NO-ferroheme is a signaling entity in the vasculature.

Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity. Here we show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase and directly activate the sGC-cGMP-PKG pathway without intermediacy of free NO. The NO-ferroheme species (with or without a protein carrier) efficiently relax isolated blood vessels and induce hypotension in rodents, which is greatly potentiated after the blockade of NOS activity. While free NO-induced relaxations are abolished by an NO scavenger and in the presence of red blood cells or blood plasma, a model compound, NO-ferroheme-myoglobin preserves its vasoactivity suggesting the physiological relevance of NO-ferroheme species. We conclude that NO-ferroheme behaves as a signaling entity in the vasculature.

Intraventricular or intrathecal polymyxin B for treatment of post-neurosurgical intracranial infection caused by carbapenem-resistant gram-negative bacteria: a 8-year retrospective study.

PURPOSE: Post-neurosurgical intracranial infection caused by carbapenem-resistant gram-negative bacteria (CRGNB) is a life-threatening complication. This study aimed to assess the current practices and clinical outcomes of intravenous (IV) combined with intraventricular (IVT)/intrathecal (ITH) polymyxin B in treating CRGNB intracranial infection. METHODS: A retrospective study was conducted on patients with post-neurosurgical intracranial infection due to CRGNB from January 2013 to December 2020. Clinical characteristics and treatment outcomes were collected and described. Kaplan-Meier survival and multivariate logistic regression analyses were performed. RESULTS: The study included 114 patients, of which 72 received systemic antimicrobial therapy combined with IVT/ITH polymyxin B, and 42 received IV administration alone. Most infections were caused by carbapenem-resistant Acinetobacter baumannii (CRAB, 63.2%), followed by carbapenem-resistant Klebsiella pneumoniae (CRKP, 31.6%). Compared with the IV group, the IVT/ITH group had a higher cerebrospinal fluid (CSF) sterilization rate in 7 days (p < 0.001) and lower 30-day mortality (p = 0.032). In the IVT/ITH group, patients with CRKP infection had a higher initial fever (p = 0.014), higher incidence of bloodstream infection (p = 0.040), lower CSF sterilization in 7 days (p < 0.001), and higher 30-day mortality (p = 0.005) than those with CRAB infection. Multivariate logistic regression analysis revealed that the duration of IVT/ITH polymyxin B (p = 0.021) was independently associated with 30-day mortality. CONCLUSIONS: Intravenous combined with IVT/ITH polymyxin B increased CSF microbiological eradication and improved clinical outcomes. CRKP intracranial infections may lead to more difficult treatment and thus warrant attention and further optimized treatment.

Himalayan mountains imposing a barrier on gene flow of wheat yellow rust pathogen in the bordering regions of Pakistan and China.

The wheat yellow rust pathogen has been shown to be diverse and potentially originated in the Himalayan region. Although Himalayan populations of Pakistan, Nepal and Bhutan have been previously compared, little is known about the relative divergence and diversity in Puccinia striiformis populations in the bordering regions of Pakistan and China. To assess the relative diversity and divergence in these regions of Pakistan (Gilgit-Baltistan, Hazara and Azad Jammu Kashmir) and China (Xinjiang, Qinghai, Tibet, Sichuan, Guizhou and Yunnan), a total of 1245 samples were genotyped using 17 microsatellite SSR markers. A clear divergence was observed between the bordering regions of Pakistan and China (FST = 0.28) without any resampling of genetic groups and multilocus genotypes across two sides of the Himalayan mountains. The closest subpopulations across the two countries were Xinjiang and Gilgit-Baltistan (Nei's distance = 0.147), which were close geographically. A very high diversity and recombinant population structure was observed in both populations, though slightly higher in China (Genotypic diversity = 0.970; r¯d = 0.000) than in Pakistan (Genotypic diversity = 0.902; r¯d = 0.065). The distribution of genetic groups and resampling of MLGs revealed more gene flow across Yunnan, Guizhou and Sichuan regions in China, while between Hazara and Azad-Jammu Kashmir in Pakistan. The lack of gene flow between Pakistan and China populations is due to geographical barriers and a large patch of land without wheat. The information on the relative diversity and divergence in different geographical zones of the pathogen center of diversity and neighboring region should be considered in resistant wheat deployment while considering the invasion potential of the pathogen at regional and global contexts.

