Melatonin partially rescues defects induced by tranexamic acid exposure during oocyte maturation in mice.

Tranexamic acid (TXA) is widely used among young women because of its ability to whiten skin and treat menorrhagia. Nevertheless, its potential effects on oocyte maturation and quality have not yet been clearly clarified. Melatonin (MT) is an endogenous hormone released by the pineal gland and believed to protect cells from oxidative stress injury. In the present study, we used an in vitro maturation model to investigate the toxicity of TXA and the protective role of MT in mouse oocytes. Compared with the control group, the TXA-exposed group had significantly lower nuclear maturation (57.72% vs. 94.08%, P < 0.001) and early embryo cleavage rates (38.18% vs. 87.66%, P < 0.001). Further study showed that spindle organization (52.56% vs. 18.77%, P < 0.01) and chromosome alignment (33.23% vs. 16.66%, P < 0.01) were also disrupted after TXA treatment. Mechanistically, we have demonstrated that TXA induced early apoptosis of oocytes (P < 0.001) by raising the level of reactive oxygen species (P < 0.001), which was consistent with an increase in mitochondrial damage (P < 0.01). Fortunately, all these effects except the spindle defect were successfully rescued by an appropriate level of MT. Collectively, our findings indicate that MT could partially reverse TXA-induced oocyte quality deterioration in mice by effectively improving mitochondrial function and reducing oxidative stress-mediated apoptosis.NEW & NOTEWORTHY Tranexamic acid is increasingly used to whiten skin, reverse dermal damages, and treat heavy menstrual bleeding in young women. However, its potential toxicity in mammalian oocytes is still unclear. Our study revealed that tranexamic acid exposure impaired the mouse oocyte quality and subsequent embryo development. Meanwhile, melatonin has been found to exert beneficial effects in reducing tranexamic acid-induced mitochondrial dysfunction and oxidative stress.

Pediococcus pentosaceus ZZ61 enhances growth performance and pathogenic resistance of silkworm Bombyx mori by regulating gut microbiota and metabolites.

Probiotics have attracted considerable attention in animal husbandry due to their positive effect on animal growth and health. This study aimed to screen candidate probiotic strain promoting the growth and health of silkworm and reveal the potential mechanisms. A novel probiotic Pediococcus pentosaceus strain (ZZ61) substantially promoted body weight gain, feed efficiency, and silk yield. These effects were likely mediated by changes in the intestinal digestive enzyme activity and nutrient provisioning (e.g., B vitamins) of the host, improving nutrient digestion and assimilation. Additionally, P. pentosaceus produced antimicrobial compounds and increased the antioxidant capacity to protect the host against pathogenic infection. Furthermore, P. pentosaceus affected the gut microbiome and altered the levels of gut metabolites (e.g., glycine and glycerophospholipids), which in turn promotes host nutrition and health. This study contributes to an improved understanding of the interactions between probiotic and host and promotes probiotic utilization in sericulture.

Arterial stiffness progression in metabolic dysfunction-associated fatty liver disease subtypes: A prospective cohort study.

BACKGROUND AND AIMS: We aimed to investigate the correlation and to explore which MAFLD subtypes have the greatest influence on progression of arterial stiffness risk. METHODS AND RESULTS: Using data from a health examination-based cohort, a total of 12,129 participants who underwent two repeated health examinations that included brachial-ankle pulse wave velocity (baPWV) from 2012 to 2020 were enrolled. Participants were separated into non-MAFLD, overweight/obese (OW-MAFLD), lean/normal weight (lean-MAFLD) and diabetes (DM-MAFLD) groups. Among the participants with a median follow-up of 2.17 years, 4511 (37.2%) participants had MAFLD at baseline, among which 3954 (87.7%), 123 (2.7%), and 434 (9.6%) were OW-, lean- and DM-MAFLD, respectively. Analyses using linear regression models confirmed that compared with the non-MAFLD group, the elevated baPWV change rates (cm/s/year) were 12.87 (8.81-16.94), 25.33 (7.84-42.83) and 38.49 (27.88-49.10) in OW, lean and DM-MAFLD, respectively, while the increased change proportions (%) were 1.53 (1.10-1.95), 3.56 (1.72-5.40) and 3.94 (2.82-5.05), respectively. Similar patterns were observed when these two baPWV parameters were transformed in the form of the greatest increase using Cox proportional hazards model analyses. Furthermore, the risk of arterial stiffness progression across MAFLD subtypes presented a significant, gradient, inverse relationship in the order of DM-, lean-, OW with metabolic abnormalities (MA)-, and OW without MA-MAFLD. CONCLUSION: MAFLD, especially DM-MAFLD and lean-MAFLD, was significantly associated with arterial stiffness progression, providing evidence that stratification screening and surveillance strategies for CVD risk have important clinical implications.

