

Inhibition of Hsp110-STAT3 interaction in endothelial cells alleviates vascular remodeling in hypoxic pulmonary arterial Hypertension model.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary vascular remodeling which is associated with the malignant phenotypes of pulmonary vascular cells. Recently, the effects of heat shock protein 110 (Hsp110) in human arterial smooth muscle cells were reported. However, the underlying roles and mechanisms of Hsp110 in human pulmonary arterial endothelial cells (HPAECs) that was disordered firstly at the early stage of PAH remain unknown. METHODS: In this research, the expression of Hsp110 in PAH human patients and rat models was investigated, and the Hsp110 localization was determined both in vivo and in vitro. The roles and mechanism of elevated Hsp110 in excessive cell proliferation and migration of HPAECs were assessed respectively exposed to hypoxia. Small molecule inhibitors targeting Hsp110-STAT3 interaction were screened via fluorescence polarization, anti-aggregation and western blot assays. Moreover, the effects of compound 6 on HPAECs abnormal phenotypes in vitro and pulmonary vascular remodeling of hypoxia-indued PAH rats in vivo by interrupting Hsp110-STAT3 interaction were evaluated. RESULTS: Our studies demonstrated that Hsp110 expression was increased in the serum of patients with PAH, as well as in the lungs and pulmonary arteries of PAH rats, when compared to their respective healthy subjects. Moreover, Hsp110 levels were significantly elevated in HPAECs under hypoxia and mediated its aberrant phenotypes. Furthermore, boosted Hsp110-STAT3 interaction resulted in abnormal proliferation and migration via elevating p-STAT3 and c-Myc in HPAECs. Notably, we successfully identified compound 6 as potent Hsp110-STAT3 interaction inhibitor, which effectively inhibited HPAECs proliferation and migration, and significantly ameliorated right heart hypertrophy and vascular remodeling of rats with PAH. CONCLUSIONS: Our studies suggest that elevated Hsp110 plays a vital role in HPAECs and inhibition of the Hsp110-STAT3 interaction is a novel strategy for improving vascular remodeling. In addition, compound 6 could serve as a promising lead compound for developing first-in-class drugs against PAH.

Retrospective analysis of pulmonary cryptococcosis and extrapulmonary cryptococcosis in a chinese tertiary hospital.

Cryptococcosis is an invasive fungal disease with increased morbidity in China over the past two decades. Cryptococci can infect immunocompromised hosts as well as immunocompetent ones. In this study, we reviewed data of 71 inpatients with cryptococcosis at Ningbo First Hospital from May 2010 to May 2020 and compared the clinical profiles of pulmonary cryptococcosis (PC) and extrapulmonary cryptococcosis (EPC). Of 71 patients (38 males, 33 females), 70 were non-HIV. The annual inpatient population increased dramatically, especially in the PC group. PC was confirmed in 77.46% (55/71) of cases by pathology. The rest were EPC including intracranial infection (15.49%, 11/71) and cryptococcemia (7.04%, 5/71). Compared with PC, a larger proportion of EPC patients were found to have immunocompromised conditions judged by predisposing factors (p < 0.01), or detectable humoral or cellular immunodeficiency. Fever and headache were more common in EPC patients (p < 0.001). Patients with EPC had lower serum sodium level (p = 0.041), lower monocyte counts (p = 0.025) and higher C-reactive protein (p = 0.012). In our study, the sensitivity of cryptococcus antigen detection for EPC was 100% regardless of sample type, while serum lateral flow assay (LFA) tested negative in 25% (5/20) of PC. Immunocompromised hosts are more likely to suffer from EPC than PC.

A first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi.

Proteins of the Hsp110 family are molecular chaperones that play important roles in protein homeostasis in eukaryotes. The pathogenic fungus Candida albicans, which causes infections in humans, has a single Hsp110, termed Msi3. Here, we provide proof-of-principle evidence supporting fungal Hsp110s as targets for the development of new antifungal drugs. We identify a pyrazolo[3,4-b] pyridine derivative, termed HLQ2H (or 2H), that inhibits the biochemical and chaperone activities of Msi3, as well as the growth and viability of C. albicans. Moreover, the fungicidal activity of 2H correlates with its inhibition of in vivo protein folding. We propose 2H and related compounds as promising leads for development of new antifungals and as pharmacological tools for the study of the molecular mechanisms and functions of Hsp110s.

Baicalein Inhibits Plasmid-Mediated Horizontal Transmission of the blaKPC Multidrug Resistance Gene from Klebsiella pneumoniae to Escherichia coli.