Dihydromyricetin attenuates cisplatin-induced acute kidney injury by reducing oxidative stress, inflammation and ferroptosis.

BACKGROUND: Cisplatin is effective against various types of cancers. However, its clinical application is limited owing to its adverse effects, especially acute kidney injury (AKI). Dihydromyricetin (DHM), a flavonoid derived from Ampelopsis grossedentata, has varied pharmacological activities. This research aimed to determine the molecular mechanism for cisplatin-induced AKI. METHODS: A murine model of cisplatin-induced AKI (22 mg/kg, I.P.) and a HK-2 cell model of cisplatin-induced damage (30 µM) were established to evaluate the protective function of DHM. Renal dysfunction markers, renal morphology and potential signaling pathways were investigated. RESULTS: DHM decreased the levels of renal function biomarkers (blood urea nitrogen and serum creatinine), mitigated renal morphological damage, and downregulated the protein levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. It upregulated the expression levels of antioxidant enzymes (superoxide dismutase and catalase expression), nuclear factor-erythroid-2-related factor 2 (Nrf2) and its downstream proteins, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic (GCLC) and modulatory (GCLM) subunits, thus eventually reducing cisplatin-induced reactive oxygen species (ROS) production. Moreover, DHM partially inhibited the phosphorylation of the active fragments of caspase-8 and -3 and mitogen-activated protein kinase and restored glutathione peroxidase 4 expression, which attenuated renal apoptosis and ferroptosis in cisplatin-treated animals. DHM also mitigated the activation of NLRP3 inflammasome and nuclear factor (NF)-κB, attenuating the inflammatory response. In addition, it reduced cisplatin-induced HK-2 cell apoptosis and ROS production, both of which were blocked by the Nrf2 inhibitor ML385. CONCLUSIONS: DHM suppressed cisplatin-induced oxidative stress, inflammation and ferroptosis probably through regulating of Nrf2/HO-1, MAPK and NF-κB signaling pathways.

Clinical characteristics and prognostic risk factors of candidemia in non-neutropenic patients: a retrospective cohort study.

This study aimed to determine the clinical characteristics and the prognostic risk factors in non-neutropenic patients with candidemia. Data were retrospectively collected through the medical record information system. Non-neutropenic patients with candidemia were relatively aged, with a more than one-third rate of in-hospitalization mortality. In multivariate analysis, APACHE II score (adjusted odds ratio [aOR], 1.138; 95% confidence interval [CI], 1.067-1.213), septic shock (aOR, 5.704; 95% CI, 2.639-12.326) and RRT (aOR, 16.152; 95% CI, 2.628-99.275) (all P < 0.01) were independent related with non-survivors. In conclusion, non-neutropenic patients with candidemia have a high in-hospitalization mortality, and APACHE II, septic shock, and RRT are independently factors.

Neddylation Alleviates Methicillin-Resistant Staphylococcus aureus Infection by Inducing Macrophage Reactive Oxygen Species Production.

Neddylation, a posttranslational modification in which NEDD8 is covalently attached to target proteins, has emerged as an endogenous regulator of innate immunity. However, the role of neddylation in methicillin-resistant Staphylococcus aureus (MRSA) infection remains unknown. In this study, we found that neddylation was activated after MRSA infection in vivo and in vitro. Inhibition of neddylation with MLN4924 promoted injury of liver and kidneys in C57BL/6 mice with MRSA bloodstream infection and increased mortality. Blockade of neddylation, either pharmacologically (MLN4924, DI591) or through the use of Uba3 small interfering RNA, inhibited Cullin3 neddylation and promoted Nrf2 accumulation, thus reducing reactive oxygen species (ROS) induction and bacterial killing ability in mouse peritoneal macrophages. In summary, our findings suggest that activation of neddylation in macrophages plays a critical protective role against MRSA infection by increasing ROS production, partially by signaling through the NEDD8-Cullin3-Nrf2-ROS axis. Furthermore, our results may provide a new non-antibiotic treatment strategy for MRSA infection through targeting of neddylation.

Mifepristone increases AQP1 mRNA expression, angiogenesis, and cell permeability through the ERK MAPK pathway.