Histoplasmosis: An epidemiological and clinical update in China, review and a case report.

Histoplasmosis is a systemic mycosis caused by the dimorphic fungus in the genus Histoplasma. Histoplasmosis is overlooked in China. This study aims to provide an epidemiological and clinical update on histoplasmosis in China by literature review. We reviewed cases of histoplasmosis reported in recent 11 years and described a case of histoplasmosis-triggered hemophagocytic lymphohistiocytosis (HLH) in an immunocompetent patient. A total of 225 cases of histoplasmosis diagnosed in China between 2012 and 2022 were involved in this study, compared with 300 cases reviewed from 1990 to 2011, an increasing number of cases of histoplasmosis have been diagnosed in the last 11 years. The majority of cases of histoplasmosis were autochthonous cases, mainly from provinces Sichuan (56/225, 24.9%), Hunan (50/225, 22.2%), Guangdong (31/225, 13.8%), and Yunnan (24/225, 10.7%). Higher incidence (52.5%, 53/99) of histoplasmosis occurred in immunocompetent patients which is similar to those from the previous 21 years, and the prevalence of the disease did not vary highly over time. Of note, the number of histoplasmosis cases is increasing, and the geographic distribution is shifting southwards over time. Improved awareness is critically important for informing clinical practice in China.

Effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus (COVID-19) vaccination on male fertility.

Coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global public health challenge. This disease causes damage not only to the respiratory system, affecting the normal physiological function of the lungs, but also to other vital organs, such as the heart and testicles. Existing studies have shown that co-expression of angiotensin-converting enzyme 2 and transmembrane serine protease 2 is the main mechanism by which SARS-CoV-2 invades host cells. Angiotensin-converting enzyme 2-expressing cells are widespread in the corpus cavernosum, reproductive tract and testis of men, which has raised concerns. Furthermore, abnormal sex hormone levels and decreased semen parameters were observed in coronavirus disease 2019 patients. This study comprehensively assessed the effects of SARS-CoV-2 infection on the testis, semen parameters, sex hormone levels and erectile function, and discussed possible transmission routes during sexual intercourse and the effect of vaccination on male fertility.

Galleria mellonella in vitro model for chromoblastomycosis shows large differences in virulence between isolates.

BACKGROUND: Chromoblastomycosis is the World Health Organization (WHO)-recognized fungal implantation disease that eventually leads to severe mutilation. Cladophialophora carrionii (C. carrionii) is one of the agents. However, the pathogenesis of C. carrionii is not fully investigated yet. METHODS: We investigated the pathogenic potential of the fungus in a Galleria mellonella (G. mellonella) larvae infection model. Six strains of C. carrionii, and three of its environmental relative C. yegresii were tested. The G. mellonella model was also applied to determine antifungal efficacy of amphotericin B, itraconazole, voriconazole, posaconazole, and terbinafine. RESULTS: All strains were able to infect the larvae, but virulence potentials were strain-specific and showed no correlation with clinical background of the respective isolate. Survival of larvae also varied with infection dose, and with growth speed and melanization of the fungus. Posaconazole and voriconazole exhibited best activity against Cladophialophora, followed by itraconazole and terbinafine, while limited efficacy was seen for amphotericin B. CONCLUSION: Infection behavior deviates significantly between strains. In vitro antifungal susceptibility of tested strains only partly explained the limited treatment efficacy in vivo.

Variability in competitive fitness among environmental and clinical azole-resistant Aspergillus fumigatus isolates.

