Emergence of multiple fluconazole-resistant Candida parapsilosis sensu stricto clones with persistence and transmission in China.

OBJECTIVES: We explored the epidemiological and molecular characteristics of Candida parapsilosis sensu stricto isolates in China, and their mechanisms of azole resistance. METHODS: Azole susceptibilities of 2318 non-duplicate isolates were determined using CLSI broth microdilution. Isolates were genotyped by a microsatellite typing method. Molecular resistance mechanisms were also studied and functionally validated by CRISPR/Cas9-based genetic alterations. RESULTS: Fluconazole resistance occurred in 2.4% (n = 56) of isolates, and these isolates showed a higher frequency of distribution in ICU inpatients compared with susceptible isolates (48.2%, n = 27/56 versus 27.8%, 613/2208; P = 0.019). Microsatellite-genotyping analysis yielded 29 genotypes among 56 fluconazole-resistant isolates, of which 10 genotypes, including 37 isolates, belonged to clusters, persisting and transmitting in Chinese hospitals for 1-29 months. Clusters harbouring Erg11Y132F (5/10; 50%) were predominant in China. Among these, the second most dominant cluster MT07, including seven isolates, characteristically harbouring Erg11Y132F and Mrr1Q625K, lent its carriage to being one of the strongest associations with cross-resistance and high MICs of fluconazole (>256 mg/L) and voriconazole (2-8 mg/L), causing transmission across two hospitals. Among mutations tested, Mrr1Q625K led to the highest-level increase of fluconazole MIC (32-fold), while mutations located within or near the predicted transcription factor domain of Tac1 (D440Y, T492M and L518F) conferred cross-resistance to azoles. CONCLUSIONS: This study is the first Chinese report of persistence and transmissions of multiple fluconazole-resistant C. parapsilosis sensu stricto clones harbouring Erg11Y132F, and the first demonstration of the mutations Erg11G307A, Mrr1Q625K, Tac1L263S, Tac1D440Y and Tac1T492M as conferring resistance to azoles.

Draft Genome Sequence of Candida saopaulonensis from a Very Premature Infant with Sepsis.

The rare fungus Candida saopaulonensis has never been reported to be associated with human infection. We report the draft genome sequence of the first clinical isolate of C. saopaulonensis, which was isolated from a very premature infant with sepsis. This is the first genome assembly reaching the near-complete chromosomal level with structural annotation for this species, opening up avenues for exploring evolutionary patterns and genetic mechanisms of pathogenesis.

Genome-wide analysis of in vivo-evolved Candida auris reveals multidrug-resistance mechanisms.

Candida auris, an emerging and multidrug-resistant fungal pathogen, has led to numerous outbreaks in China. While the resistance mechanisms against azole and amphotericin B have been studied, the development of drug resistance in this pathogen remains poorly understood, particularly in in vivo-generated drug-resistant strains. This study employed pathogen whole-genome sequencing to investigate the epidemiology and drug-resistance mutations of C. auris using 16 strains isolated from two patients. Identification was conducted through Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and antimicrobial susceptibilities were assessed using broth microdilution and Sensititre YeastOne YO10. Whole-genome sequencing revealed that all isolates belonged to the South Asian lineage, displaying genetic heterogeneity. Despite low genetic variability among patient isolates, notable mutations were identified, including Y132F in ERG11 and A585S in TAC1b, likely linked to increased fluconazole resistance. Strains from patient B also carried F214L in TAC1b, resulting in a consistent voriconazole minimum inhibitory concentration of 4 µg/mL across all isolates. Furthermore, a novel frameshift mutation in the SNG1 gene was observed in amphotericin B-resistant isolates compared to susceptible ones. Our findings suggest the potential transmission of C. auris and emphasize the need to explore variations related to antifungal resistance. This involves analyzing genomic mutations and karyotypes, especially in vivo, to compare sensitive and resistant strains. Further monitoring and validation efforts are crucial for a comprehensive understanding of the mechanisms of drug resistance in C. auris.

Triterpenoid saponins from Bupleurum marginatum and their anti-liver fibrotic activities.