AIMS: The purpose of this study was to investigate the mechanism of mifepristone serves as an anti-implantation contraceptive drug on aquaporins 1 (AQP1) expression. METHODS: Human umbilical vein endothelial cells (HUVECs) were used to detect the effects of different concentrations of mifepristone (0, 0.065, 0.2, and 1 µmol/L) on the activity of angiogenesis and AQP1 expression. The expression of AQP1 was tested by the real-time PCR. The angiogenesis and penetration function of HUVECs was investigated by Matrigel lumen formation and trans-well assay, respectively. RESULTS: The expression of AQP1, angiogenesis and cell permeability were significantly higher than control groups in HUVECs treatment with mifepristone at 1 µmol/L for 12 h. Estrogen and progesterone decreased the up-regulation of AQP1 and cell permeability, not angiogenesis, induced by mifepristone. Mifepristone increased protein levels of p-ERK, not p-p38 or p-JNK, and pre-treatment with ERK MAPK-specific inhibitor significantly inhibited the up-regulation of AQP1 mRNA expression, angiogenesis and cell permeability induced by mifepristone. si-AQP1 significantly reduced the up-regulation of angiogenesis, cell permeability and p-ERK/ERK ratio expression induced by mifepristone treatment. Overexpression of AQP1 enhanced the increase of expression ratio of p-ERK/ERK induced by mifepristone. CONCLUSIONS: Low-dose mifepristone increased cell permeability, angiogenesis and AQP1 expression, which was involved in MAPK pathways. This provides new insights into the molecular mechanism of mifepristone serves as an anti-implantation contraceptive drug.

Clinical characteristics, risk factors and outcomes of Klebsiella pneumoniae pneumonia developing secondary Klebsiella pneumoniae bloodstream infection.

PURPOSE: The clinical characteristics of Klebsiella pneumoniae (KP) pneumonia and KP bloodstream infection (KP-BSI) are often reported, while the risk factors for KP pneumonia developing into secondary KP-BSI (KP-pneumonia/KP-BSI) are largely unknown. Therefore, this study attempted to investigate the clinical characteristics, risk factors and outcomes of KP-pneumonia/KP-BSI. METHODS: A retrospective observational study was conducted at a tertiary hospital between January 1, 2018, and December 31, 2020. The patients were divided into groups of KP pneumonia alone and KP pneumonia/KP-BSI, and the clinical information were collected from medical records electronic system. RESULTS: A total of 409 patients were finally recruited. According to the multivariate logistic regression analysis, male sex (adjusted odds ratio [aOR] 3.7; 95% CI, 1.44-9.5), immunosuppression (aOR, 13.52; 95% CI, 2.53,72.22), APACHE II score higher than 21 (aOR, 3.39; 95% CI, 1.41-8.12), serum procalcitonin (PCT) levels above 1.8 ng/ml (aOR, 6.37; 95% CI, 2.67-15.27), ICU stay of more than 2.5 days before pneumonia onset (aOR, 1.09; 95% CI, 1.02,1.17), mechanical ventilation (aOR, 4.96; 95% CI, 1.2,20.5), Klebsiella pneumoniae isolates producing extended spectrum ß-lactamase (ESBL-positive KP) (aOR, 12.93; 95% CI, 5.26-31.76), and inappropriate antibacterial therapy (aOR, 12.38; 95% CI, 5.36-28.58) were independent factors of KP pneumonia/KP BSI. In comparison with the patients with KP pneumonia alone, the patients with KP pneumonia/KP BSI showed an almost 3 times higher incidence of septic shock (64.4% vs. 20.1%, p < 0.01), a longer duration of mechanical ventilation, and longer lengths of ICU stay and total hospital stay (median days, 15 vs. 4,19 vs. 6, 34 vs. 17, respectively, both p < 0.01). Additionally, the overall in-hospital crude mortality rate in the patients with KP-pneumonia/KP-BSI was more than two times higher than that in those with KP pneumonia alone (61.5% vs. 27.4%, p < 0.01). CONCLUSION: Factors including male sex, immunosuppression, APACHE II score higher than 21, serum PCT levels above 1.8 ng/ml, ICU stay of more than 2.5 days before pneumonia onset, mechanical ventilation, ESBL-positive KP, and inappropriate antibacterial therapy are independent risk factors for KP pneumonia/KP-BSI. Of note, the outcomes in patients with KP pneumonia worsen once they develop secondary KP-BSI, which merits more attention.