Azoles are the primary antifungal drugs used to treat infections caused by Aspergillus fumigatus. However, the emergence of azole resistance in A. fumigatus has become a global health concern despite the low proportion of resistant isolates in natural populations. In bacteria, antibiotic resistance incurs a fitness cost that renders strains less competitive in the absence of antibiotics. Consequently, fitness cost is a key determinant of the spread of resistant mutations. However, the cost of azole resistance and its underlying causes in A. fumigatus remain poorly understood. In this observation, we revealed that the 10 out of 15 screened azole-resistant isolates, which possessed the most common azole-targeted cyp51A mutations, particularly the presence of tandem repeats in the promoter region, exhibit fitness cost when competing with the susceptible isolates in azole-free environments. These results suggest that fitness cost may significantly influence the dynamics of azole resistance, which ultimately contributes to the low prevalence of azole-resistant A. fumigatus isolates in the environment and clinic. By constructing in situ cyp51A mutations in a parental azole-susceptible strain and reintroducing the wild-type cyp51A gene into the azole-resistant strains, we demonstrated that fitness cost is not directly dependent on cyp51A mutations but is instead associated with the evolution of variable mutations related to conidial germination or other unknown development-related processes. Importantly, our observations unexpectedly revealed that some azole-resistant isolates showed no detectable fitness cost, and some even exhibited significantly increased competitive fitness in azole-free environments, highlighting the potential risk associated with the prevalence of these isolates. IMPORTANCE: Azole resistance in the human fungal pathogen Aspergillus fumigatus presents a global public health challenge. Understanding the epidemic trends and evolutionary patterns of azole resistance is critical to prevent and control the spread of azole-resistant isolates. The primary cause is the mutation of the drug target 14α-sterol-demethylase Cyp51A, yet its impact on competitive ability remains uncertain. Our competition assays revealed a diverse range of fitness outcomes for environmental and clinical cyp51A-mutated isolates. We have shown that this fitness cost is not reliant on cyp51A mutations but might be linked to unknown mutations induced by stress conditions. Among these isolates, the majority displayed fitness costs, while a few displayed enhanced competitive ability, which may have a potential risk of spread and the need to closely monitor these isolates. Our observation reveals the variation in fitness costs among azole-resistant isolates of A. fumigatus, highlighting the significant role of fitness cost in the spread of resistant strains.

Not only baseline but cumulative exposure of remnant cholesterol predicts the development of nonalcoholic fatty liver disease: a cohort study.

BACKGROUND AND AIM: Remnant cholesterol (remnant-C) mediates the progression of major adverse cardiovascular events. It is unclear whether remnant-C, and particularly cumulative exposure to remnant-C, is associated with nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether remnant-C, not only baseline but cumulative exposure, can be used to independently evaluate the risk of NAFLD. METHODS: This study included 1 cohort totaling 21,958 subjects without NAFLD at baseline who underwent at least 2 repeated health checkups and 1 sub-cohort totaling 2,649 subjects restricted to those individuals with at least 4 examinations and no history of NAFLD until Exam 3. Cumulative remnant-C was calculated as a timeweighted model for each examination multiplied by the time between the 2 examinations divided the whole duration. Cox regression models were performed to estimate the association between baseline and cumulative exposure to remnant-C and incident NAFLD. RESULTS: After multivariable adjustment, compared with the quintile 1 of baseline remnant-C, individuals with higher quintiles demonstrated significantly higher risks for NAFLD (hazard ratio [HR] 1.48, 95%CI 1.31-1.67 for quintile 2; HR 2.07, 95%CI 1.85-2.33 for quintile 3; HR 2.55, 95%CI 2.27-2.88 for quintile 4). Similarly, high cumulative remnant-C quintiles were significantly associated with higher risks for NAFLD (HR 3.43, 95%CI 1.95-6.05 for quintile 2; HR 4.25, 95%CI 2.44-7.40 for quintile 3; HR 6.29, 95%CI 3.59-10.99 for quintile 4), compared with the quintile 1. CONCLUSION: Elevated levels of baseline and cumulative remnant-C were independently associated with incident NAFLD. Monitoring immediate levels and longitudinal trends of remnant-C may need to be emphasized in adults as part of NAFLD prevention strategy.