A new triterpenoid saponin (1), along with five known compounds (2-6), was isolated from Bupleurum marginatum Wall. ex DC, of which compounds 2-4 were obtained for the first time from this plant. The structures were confirmed by the analysis of 1D, 2D NMR, and HR-ESIMS data, and comparison with previous spectral data. Anti-liver fibrotic activities of the isolates were determined as proliferation inhibition of LPS-induced activation of HSC-T6 in vitro.

Atopic Dermatitis Associated Retinal Detachment and Retinal Vasculitis: A Case Report.

Atopic dermatitis is usually associated with various ocular complications. We report a 21-year-old Chinese male who presented to our ophthalmology clinic with bilateral retinal detachment and cataracts. The patient had a clear medical history of atopic dermatitis, which had been diagnosed eight years earlier and had been treated with loratadine and pimecrolimus. Cataract surgery was performed for both eyes, combined with scleral buckling for the right eye and pars plana vitrectomy for the left eye. During postoperative follow-up, fundus fluorescein angiography showed retinal vasculitis in both eyes and macular edema in the left eye, which coincided with an exacerbation of atopic dermatitis. Macular edema improved after four months of regular dupilumab treatment in the dermatology department. The ocular condition remained stable three years postoperatively.

Retinal Vasculitis as an Ocular Manifestation in Atopic Dermatitis-Associated Retinal Detachment: A Case Report.

Atopic dermatitis is usually associated with various ocular complications. We report a 21-year-old Chinese male who presented to our ophthalmology clinic with bilateral retinal detachment and cataracts. The patient had a clear medical history of atopic dermatitis, which had been diagnosed eight years earlier and had been treated with loratadine and pimecrolimus. Cataract surgery was performed in both eyes, combined with scleral buckling in the right eye and pars plana vitrectomy in the left eye. During postoperative follow-up, fundus fluorescein angiography indicated retinal vasculitis in both eyes and macular edema in the left eye, which coincided with an exacerbation of atopic dermatitis. Macular edema improved after four months of regular dupilumab treatment in the dermatology department. The ocular condition remained stable three years postoperatively.

Three-Dimensional Morphology and Contour Quality of Conductive Lines Printed by High-Viscosity Paste Jetting.

The utilization of high-viscosity paste jetting technology has the potential to significantly expand the range of available materials and enhance the three-dimensional forming efficiency compared to inkjet printing. In this study, the three-dimensional morphology and contour quality of lines printed using high-viscosity silver paste were investigated. Four types of lines were identified based on differences in the printing shape, and contour fluctuation evaluation indices were defined in both the transverse and longitudinal directions to establish quantitative distinction principles. Based on the research of inkjet printing, a modified theoretical model relating the dimensionless line width and droplet spacing was established considering the cross-sectional characteristics of the lines printed by high-viscosity paste jetting. With the establishment of mathematical models, distinction criteria between various line shapes were obtained and the printable range of uniform lines was determined. Finally, based on response surface methodology, the influences of single droplet jetting parameters, the line printing speed, and their interactions on the line contour fluctuation were analyzed. This study involved theoretical and experimental research on the line morphology and contour quality, which can provide support for control of the line printing quality in high-viscosity paste jetting technology.

Iron and Steel Industry Emissions: A Global Analysis of Trends and Drivers.

The iron and steel industry (ISI) is important for socio-economic progress but emits greenhouse gases and air pollutants detrimental to climate and human health. Understanding its historical emission trends and drivers is crucial for future warming and pollution interventions. Here, we offer an exhaustive analysis of global ISI emissions over the past 60 years, forecasting up to 2050. We evaluate emissions of carbon dioxide and conventional and unconventional air pollutants, including heavy metals and polychlorinated dibenzodioxins and dibenzofurans. Based on this newly established inventory, we dissect the determinants of past emission trends and future trajectories. Results show varied trends for different pollutants. Specifically, PM2.5 emissions decreased consistently during the period 1970 to 2000, attributed to adoption of advanced production technologies. Conversely, NOx and SO2 began declining recently due to stringent controls in major contributors such as China, a trend expected to persist. Currently, end-of-pipe abatement technologies are key to PM2.5 reduction, whereas process modifications are central to CO2 mitigation. Projections suggest that by 2050, developing nations (excluding China) will contribute 52-54% of global ISI PM2.5 emissions, a rise from 29% in 2019. Long-term emission curtailment will necessitate the innovation and widespread adoption of new production and abatement technologies in emerging economies worldwide.