Genetic Characteristics and Linkage of Virulence Genes of the Puccinia striiformis f. sp. tritici TSA-6 Isolate to Yr5 Host Resistance.

To understand the inheritance of the TSA-6 Puccinia striiformis f. sp. tritici (Pst) isolate that is virulent to Yr5 and was recently detected in China, we analyzed avirulence and virulence of 120 selfed progeny lines from Berberis shensiana. The results showed that the TSA-6 isolate is virulent against the Yr5 resistance gene, and overall progeny lines were categorized into 73 virulence phenotypes (VPs); of these, 72 VPs differed from the isolate TSA-6, and only one VP, including three progeny, was identical to the parental isolate. The analyses indicated that the TSA-6 isolate is homozygous for avirulence at the Yr10, Yr15, and Yr26 resistance loci and virulence at the YrA resistance locus. The TSA-6 isolate is heterozygous for avirulence at the Yr2, Yr3, Yr5, Yr7, and Yr8 resistance loci, which are controlled by a dominant/recessive relationship. The Yr1, Yr6, Yr9, Yr17, Yr27, Yr25, Yr28, Yr29, Yr32, YrTr1, and YrSP resistance loci are governed by two complementary dominant/recessive genes. Avirulence against heterozygous Yr4, Yr43, Yr44, Yr76, and YrExp2 resistance loci is regulated by a dominant and recessive or a dominant and suppressor gene pair. In total, 117 multilocus genotypes were detected at 24 KASP-SNP marker loci among the 120 progenies. Using these marker loci, we constructed a linkage map with a genetic distance interval spanning 624.5 cM. Quantitative trait loci corresponding to phenotypic segregation for virulence at 20 Yr resistance loci in addition to the Yr1 resistance locus were identified. These results facilitate our understanding of Pst virulence evolution and simplify breeding of wheat cultivars with effective resistance to wheat stripe rust.

Direct Evidence Demonstrates that Puccinia striiformis f. sp. tritici Infects Susceptible Barberry to Complete Sexual Cycle in Autumn.

Wheat stripe rust is an airborne and destructive disease caused by a heteroecious rust fungus Puccinia striiformis f. sp. tritici (Pst). Studies have demonstrated that the rust pathogen accomplishes sexual reproduction on susceptible barberry under natural conditions in spring, whereas Pst infection on barberry is still in blank in other seasons. In late October 2016, aecial production on barberry shrubs were observed in Linzhi, Tibet, China. Therefore, experimental tests were conducted to verify the existence of sexual cycles of Pst in this season. By inoculating 52 aecial clusters from 30 rusted barberry leaves, four Pst samples, T1 to T4, were successfully recovered from the rusted barberry shrubs. Sixty-five single uredinium (SU) isolates were derived from the four Pst samples. Based on virulence tests on the Chinese differential hosts, T1 to T4 samples were unknown races and showed mixed reactions on some differentials. Twenty-one known races and 44 unknown races belonging to five race groups were identified among the 65 SU isolates. Meanwhile, the 65 SU isolates produced 26 various virulence patterns (VPs; called VP1-VP26) on 25 single Yr gene lines and 15 multilocus genotypes (MLGs) at nine simple sequence repeat marker loci. Clustering analysis showed similar lineage among subpopulations and different lineage between subpopulations. Linkage disequilibrium analysis indicated that the SU population was produced sexually. This study first reported that Pst infects susceptible barberry to complete sexual reproduction in autumn. The results update the knowledge of disease cycle and management of wheat stripe rust and contribute to the understanding of rust genetic diversity in Tibet.

NETs Promote Inflammatory Injury by Activating cGAS-STING Pathway in Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) threatens the survival of critically ill patients, the mechanisms of which are still unclear. Neutrophil extracellular traps (NETs) released by activated neutrophils play a critical role in inflammatory injury. We investigated the role of NETs and the underlying mechanism involved in acute lung injury (ALI). We found a higher expression of NETs and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) in the airways, which was reduced by Deoxyribonuclease I (DNase I) in ALI. The administration of the STING inhibitor H-151 also significantly relieved inflammatory lung injury, but failed to affect the high expression of NETs in ALI. We isolated murine neutrophils from bone marrow and acquired human neutrophils by inducing HL-60 to differentiate. After the PMA interventions, exogenous NETs were obtained from such extracted neutrophils. Exogenous NETs intervention in vitro and in vivo resulted in airway injury, and such inflammatory lung injury was reversed upon degrading NETs with or inhibiting cGAS-STING with H-151 as well as siRNA STING. In conclusion, cGAS-STING participates in regulating NETs-mediated inflammatory pulmonary injury, which is expected to be a new therapeutic target for ARDS/ALI.