Carbapenem-resistant bacterial infections pose an urgent threat to public health worldwide. Horizontal transmission of the ß-lacatamase Klebsiella pneumoniae carbapenemase (blaKPC) multidrug resistance gene is a major mechanism for global dissemination of carbapenem resistance. Here, we investigated the effects of baicalein, an active ingredient of a Chinese herbal medicine, on plasmid-mediated horizontal transmission of blaKPC from a meropenem-resistant K. pneumoniae strain (JZ2157) to a meropenem-sensitive Escherichia coli strain (E600). Baicalein showed no direct effects on the growth of JZ2157 or E600. Co-cultivation of JZ2157 and E600 caused the spread of meropenem resistance from JZ2157 to E600. Baicalein at 40 and 400 µg/mL significantly inhibited the spread of meropenem resistance. Co-cultivation also resulted in plasmid-mediated transmission of blaKPC from JZ2157 to E600, which was inhibited by baicalein. Therefore, baicalein may be used in clinical practice to prevent or contain outbreaks of carbapenem-resistant infections by inhibiting the horizontal transfer of resistance genes across bacteria species.

Clinical features of patients with talaromycosis marneffei and microbiological characteristics of the causative strains.

BACKGROUND: Talaromyces marneffei (T. marneffei) is a temperature-dependent dimorphic fungus that is mainly prevalent in Southeast Asia and South China and often causes disseminated life-threatening infections. This study aimed to investigate the clinical features and improve the early diagnosis of talaromycosis marneffei in nonendemic areas. METHODS: We retrospectively analyzed the medical records of six cases of T. marneffei infection. We describe the clinical manifestations, laboratory tests, and imaging manifestations of the six patients. RESULTS: Talaromyces marneffei infection was confirmed by sputum culture, blood culture, tissue biopsy, and metagenomic next-generation sequencing (mNGS). In this study, there were five disseminated-type patients and two HIV patients. One patient died within 24 h, and the others demonstrated considerable improvement after definitive diagnosis. CONCLUSIONS: Due to the lack of significant clinical presentations of talaromycosis marneffei, many cases may be easily misdiagnosed in nonendemic areas. It is particularly important to analyze the imaging manifestations and laboratory findings of infected patients. With the rapid development of molecular biology, mNGS may be a rapid and effective diagnostic method.

The diagnostic utility of IL-10, IL-17, and PCT in patients with sepsis infection.

Objective: The purpose of this study is to determine the diagnostic value and net clinical benefit of interleukin-10 (IL-10), interleukin-17 (IL-17), procalcitonin (PCT), and combination tests in patients with sepsis, which will serve as a standard for sepsis early detection. Patients and methods: An investigation of 84 sepsis patients and 81 patients with local inflammatory diseases admitted to the ICU of Tongji University Hospital in 2021. In addition to comparing inter-group variability, indicators relevant to sepsis diagnosis and therapy were screened. Results: LASSO regression was used to examine PCT, WBC, CRP, IL-10, IFN-, IL-12, and IL-17. Multivariate logistic regression linked IL-10, IL-17, and PCT to sepsis risk. The AUC values of IL-10, IL-17, PCT, and the combination of the three tests were much higher than those of standard laboratory infection indicators. The combined AUC was greater than the sum of IL-10, IL-17, and PCT (P < 0.05). A clinical decision curve analysis of IL-10, IL-17, PCT, and the three combined tests found that the three combined tests outperformed the individual tests in terms of total clinical benefit rate. To predict the risk of sepsis using IL-10, IL-17, and PCT had an AUC of 0.951, and the model's predicted probability was well matched. An examination of the nomogram model's clinical value demonstrated a considerable net therapeutic benefit between 3 and 87%. Conclusion: The IL-10, IL-17, and PCT tests all have a high diagnostic value for patients with sepsis, and the combination of the three tests outperforms the individual tests in terms of diagnostic performance, while the combined tests have a higher overall clinical benefit rate.

Spherical piezoelectric transducers of functionally graded materials.

In this work, a functionally graded spherical piezoelectric transducer (FG-sPET) is proposed and an accurate theoretical model is constructed, mainly composed of a three-port electromechanical equivalent circuit model (EECM). The EECM of FG-sPET can be connected to that of other vibration systems according to the boundary conditions (force and vibration velocity), making it easier to evaluate the whole mechanical vibration system. The validity of the EECM for FG-sPET is verified by comparison with other literature. The effects of geometric dimensions and non-uniform coefficients on the vibration characteristics (resonance/anti-resonance frequencies and effective electromechanical coupling coefficient) of FG-sPET are also studied, contributing to systematically evaluating the key factors determining the vibration characteristics of FG-sPET. The proposed analytical system is of excellent guidance for the structural optimization design of functionally graded piezoelectric devices.

TPN171H alleviates pulmonary hypertension via inhibiting inflammation in hypoxia and monocrotaline-induced rats.