Genome-Wide Identification and Expression Analysis of WNK Kinase Gene Family in Acorus.

WNK (With No Lysine) kinases are members of serine/threonine protein kinase family, which lack conserved a catalytic lysine (K) residue in protein kinase subdomain II and this residue is replaced by either asparagine, serine, or glycine residues. They are involved in various physiological regulations of flowering time, circadian rhythms, and abiotic stresses in plants. In this study, we identified the WNK gene family in two species of Acorus, and analyzed their phylogenetic relationship, physiochemical properties, subcellular localization, collinearity, and cis-elements. The results showed twenty-two WNKs in two Acorus (seven in Ac. gramineus and fifteen in Ac. calamus) have been identified and clustered into five main clades phylogenetically. Gene structure analysis showed all WNKs possessed essential STKc_WNK or PKc_like superfamily domains, and the gene structures and conserved motifs of the same clade were similar. All the WNKs harbored a large number of light response elements, plant hormone signaling elements, and stress resistance elements. Through a collinearity analysis, two and fourteen segmental duplicated gene pairs were identified in the Ac. gramineus and Ac. calamus, respectively. Moreover, we observed tissue-specificity of WNKs in Acorus using transcriptomic data, and their expressions in response to salt stress and cold stress were analyzed by qRT-PCR. The results showed WNKs are involved in the regulation of abiotic stresses. There were significant differences in the expression levels of most of the WNKs in the leaves and roots of Acorus under salt stress and cold stress, among which two members in Ac. gramineus (AgWNK3 and AgWNK4) and two members in Ac. calamus (AcWNK8 and AcWNK12) were most sensitive to stress. In summary, this paper will significantly contribute to the understanding of WNKs in monocots and thus provide a set up for functional genomics studies of WNK protein kinases.

Metabolic health phenotype better predicts subclinical atherosclerosis than body mass index-based obesity phenotype in the non-alcoholic fatty liver disease population.

Background: Non-alcoholic fatty liver disease (NAFLD), especially lean NAFLD is associated with an increased risk of atherosclerotic cardiovascular disease (CVD). It is not currently known which clinical phenotypes of NAFLD contribute most to individual subclinical atherosclerosis risk. We examined the relationship between body mass index (BMI), the metabolically healthy status, and subclinical atherosclerosis in the NAFLD population. Methods: Data from asymptomatic NAFLD subjects who participated in a routine health check-up examination were collected. Participants were stratified by BMI (cutoff values: 24.0-27.9 kg/m2 for overweight and ≥28.0 kg/m2 for obesity) and metabolic status, which was defined by Adult Treatment Panel III criteria. Subclinical atherosclerosis was evaluated by brachial-ankle pulse wave velocity (baPWV) in 27,738 participants and by carotid plaque in 14,323 participants. Results: Within each BMI strata, metabolically unhealthy subjects had a significantly higher prevalence of subclinical atherosclerosis than metabolically healthy subjects, whereas fewer differences were observed across subjects within the same metabolic category. When BMI and metabolic status were assessed together, a metabolically unhealthy status was the main contributor to the association of clinical phenotypes with the subclinical atherosclerosis burden (all p < 0.001). When BMI and metabolic abnormalities were assessed separately, the incidence of subclinical disease did not increase across BMI categories; however, it increased with an increase in the number of metabolic abnormalities (0, 1, 2 and ≥3). Conclusion: A metabolically healthy status in NAFLD patients was closely correlated with subclinical atherosclerosis, beyond that of the BMI-based obesity phenotype. The application of metabolic phenotyping strategies could enable more precise classification in evaluating cardiovascular risk in NAFLD.