Countrywide inter-epidemic region migration pattern suggests the role of southwestern population in wheat stripe rust epidemics in China.

Understanding countrywide pathogen population structure and inter-epidemic region spread is crucial for deciphering crop potential losses. Wheat stripe rust caused by Puccinia striiformis f. sp. tritici is a destructive disease that affects worldwide wheat production, widespread in China, representing largest epidemic region globally. This study aimed to understand the population structure and migration route of P. striiformis f. sp. tritici across China based on sampling from 15 provinces representing six epidemic zones, viz., over-summering, over-wintering, eastern, Yun-Gui, Xinjiang and Tibet epidemic regions. High genotypic diversity was recorded in over-summering, Tibet and over-wintering epidemic regions. Epidemic regions partly explain population subdivision with variable divergence (FST  = 0.005-0.344). Xinjiang and Tibet epidemic regions were independent epidemic zones with least sharing of genotypes. Among other epidemic zones, i.e. over-summering, over-wintering, eastern and Yun-Gui epidemic zones, re-sampling MLGs, clustering-based structure, DAPC analyses, relative migration and low divergence (FST from 0.006 to 0.073) revealed frequent geneflow. Yun-Gui epidemic regions, with a potential for both over-summering and over-wintering, could play an important role in causing epidemics in main wheat-cultivating areas of China. High diversity, recombination signatures and inter-epidemic region migration patterns need to be considered in host-resistant cultivar development in China and neighbouring countries, considering risk of long-distance migration capacity of pathogen.

Dopamine 1 receptors inhibit apoptosis via activating CSE/H2 S pathway in high glucose-induced vascular endothelial cells.

High glucose (HG)-induced dysfunction of vascular endothelial cells plays a crucial role in the development of diabetic vascular complications. Inhibition of cystathionine γ-synthase/hydrogen sulfide (CSE/H2 S) pathway is one of the causes of vascular endothelial cell injury induced by HG. Dopamine D1 receptors (DR1) are widely expressed and regulate important physiological functions in the vascular system. However, the effect of DR1 inhibition on HG-induced vascular endothelial apoptosis by regulating the CSE/H2 S pathway is unclear. Therefore, we aimed to determine if DR1 can regulate the CSE/H2 S pathway and regulate the effect of DR1 on HG-induced apoptosis in human umbilical vein endothelial cells. In this study, we found that HG treatment significantly decreased the expression of DR1 and CSE and the endogenous content of H2 S; DR1 agonist SKF 38393 reversed these effects, while sodium hydrosulfide (NaHS) only increased CSE expression and the endogenous H2 S production and had no effect on DR1 expression. Meanwhile, HG significantly increased the intracellular calcium concentration ([Ca2+ ]i ), and SKF 38393 further increased HG-induced [Ca2+ ]i . In addition, HG increased the lactate dehydrogenase activity, malondialdehyde and reactive oxygen species contents, apoptotic rate, the expression of cleaved caspase-3, caspase-9, and cytochrome c, and the activity of phosphorylated-inhibitor of nuclear factor-kappaBα (NF-κBα) (p-IκBα) and phosphorylated-NF-κB (p-NF-κB), and reduced cell viability, superoxide dismutase activity, and Bcl-2 expressions. SKF 38393 and NaHS markedly reversed the effect of HG. The effect of SKF 38393 was similar to N-acetyl- l-cysteine (an inhibitor of oxidative stress) or pyrrolidinedithiocarbamate ammonium (an NF-kB inhibitor). Taken together, DR1 upregulates the CSE/H2 S pathway by increasing the [Ca2+ ]i , which inhibits HG-induced apoptosis via downregulating NF-κB/IκBα pathway in vascular endothelial cells.

Incidence, clinical characteristics, risk factors and outcomes of patients with mixed Candida/bacterial bloodstream infections: a retrospective study.