A Stabilized Kriging Method for Mapping Disease Rates.

BACKGROUND: Mapping disease rates is an important aspect of epidemiological research because it helps inform public health policy. Disease maps are often drawn according to local administrative areas (LAAs), such as counties, cities, or towns. In LAAs with small populations, disease rates are unstable and are prone to appear extremely high or low. The empirical Bayes methods consider variance differences among different LAAs, thereby stabilizing the disease rates. The methods of kriging break the constraints of geopolitical boundaries and produce a smooth curved surface in the form of contour lines, but the methods lack the stabilizing effect of the empirical Bayes methods. METHODS: An easy-to-implement stabilized kriging method is proposed to map disease rates, which allows different errors in different LAAs. RESULTS: Monte Carlo simulations revealed that the stabilized kriging method had smaller symmetric mean absolute percentage error than three other types of methods (the original LAA-based method, empirical Bayes methods, and traditional kriging methods) in nearly all scenarios considered. Real-world data analysis of oral cancer incidence rates in men from Taiwan demonstrated that the age-standardized rates in the central mountainous sparsely-populated region of Taiwan were stabilized using our proposed method, with no more large differences in numerical values, whereas the rates in other populous regions were not over-smoothed. Additionally, the stabilized kriging map had improved resolution and helped locate several hot and cold spots in the incidence rates of oral cancer. CONCLUSION: We recommend the use of the stabilized kriging method for mapping disease rates.

Simultaneous determination of multiple constituents, serum composition, and tissue distribution of Qingshen granule using ultra-high performance liquid chromatography-quadrupole-orbitrap high-resolution mass spectrometry.

Qingshen granule, composed of 14 herbal drugs, is primarily used as the assistant therapy for chronic kidney disease. Qingshen granule chemical composition was complex, but its chemical constituents and the pharmacodynamic material basis remain unreported. Ultra-high-performance liquid chromatography (UHPLC)-quadrupole-orbitrap high-resolution mass spectrometry was applied to recognize the chemical constituents of Qingshen granule. The analysis was performed using the ACQUITY UHPLC BEH C18 column (2.1 × 50 mm, 1.7 µm) with acetonitrile-0.1% formic acid as the mobile phase for gradient elution. The data were collected using heated electrospray ionization in positive and negative ion modes. This study successfully applied the UPHLC-quadrupole-orbitrap high-resolution mass spectrometry technique with the Compound Discoverer 3.3 platform to analyze Qingshen granule chemical composition. A total of 127 and 42 chemical components were identified in Qingshen granule in vitro and in vivo, respectively. In the tissue distribution of Qingshen granule, 9, 10, 11, 10, and 18 prototype components were detected in the heart, liver, spleen, lungs, and kidneys, respectively. Qingshen granule chemical constituents were characterized rapidly for the first time in this study, laying a foundation for further research on the substance basis and quality control of Qingshen granule in treating chronic kidney disease.

A novel bidirectional perfusion-like administered system for NIR-II fluorescence imaging precision diagnosis of bladder cancer.

Intravesical instillation has been considered an efficient route for detecting bladder cancer. However, only a small fraction of administered dose permeates into tumor tissues, and insufficient retention time limits their application. In this work, a novel intravesical bidirectional perfusion-like administered mode was developed to improve diagnostic accuracy of bladder tumor imaging. Specifically, the ultrasmall AuPd-P-FA Nanoprobe exhibit excellent NIR-II FL imaging performance due to electronic structure perturbation. Benefiting from the size advantage for kidney metabolism and FA targeting specificity, AuPd-P-FA could effectively administration to bladder tumor. When AuPd-P-FA reached maximum enrichment at 1 h post-injection, the localized and mild thermal energy produced upon laser irradiation activated a phase transition. This thermo-sensitive characteristic could prolong the retention time in bladder and the fluorescence signal could be clearly observed at 6 h post-injection with high accuracy. This novel intravesical bidirectional perfusion-like administered mode is expected to achieve a non-invasive diagnosis of early bladder cancer.

Clinical, Microbiological, and Molecular Characterization of Candia (Starmera) stellimalicola, a Rare Fungal Pathogen Causing Human Infections.