Efficacy and safety of blonanserin versus risperidone in the treatment of schizophrenia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of blonanserin and risperidone for the treatment of schizophrenia and to provide reliable pharmacotherapeutic evidence for in the clinical treatment of schizophrenia. METHODS: We systematically searched the PubMed, Cochrane Library, Embase, Chinese Biomedical Literature Database (CBM), and China National Knowledge Infrastructure (CNKI) databases for head-to-head randomized controlled trials that compared blonanserin with risperidone for the treatment of schizophrenia. We extracted the following data: author, year, country, diagnostic criteria, sample size, course of treatment, dosage and outcomes. Our main endpoint was the changes in the Positive and Negative Syndrome Scale (PANSS) total scores. Meta-analysis of the included data was conducted by RevMan 5.3 software. We used the GRADE criteria to evaluate the certainty of the evidence. RESULTS: A total of 411 studies were initially; 8 trials were eligible and were included in our analysis (N = 1386 participants). Regarding efficacy, there was no difference in changes in the PANSS total scores between the two groups (P > 0.05). In terms of safety, compared to risperidone, the incidence of serum prolactin increases and weight gain in the blonanserin group was lower (P<0.05), but the incidence of extrapyramidal symptoms (EPS) was higher (P<0.05). CONCLUSION: The efficacy of blonanserin is similar to that of risperidone, but it is unclear whether blonanserin is more effective than risperidone at improving cognitive and social function. More high-quality studies are needed to verify the efficacy and safety of blonanserin in the future.

The in vitro Activity of Echinocandins Against Clinical Trichophyton rubrum Isolates and Review of the Susceptibility of T. rubrum to Echinocandins Worldwide.

Introduction: The emergence of resistance in Trichophyton rubrum to azoles and terbinafine has become increasingly evident in recent years, necessitating the development of novel antifungal drugs and the exploration of new indications for existing agents. Methods: In this study, we retrospectively evaluated the in vitro antifungal activity of 3 echinocandins (anidulafungin, caspofungin, and micafungin) against 73 clinical isolates of T. rubrum collected from a teaching hospital in Shanghai, China, using EUCAST E.DEF 9.3.1 with minor modification. We also reviewed the susceptibility of T. rubrum to echinocandins globally by literature searching. Results: Our findings revealed that micafungin exhibited the lowest modal minimum effective concentration (MEC) value (0.08 mg/L, n = 28) and the lowest geometric mean (GM) MEC value (0.014 mg/L) among the 73 isolates of T. rubrum tested, followed by anidulafungin with a modal MEC value of 0.016 mg/L (n = 67) and a GM of 0.018 mg/L. Caspofungin displayed a higher modal MEC value of 0.5 mg/L (n = 35) and a GM of 0.308 mg/L. Despite variations in methodologies, similar results were obtained from the review of five relevant studies included in our analysis. Discussion: Echinocandins exhibited excellent in vitro activity against T. rubrum isolates, with micafungin and anidulafungin demonstrating greater potency than caspofungin. These findings suggest that echinocandins could be considered as potential treatment options for managing recalcitrant dermatophytoses resulting from the emergence of resistance. However, it is important to note that the clinical efficacy of these in vitro findings has yet to be established and warrants further investigation.

Transition patterns of metabolic dysfunction-associated fatty liver disease status in relation to arterial stiffness progression: a health check-up cohort study.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new diagnostic criterion based on hepatic steatosis and metabolic dysfunction. However, a comprehensive evaluation of the association of MAFLD dynamic transitions with arterial stiffness progression has yet to be conducted. This cohort study included 8807 Chinese health check-up participants (median follow-up = 50.2 months). Participants were categorized into four groups according to MAFLD status at baseline and follow-up (none, persistent, developed and regressed). Arterial stiffness progression was assessed by the annual brachial-ankle pulse wave velocity (ba-PWV) increase and arterial stiffness incidence. Compared with the non-MAFLD group, the annual increase in ba-PWV was highest in the persistent-MAFLD group [6.75 cm/s/year, (95% CI 4.03-9.33)], followed by the developed-[6.35 cm/s/year, (95% CI 3.80-8.91)] and the regressed-[1.27 cm/s/year, (95% CI - 2.18 to 4.72)] MAFLD groups. Similarly, compared with the non-MAFLD group, the persistent-MAFLD group had a 1.31-fold increased arterial stiffness risk [OR 1.31; 95% CI 1.03-1.66]. The associations of MAFLD transition patterns with arterial stiffness incidence did not differ across any clinically specific subgroups evaluated. Furthermore, the potential effect of dynamic changes in cardiometabolic risk factors on arterial stiffness incidence among persistent-MAFLD participants was mostly driven by annual fasting glucose and triglyceride increases. In conclusion, persistent MAFLD was associated with an increased risk of arterial stiffness development. Moreover, in persistent-MAFLD subjects, elevated blood glucose and triglyceride levels might facilitate the arterial stiffness incidence.