Pulmonary hypertension (PH) is a progressive and life-threatening disease with poor prognosis despite many advances in medical therapy over the past 20 years. Novel therapies which target on the underlying pathology of PH are still urgent to be met. TPN171H is a recently found new compound that exhibits potent pharmacological effects in PH via inhibiting phosphodiesterase type 5 (PDE-5). However, as one icariin derivative, the anti-inflammatory effects of TPN171H for treating PH are not clear. The present study was designed to investigate the therapeutical effect of TPN171H against inflammation in PH and reveal the underlying mechanism. Hypoxia and monocrotaline (MCT)-induced PH rat models were established, which were treated by oral administration of TPN171H (5, 25 mg/kg/d) or sildenafil (25 mg/kg/d). The right ventricle systolic pressure (RVSP), right ventricle hypertrophy index (RVHI) and vascular remodeling were measured. The results suggested that TPN171H significantly reduced RVSP and RVHI, and reversed pulmonary vascular remodeling in rats with both models. Furthermore, in in vivo and in vitro research, our data suggested that TPN171H remarkably suppressed cathepsin B-mediated NLRP3 inflammasome activation, which may contribute to its therapeutical function for PH.

Identification of selective homeodomain interacting protein kinase 2 inhibitors, a potential treatment for renal fibrosis.

Homeodomain interacting protein kinase 2 (HIPK2) has emerged as a promising target for the discovery of anti-renal fibrosis drugs. Herein, to develop specific pharmacologic inhibitors of HIPK2, we designed and synthesized a series of compounds containing benzimidazole and pyrimidine scaffolds via fragment-based drug design strategy. Kinase assay was applied to evaluate the inhibitory activity of target compounds against HIPKs enzyme. The molecular docking study suggest the contribution of tyrosine residues beside the active sites of HIPK1-3 to the selectivity of active compounds. Compound 15q displayed good selectivity and potent inhibitory activity against HIPK2 compared to other two subtype enzymes. 15q could downregulate phosphorylated p53, the direct substrate of HIPK2, and decrease the fibrosis-related downstream of HIPK2, such as p-Smad3 and α-SMA in NRK-49F cells. 15q showed no effect on the cell apoptosis in fibrotic or cancer cell lines, suggesting little cancer risk of 15q. Notably, 15q displayed encouraging in vivo anti-fibrotic effects in the unilateral ureteral obstruction mouse model, which could be used as a potential lead for structural optimization and candidate for the development of selective HIPK2 inhibitors.

Multi-mode coupled vibration performance analysis of a radial-longitudinal (R-L) ultrasonic transducer.

A radial-longitudinal (R-L) ultrasonic transducer is designed by compounding a piezoelectric ceramic and an outer metal ring on the central coupling cylinder of a longitudinal cascade transducer. This design is used to realize multi-mode vibration and increase the radiation range. By applying longitudinal and radial double excitation, three coupled vibration modes of the transducer are generated in the frequency range of 15-65 kHz. The coupled vibration dominated by radial vibration is regarded as the best vibration mode of this transducer. The electromechanical equivalent circuit and the resonance frequency equation of the transducer's coupled vibration are derived by using the equivalent elastic method and one-dimensional vibration theory and verified by the finite element method and experimental method. The results show that the electrical impedance frequency curves of the transducer from the three methods are consistent. The transducer is expected to be used in ultrasonic cleaning and liquid processing applications.

Health economic evaluation of noninvasive prenatal testing and serum screening for down syndrome.

BACKGROUND: Down syndrome (DS), also known as trisomy 21 (T21), is the most common genetic disorder associated with intellectual disability. There are two methods commonly used for prenatal testing of DS: serum screening (SS) for biomarkers in maternal serum and noninvasive prenatal testing (NIPT) for aneuploidy by cell-free DNA (cfDNA) in maternal plasma. However, cost-effectiveness analyses of these two methods are mostly based on data derived from simulations with various models, with theoretical values calculated. In this study, we statistically analyzed clinical DS screening data and pregnancy outcomes during the follow-up of pregnant women in Zhuhai City, China. The economics of the two mainstream prenatal DS screening methods was evaluated from a public health perspective. METHODS: A retrospective analysis was performed on the data of 17,363 pregnant women who received SS and NIPT during gestation in Zhuhai from 2018 to 2019, and a cost-effectiveness analysis was performed with four screening strategies. In strategy I, all pregnant women received SS, and those with T21 risk ≥1/270 had invasive prenatal diagnosis (IPD). In strategy II, all pregnant women received SS, those with T21 risk ≥ 1/270 had IPD, and those with 1/270 > T21 risk ≥ 1/1,000 had NIPT; then, women at high risk based on NIPT also had IPD. In strategy III, all pregnant women received SS, and those with T21 risk ≥1,000 had NIPT; then, women at high risk based on NIPT results had IPD. In strategy IV, all pregnant women received NIPT and those at high risk based on NIPT results had IPD. Finally, to assess the cost and effectiveness of DS screening, the total costs were calculated as the sum of screening and diagnosis as well as the direct and indirect economic burden during the average life cycle of DS patients. RESULTS: A total of 22 of the 17,363 (1/789) pregnant women had DS, of which only one woman was over 35 years of age. SS detected 1,024 cases at high risk of T21 (≥1/270), 8 cases were true positive, with a positive predictive value of 0.78% and a detection rate of 36.4%. NIPT detected 27 cases at high risk of T21 (Z ≥ 3) and 22 cases of DS, with a positive predictive value of 81.5% and a detection rate of 100%. Strategy I had the largest total cost of 65.54 million CNY, strategy II and III had similar total costs of 40 million CNY, and strategy IV had the lowest total cost of 14.91 million CNY. By comparison, the screening strategy with NIPT alone had the highest health economic value for DS. CONCLUSIONS: SS was greatly affected by nuchal translucency and the accuracy of gestational age measured by ultrasonography. Unstandardized ultrasonography was an important reason for the low DS detection rate with SS. The influence of interfering factors on NIPT was much lower than in SS. NIPT can be used as an alternative to SS and as a primary screening strategy of prenatal DS screening for secondary prevention and control of birth defects. NIPT greatly decreased the frequency of IPD and the miscarriages associated with IPD, saved the limited medical and health resources, and greatly increased DS detection rate. Therefore, NIPT has great social and economic benefits.