Candia (Starmera) stellimalicola is a yeast species spread worldwide and recovered from varieties of ecological reservoirs, but human infections are rarely reported. In this study, we reported an intra-abdominal infection case caused by C. stellimalicola and described its microbiological and molecular characteristics. C. stellimalicola strains were isolated from ascites fluid of an 82-year-old male patient having diffuse peritonitis with fever and elevated WBC counts. Routine biochemical and MALDI-TOF MS methods failed to identify the pathogenic strains. Phylogenetic analysis of 18S, 26S and internal transcribed space (ITS) rDNA regions, as well as whole-genome sequence identified the strains as C. stellimalicola. Compared with other Starmera species, C. stellimalicola had unique physiological characteristics including thermal tolerance (able to grow at 42 °C), which may prompt its environmental adaptability and potential for opportunistic human infection. Fluconazole minimum inhibitory concentration (MIC) values of the strains identified in this case was 2 mg/L, and the patient had a favorable outcome after receiving fluconazole treatment. In comparison, the majority of C. stellimalicola strains previously documented had high MIC values (≥ 16 mg/L) to fluconazole. In conclusion, with the raise in human infections caused by rare fungal pathogens, molecular diagnostic remains the most efficient way for accurate species identification; and antifungal susceptibility testing is essential to guide proper patient management.

Iridociliary Body Metastasis of Atypical Carcinoid: Case Management with Intravitreal Anti-Vascular Endothelial Growth Factor Injections.

We report a rare case involving a 52-year-old female diagnosed with an atypical bronchial carcinoid tumor with metastases to the mediastinum, hilar lymph nodes, breast, and pancreas. In additional, the patient had metastases to the iris and ciliary body, resulting in progressive vision loss in her left eye. Treatment was successful by intravitreal injections of anti-vascular endothelial growth factor.

Association between periodontitis treatment and dementia in Taiwanese adults.

BACKGROUND: The chronic systemic inflammatory response in periodontitis may be a potential risk factor for dementia, especially in adults. This study determined the association between periodontal treatment and dementia in adults and evaluated the effect of regular scaling treatment on the risk of dementia in this population. METHODS: This case-control study identified 18,930 patients with a dementia-related diagnosis from the Taiwan National Health Insurance Research Database. Scaling and periodontal emergency treatments were evaluated after 1 year and 3 years. Using multivariable logistic regression analysis to evaluate the association between periodontal emergency treatment and dementia risk. RESULTS: The results showed that scaling treatment rates were lower in the dementia cohort than the non-dementia cohort after 1 and 3 years. Patients who received periodontal emergency treatment within 3 years had a significantly increased risk of dementia. Furthermore, patients with periodontitis who did not receive scaling treatment within 3 years had a higher risk of dementia than patients without periodontitis (OR, 1.22; 95% CI, 1.10-1.35). CONCLUSION: This study demonstrated that periodontitis and dementia are associated, and that periodontitis is a risk factor for dementia in adults. The risk of dementia was dependent on the periodontal health status of adults, and our findings suggest that regular scaling can reduce the incidence of dementia in adults. Therefore, regular and routine scaling treatment is suggested for adults.

Assessing the ecological loss of mining areas in Taiwan.

Mines are mostly located in the mountains and national forestlands in Taiwan. The development and use of mines have severely damaged the environment. Despite the long history of mining, the value of forest ecological services lost during mining operations have not yet been incorporated into the expenses borne by miners, and miners are not liable for compensation for ecological damage. This study evaluated the forest ecosystem service benefits lost since mining began, with the aim of providing future reference for calculating ecological damage related to mining. We investigated Mount Taibai mines in Yilan (northeast Taiwan) and Mount Yongshi mines in Hualian (east Taiwan), which are richly forested areas. According to Article 13 of the Mining Act in Taiwan, mining rights have a limitation of 20 years, and the two mines in this study have been in operation for 20 years. By using four ecological services-forest production, carbon sequestration, water resource replenishment, and forest recreation-we estimated the loss of ecological values in both mining regions. The result indicated that the loss of total forest production benefits over 20 years was 7,498.6 k New Taiwanese dollars (NTD) in Mount Taibai mines and 6,543.1 k NTD for Mount Yongshi mines, while the loss for the total carbon sequestration benefits over 20 years was 19,950 k NTD in Mount Taibai mines and 17,400 k NTD in Mount Yongshi mines. The loss of value for the total water conservation benefits over 20 years was 11,160 k NTD in Mount Taibai mines and 5,070 k NTD in Mount Yongshi mines. The loss value of forest recreation over 20 years was 1,443,855 k NTD for the two mines.