Baseline level and change trajectory of the triglyceride-glucose index in relation to the development of NAFLD: a large population-based cohort study.

Background: Insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD) are closely related. The triglyceride-glucose index (TyG index) has been proposed as a new indicator of IR. It remains unclear whether the triglyceride-glucose (TyG) index is prospectively associated with incident nonalcoholic fatty liver disease (NAFLD). Methods: This large-scale study comprised 1 prospective cohort totaling 22,758 subjects without NAFLD at baseline who underwent repeated health examinations and 1 subcohort totaling 7,722 subjects with more than three visits. The TyG index was ascertained mathematically by ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). NAFLD was diagnosed by ultrasound without other concomitant liver diseases. A combinatorial Cox proportional hazard model and latent class growth mixture modeling method were used to identify the association of the TyG index and its transition trajectories with NAFLD risk. Results: During 53,481 person-years of follow-up, there were 5319 incident cases with NAFLD. Compared with those in the lowest quartile of the baseline TyG index, participants in the highest quartile had 2.52-fold (95% confidence interval, 2.21-2.86) higher odds of incident NAFLD. Similarly, restricted cubic spline analysis showed a dose-response relationship (p nonlinearity<0.001). Subgroup analyses showed a more significant association in the female and normal body size populations (p for interaction<0.001). Three distinct trajectories of changes in the TyG index were identified. Compared with the continued low group, the moderately increasing and highly increasing groups conferred 1.91-fold (1.65-2.21) and 2.19-fold (1.73-2.77) higher NAFLD risk, respectively. Conclusions: Participants with a higher baseline TyG index or a higher excessive TyG exposure were associated with an increased NAFLD risk. The findings imply that lifestyle interventions and modulation of IR might be considered to both reduce TyG index levels and prevent NAFLD development.

Molecular Characteristics of Macrolide Resistance in Treponema pallidum from Patients with Latent Syphilis in Xinjiang, China.

Background: Macrolide resistance in Treponema pallidum (T. pallidum) has been increasing in recent years worldwide. However, few data are available on macrolide resistance in T. pallidum from Xinjiang province, located in the western part of China, which is an area with a high incidence of syphilis. In this study, we investigated the molecular characteristics of macrolide resistance in T. pallidum from patients with latent syphilis in Xinjiang, China. Methods: In total, 204 whole blood samples were collected from patients with latent syphilis during 2016 to 2017, in the First Hospital of Xinjiang Medical University. Genomic DNA of blood samples was extracted using a QIAamp DNA Mini Kit and T. pallidum was detected by PCR with the specific polA gene of T. pallidum. The 23S rRNA gene of T. pallidum was amplified among the T. pallidum-positive samples by nested PCR, and macrolide resistance-associated mutation sites A2058G and A2059G in the 23S rRNA gene were identified using restriction enzymes MboII and BsaI. Results: The specific polA gene of T. pallidum (T. pallidum positive) was detected in 27 blood samples (13.2%) from 204 patients with latent syphilis. The 23S rRNA gene was then amplified in all 27 T. pallidum-positive samples, among which 24/27 samples (88.9%) harbored the A2058G mutation in the 23S rRNA gene and 3/27 (11.1%) had the A2059G mutation. Conclusion: Our results indicated that T. pallidum macrolide resistance should not be ignored in Xinjiang, China, and that A2058G was the predominant macrolide resistance mechanism. Blood may be a suitable specimen for the detection of resistant mutations of T. pallidum in patients with latent syphilis who do not show any clinical symptoms.

Potency of olorofim (F901318) compared to contemporary antifungal agents against clinical Aspergillus fumigatus isolates, and review of azole resistance phenotype and genotype epidemiology in China.