Whole genome sequence of EC16, a blaNDM-5-, blaCTX-M-55-, and fosA3-coproducing Escherichia coli ST167 clinical isolate from China.

OBJECTIVES: Escherichia coli sequence type 167 (ST167) is an international multiresistant high-risk clone associated with New Delhi metallo-beta-lactamase (NDM) carbapenemase. Here, we report the whole genome sequence of an ST167 clinical isolate (EC16), obtained from a patient with abdominal infection in China, coharbouring the blaNDM-5, blaCTX-M-55, fosA3, aac(3)-IV, and qnrS1 genes. METHODS: E. coli strain EC16 was subjected to antimicrobial susceptibility testing by the broth microdilution method. Whole-genome sequencing of E. coli EC16 was performed using both Oxford Nanopore PromethION and Illumina NovaSeq 6000 platforms. De novo hybrid assembly of short Illumina reads and long PromethION reads was performed using Unicycler. Genome annotation was performed using Prokka 1.14.6, and further whole-genome sequence data analyses were performed. Easyfig 2.2.3 was used to analyse the genetic surroundings of blaNDM-5 and the homologous regions of the blaNDM-5-carrying plasmid pEC16-NDM-5 in E. coli EC16. RESULTS: The complete genome sequence of E. coli EC16 consists of six contigs comprising 5 317 797 bp, including one chromosome and five plasmids. Whole-genome sequencing and further bioinformatics analysis revealed that E. coli EC16 belonged to serotype O101:H9, fumC11 type, and ST167.blaNDM-5 was carried by a novel 145,550-bp IncFII-type plasmid pEC16-NDM-5 within a Tn2-IS26-ISAba125- blaNDM-5- bleMBL-trpF-dsbD-IS91 cassette. CONCLUSION: In this study, we report a clinical E. coli ST167 strain carrying a novel IncFII-type blaNDM-5 plasmid obtained from abdominal infection in China. The presented genome sequences of the blaNDM-5-producing E. coli strain ST167 could provide further insight into the acquisition of multiple resistance genes by this successful lineage.

An emerging strategy for targeted therapy of pulmonary arterial hypertension: Vasodilation plus vascular remodeling inhibition.

Pulmonary arterial hypertension (PAH) is a rapidly progressing disease with limited therapeutic options. Studies have elucidated the multifactorial pathological characteristics of PAH, indicating the complexity and difficulty of PAH treatment. Currently available treatments focus primarily on vasodilation rather than on vascular remodeling, although several drugs have been developed for the latter. This paradigm for management leads to PAH remaining an incurable disease; thus, there is an urgent need to explore new strategies for coping with this devastating disease. In this review, we discuss current strategies and options for PAH therapy and emerging novel therapeutic approaches in PAH treatment. This viewpoint suggests a shift in PAH treatment strategy from mono-activity to dual effects on vasoconstriction and vascular remodeling.

First Case of Bloodstream Infection Caused by Ruminococcus gnavus in an 85 Year Old Man in China.

Ruminococcus gnavus (R. gnavus) is a gram positive anaerobe and a member of the normal intestinal flora of humans. Here, we present a case study of bloodstream infection caused by R. gnavus in an 85 year old man. We identified R. gnavus using target DNA sequencing. The patient was treated with intravenous meropenem and ceftriaxone based on antimicrobial susceptibility tests. He recovered well and was discharged.