A "Dual-Source, Dual-Activation" Strategy for an NIR-II Window Theranostic Nanosystem Enabling Optimal Photothermal-Ion Combination Therapy.

The activatable imaging technique in the second near-infrared window (NIR-II) utilizes the stimulation of cancer-associated biomarkers for specific imaging to guide precise NIR-II photothermal therapy. However, most activatable nanoprobes with single-source stimulation are insufficient in providing comprehensive information regarding the tumor, severely restricting the therapeutic optimization, especially in NIR-II photothermal therapy (PTT)-based combination therapy. Herein, a "dual-source, dual-activation" strategy-based multifunctional nanosystem, PPAC, is reported as a promising tool for activatable NIR-II fluorescence (FL)/ratiometric photoacoustic (PA) imaging-guided "localization-timing" photothermal-ion therapy (PTIT). A fibroblast activation protein (FAP)-responsive peptide to modify the surface of Pd nanosheets with excellent NIR-II absorption ability can efficiently cross-link BSA-CQ4T to realize NIR-II FL quenching, followed by the loading of Ag to construct the PPAC. Triggered by the specific cleavage with FAP on the perivascular cancer-associated fibroblasts (first source), the PPAC can correspondingly release BSA-CQ4T for rapid fluorescence recovery. The nanosystems are subsequently taken up by tumor cells, where the overexpressed H2 O2 (second source) promotes the oxidation of Ag shell to Ag+ , and further leads the real-time ratiometric PA signals (Ag-PA660/Pd-PA1050) that can monitor the Ag+ ions-related production efficiency and therapeutic performance. Intelligent integration of dual-modality imaging information can comprehensively provide the right time-point and site-specificity for selective NIR-II PTT.

Dual H2 O2 -Amplified Nanofactory for Simultaneous Self-Enhanced NIR-II Fluorescence Activation Imaging and Synergistic Tumor Therapy.

Activatable fluorescence imaging in the second near-infrared window (NIR-II FL, 1000-1700 nm) is of great significance for accurate tumor diagnosis and targeting therapy. However, the clinical translation of most stimulus-activated nanoprobes is severely restricted by insufficient tumor response and out-of-synchronization theranostic process. Herein, an intelligent nanofactory AUC-GOx/Cel that possesses the "external supply, internal promotion" dual H2 O2 -amplification strategy for homologous activated tumor theranostic is designed. This nanofactory is constructed via a two-step biomineralization method using Au-doped Ag2 S as a carrier for glucose oxidase (GOx) and celastrol, followed by the growing of CuS to "turn off" the NIR-II FL signal. In the overexpressed H2 O2 tumor-microenvironment, the CuS featuring a responsive-degradability behavior can effectively release Cu ions, resulting in the "ON" state of NIR-II FL and Fenton-like activity. The exposed GOx can realize the intratumoral H2 O2 supply (external supply) via the effective conversion of glucose, and mediating tumor-starvation therapy; the interaction of celastrol and mitochondria can offer a substantial increase in the endogenous H2 O2 level (internal promotion), thereby significantly promoting the chemodynamic therapy (CDT) efficacy. Meanwhile, the dual H2 O2 -enhancement performance will in turn accelerate the degradation of AUC-GOx/Cel, and achieve a positive feedback mechanism for self-reinforcing CDT.

Acetylation of H3K27 activated lncRNA NEAT1 and promoted hepatic lipid accumulation in non-alcoholic fatty liver disease via regulating miR-212-5p/GRIA3.