Triazole resistance in A. fumigatus is an increasing worldwide problem that causes major challenges in the management of aspergillosis. New antifungal drugs are needed with novel targets, that are effective in triazole-resistant infection. In this study, we retrospectively evaluated potency of the novel drug olorofim compared to contemporary antifungal agents against 111 clinical A. fumigatus isolates collected from Huashan Hospital, Shanghai, China, using EUCAST methodology, and reviewed the literature on triazole resistant A. fumigatus published between 1966 and 2020 in China. Olorofim was active in vitro against all tested A. fumigatus isolates with MIC90 of 0.031mg/L (range 0.008-0.062 mg/L). For 4 triazole-resistant A. fumigatus (TRAF) isolates, the olorofim MIC ranged between 0.016-0.062mg/L. The reported rates of TRAF in China is 2.5% - 5.56% for clinical isolates, and 0-1.4% for environmental isolates.TR34/L98H/S297T/F495I is the predominant resistance mechanism, followed by TR34/L98H. Non TR-mediated TRAF isolates, mostly harboring a cyp51A single point mutation, showed greater genetic diversity than TR-mediated resistant isolates. Resistance due toTR34/L98H and TR34/L98H/S297T/F495I mutations among TRAF isolates might have evolved from separate local isolates in China. Continuous isolation of TRAF in China underscores the need for systematic resistance surveillance as well as the need for novel drug targets such as olorofim.

Clinical and Microbiological Characteristics of Aspergillosis at a Chinese Tertiary Teaching Hospital.

Background: Aspergillus spp. infection in immunocompromised patients results in increasing morbidity and mortality. This study investigated clinical and microbiological characteristics of aspergillosis in a Chinese tertiary teaching hospital. Methods: A total of 114 patients with aspergillosis were included over a 5-year period at Ruijin Hospital. In sum, 114 Aspergillus strains were isolated and identified at species level using matrix-assisted laser desorption ionization time-of-flight mass spectrometry, confirmed by ITS gene region and ß-tubulin (BenA) gene sequencing. Sensititre YeastOne was used in vitro to test susceptibility to antifungal drugs: amphotericin B, itraconazole, voriconazole, posaconazole, isavuconazole, micafungin, anidulafungin, and caspofungin. Results: The median age of the patients was 61 (19) years, men accounted for 53.5% (n=61) of the sample, about 64% were immunocompromised, and 36% had underlying diseases. Pulmonary diseases accounted for 27.2%. Aspergillus isolates were mainly isolated from sputum (n=42, 36.8%). Antifungal therapy was administered to 106 (93.0%) patients and voriconazole (n=76, 66.7%) was the most frequently used as empirical therapy. Aspergillus fumigatus (n=69, 60.5%) was the most common species. There was a 73.7% concordance between MALDI-TOF MS and molecular identification. All Aspergillus isolates showed good susceptibility to anidulafungin and caspofungin. Conclusion: Immunocompromised patients are an at-risk population for aspergillosis, and voriconazole was used as empirical therapy in Ruijin Hospital, China. A. fumigatus was the predominant Aspergillus species causing aspergillosis, and A. flavus - as non-A. fumigatus species are increasing - the second-leading cause of aspergillosis. Anidulafungin and caspofungin were the most active in vitro against the Aspergillus isolates tested. The MALDI-TOF MS method showed good accuracy for identification of common Aspergillus spp. In vitro antifungal-susceptibility testing is crucially important for decisions on effective therapy with aspergillosis.

Clinical Risk Factors and Microbiological and Intestinal Characteristics of Carbapenemase-Producing Enterobacteriaceae Colonization and Subsequent Infection.

Gastrointestinal colonization with carbapenem-resistant Enterobacteriaceae (CRE) is always a prerequisite for the development of translocated infections. Here, we sought to screen for fecal carriage of CRE and identify the risk factors for CRE colonization as well as subsequent translocated pneumonia in critically ill patients admitted to the intensive care unit (ICU) of a university hospital in China. We further focused on the intestinal flora composition and fecal metabolic profiles in CRE rectal colonization and translocated infection patients. Animal models of gastrointestinal colonization with a carbapenemase-producing Klebsiella pneumoniae (carbapenem-resistant K. pneumoniae [CRKP]) clinical isolate expressing green fluorescent protein (GFP) were established, and systemic infection was subsequently traced using an in vivo imaging system (IVIS). The intestinal barrier, inflammatory factors, and infiltrating immune cells were further investigated. In this study, we screened 54 patients hospitalized in the ICU with CRE rectal colonization, and 50% of the colonized patients developed CRE-associated pneumonia, in line with the significantly high mortality rate. Upon multivariate analysis, risk factors associated with subsequent pneumonia caused by CRE in patients with fecal colonization included enteral feeding and carbapenem exposure. Furthermore, CRKP colonization and translocated infection influenced the diversity and community composition of the intestinal microbiome. Downregulated propionate and butyrate probably play important and multiangle roles in regulating immune cell infiltration, inflammatory factor expression, and mucus and intestinal epithelial barrier integrity. Although the risk factors and intestinal biomarkers for subsequent infections among CRE-colonized patients were explored, further work is needed to elucidate the complicated mechanisms. IMPORTANCE Carbapenem-resistant Enterobacteriaceae have emerged as a major threat to modern medicine, and the spread of carbapenem-resistant Enterobacteriaceae is a clinical and public health problem. Gastrointestinal colonization by potential pathogens is always a prerequisite for the development of translocated infections, and there is a growing need to assess clinical risk factors and microbiological and intestinal characteristics to prevent the development of clinical infection by carbapenem-resistant Enterobacteriaceae.

Detection of emerging genotypes in Trichophyton mentagrophytes species complex: A proposal for handling biodiversity in dermatophytes.

A resistant and hypervirulent dermatophyte from India has been described as a taxonomic novelty, Trichophyton indotineae, a species of the Trichophyton mentagrophytes complex. Rapid detection and correct identification of closely similar dermatophytes with different predilections are essential for efficient clinical management. We evaluated the efficacy of rapid diagnostic methods clinical and environmental strains in the T. mentagrophytes complex. The methods included Real-time-PCR, DermaGenius, LAMP, and MALDI-ToF MS, using rDNA ITS sequences as taxonomic standard. The results show that only MALDI-ToF MS can distinguish 96.97% T. indotineae from other closely related species. The complex comprises numerous clones which may differ in anonymous markers but with similar evolutionary behavior. Therefore, we recommend to distinguish species only when they show an appreciable degree of adaptation and thus are clinically significant. The distinction of remaining clonal diversity is an epidemiological query and can be solved by haplotype numbering.

Genotypic diversity and antifungal susceptibility of Scedosporium species from clinical settings in China.

BACKGROUND: Scedosporium species have drawn significant interest as inhabitants of polluted soil and water and as cause of high mortality in near-drowning patients. So far, most cases have been reported from Europe and Australia, while knowledge on their prevalence and genotypic diversity from Asia is scant. OBJECTIVES: To increase the knowledge of the genetic diversity and in vitro antifungal susceptibility of Scedosporium species involved in human infections from China. METHODS: Here, we applied the ISHAM-MLST consensus scheme for molecular typing of Scedosporium species and revealed both high species diversity and high genotypic diversity among 45 Chinese clinical Scedosporium isolates. RESULTS: Among the five species, Scedosporium boydii (n = 22) was the most common, followed by S. apiospermum (n = 18), S. aurantiacum (n = 4) and S. dehoogii (n = 1). S. aurantiacum was reported for the first time from clinical samples in China. The predominant sequence types (STs) were ST17 in S. apiospermum, ST4 in S. boydii and ST92 in S. aurantiacum, including four novel STs (ST40, ST41, ST42 and ST43) in S. apiospermum. Based on the CLSI-M38 A2 criterion, voriconazole was the only antifungal compound with low MIC values (MIC90 ≤ 1 µg/ml) for all Scedosporium isolates in our study. CONCLUSIONS: The genetic diversity of clinical isolates of Scedosporium species from China is extremely high, with S. boydii being predominant and S. aurantiacum being firstly reported here. VOR was the only antifungal compound with low MIC values for all Scedosporium isolates in our study, which should be recommended as the firstline antifungal treatment against scedosporiosis in China.