Non-alcoholic fatty liver disease (NAFLD) was a world-wide health burden. H3K27 acetylation, long non-coding RNA (lncRNA), and miRNA were all implicated in NAFLD regulation, yet the detailed regulatory mechanism was not well understood. LncRNA NEAT1, miR-212-5p, and GRIA3 expression were detected both in high fatty acid-treated hepatocytes cells and NAFLD patients. Lipid droplets were stained and analyzed by oil red O staining. Expression of fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), and GRIA3 was detected by qRT-PCR and western blot. RNA level of lncRNA NEAT1 and miR-212-5p was analyzed by qRT-PCR. The binding sequences of lncRNA NEAT1/miR-212-5p and miR-212-5p/GRIA3 were predicted bioinformatically and validated through luciferase assay. ChIP was performed to analyze H3K27 acetylation on the promoter of lncRNA NEAT1. LncRNA NEAT1 and GRIA3 was upregulated, while miR-212-5p was downregulated in NAFLD patients. FFA promoted lncRNA NEAT1 and GRIA3 expression while suppressing miR-212-5p and promoted lipid accumulation as indicated by increased oil red O staining and FAS and ACC expression. ChIP indicated enrichment of H3K27 on NEAT1 promoter. Inhibition of H3K27 acetylation suppressed lncRNA NEAT1 level. Luciferase results indicated direct interaction of NEAT1/miR-212-5p (which was confirmed by RIP) and miR-212-5p/GRIA3. LncRNA NEAT1 knockdown upregulated miR-212-5p level and inhibited FFA-induced lipid accumulation while suppressing GRIA3 expression. Such function was antagonized by miR-212-5p inhibition and GRIA3 knockdown counteracted with miR-212-5p inhibition. H3K27 acetylation was enriched within the promoter of lncRNA NEAT1 and promoted lncRNA NEAT1 transcription. LncRNA NEAT1 could then interact with miR-212-5p and suppress its cellular concentration.

A stabilized spatiotemporal kriging method for disease mapping and application to male oral cancer and female breast cancer in Taiwan.

Mapping spacetime disease rates can provide a more in-depth understanding of their distribution and trends. Traditional spatiotemporal kriging methods can break the constraints of geopolitical boundaries and time intervals. Still, disease rates in densely and sparsely populated areas are stabilized to the same degree, resulting in a map that is oversmoothed in some places but undersmoothed in others. The stabilized spatiotemporal kriging method proposed in this study overcomes this problem by allowing for nonconstant variances over space and time. A spatiotemporal map of the standardized incidence ratio for oral cancer in men in Taiwan between 1997 and 2017 reveals that the high-risk areas for oral cancer are in the midwestern and southeastern regions of Taiwan, spreading toward the center and north, with persistent cold spots in the northern and southwestern urban regions. However, the corresponding map for breast cancer in women in Taiwan reveals that the high-risk areas for breast cancer are concentrated in densely populated urban regions in the west. Spatiotemporal maps facilitate our understanding of disease risk dynamics. We recommend using the proposed stabilized spatiotemporal kriging method for mapping disease rates across space and time.

Knowledge, attitudes, and practices toward cancer pain management amongst healthcare workers (physicians, pharmacists, and nurses): a cross-sectional study from first-tier cities in China.

PURPOSE: China is currently one of the countries with the largest increased number of new cancer cases in the world, but cancer pain management (CPM) is still inadequate. This study uses a questionnaire to demonstrate the status and differences in knowledge, attitude and practice (KAP) of CPM among healthcare workers (HCWs) in developed regions of China, to find deficiencies and priorities for improvement, from which areas and advantages of the role of pharmacists and mobile devices can be explored. METHODS: This study used data from a questionnaire on CPM from March to June 2019. The study population consisted of a total of 515 HCWs in four first-tier developed cities in China. The questionnaire has four major components, analysis of differences in KAP of different occupations through one-way analysis of variance (ANOVA). RESULTS: Among the respondents, the physicians had the highest knowledge scores toward CPM, pharmacists had the lowest practice scores. Around half of the respondents indicated that their hospital or department have a pharmacist participating in CPM. Physicians and nurses were more likely to expect pharmacists to provide drug counseling. The HCWs interviewed most expect that the mobile-based pain management system can automatically screen and mark patients with pain. CONCLUSION: From this study, it can be suggested that pharmacists and nurses in the CPM team should actively promote relevant knowledge. Besides, pharmacists should focus on improving practical ability such as increasing the frequency of pain assessment. Multidisciplinary collaboration and the introduction of mobile devices can improve and refine the CPM.