PURPOSE: The mixed Candida/bacterial bloodstream infections (mixed C/B-BSIs) is worthy of particular attention recently, and we analyzed the incidence, co-pathogens, clinical characteristics, risk factors, and outcomes of mixed C/B-BSIs compared with monomicrobial candidemia (mono-candidemia) in adult patients in China. METHODS: All hospitalized adults with candidemia were recruited for this retrospective observational study from January 1, 2013, to December 31, 2019. RESULTS: Of the 296 patients with candidemia, 78 cases (26.3%) were mixed C/B-BSIs. Candida albicans (C. albicans) was the most common Candida species among all candidemia, and Klebsiella pneumoniae (K. pneumoniae) was the most concomitant bacteria (30.6%), followed by Acinetobacter baumannii (A. baumannii) (12.9%) and Enterococcus faecium (E. faecium) (11.8%) in mixed C/B-BSIs. In the multivariable analysis, prior ß-lactams exposure [adjusted odds ratio (aOR), 1.97; 95% confidence interval (CI), 1.01-3.87], burn injury (aOR, 6.35; 95% CI 1.82-22.21) and continuous renal replacement therapy (CRRT) (aOR, 3.00; 95% CI 1.46-6.17) were independent risk factors for mixed C/B-BSIs. Compared with mono-candidemia, patients with mixed C/B-BSIs developed with more proportion of septic shock (55.1% vs. 39.9%, P < 0.05), prolonged stay in ICU [22.0(12.0-57.0) vs. 9.5(0.0-37.0) days, P < 0.001] and longer mechanical ventilation time [19.0(4.5-40.8) vs. 6.0(0.0-24.8) days, P < 0.001]. The in-hospital mortality in patients with mixed C/B-BSIs was higher than those with mono-candidemia (59.0% vs. 34.9%, P < 0.001). Survival analysis revealed that 28-day and 60-day mortality were significantly higher in patients with mixed C/B-BSI than in those with mono-candidemia (57.7% vs. 31.7%, P < 0.001; 59.0% vs. 34.9%, P < 0.001; respectively). CONCLUSIONS: There is a high rate of mixed C/B-BSIs cases among candidemia, and K. pneumoniae is the predominant coexisting species. Prior ß-lactams exposure, burn injury, and CRRT are independent risk factors for mixed C/B-BSIs. The mortality of patients with mixed C/B-BSIs is significantly higher than those with mono-candidemia, this deserves further attention for clinicians.

Inheritance and Linkage of Virulence Genes of Puccinia striiformis f. sp. hordei.

Puccinia striiformis f. sp. hordei (Psh) causing barley stripe rust has only recently been known to be heteroecious, for which reason the inheritance of its virulence has not been analyzed. Herein, we selfed a Psh isolate, XZ-19-972, on Berberis aggregata and obtained 53 progenies. The virulence phenotypes (VPs) for these progenies were identified on 11 barley differentials, and their genotypes were assessed with 22 Kompetitive allele specific PCR-single nucleotide polymorphism (KASP-SNP) markers. In total, 18 VPs were detected among progenies, 17 (VP2-VP18) of which, corresponding to 43 isolates, were different from the parental isolate showing VP1. Of the 53 progenies, 8 exhibited increased virulence and 34 decreased virulence. One progeny, belonging to VP18, showed a different virulence formula but without a virulence increase or decrease. The parental isolate and all progenies were avirulent to yrc6 but virulent to yrc7. The parental isolate was heterozygous in terms of avirulence/virulence to nine barley resistance gene loci. KASP-SNP marker analysis identified 36 multilocus genotypes, based on which a linkage map was constructed, with total genetic distance intervals of 516.07 cM, spanning 16 avirulence or virulence loci. Taken together, our results provide important insights into the inheritance and virulence diversity of Psh.

The risk factors for deep venous thrombosis in critically ill older adult patients: a subgroup analysis of a prospective, multicenter, observational study.

BACKGROUND: Older adult patients mainly suffer from multiple comorbidities and are at a higher risk of deep venous thrombosis (DVT) during their stay in the intensive care unit (ICU) than younger adult patients. This study aimed to analyze the risk factors for DVT in critically ill older adult patients. METHODS: This was a subgroup analysis of a prospective, multicenter, observational study of patients who were admitted to the ICU of 54 hospitals in Zhejiang Province from September 2019 to January 2020 (ChiCTR1900024956). Patients aged > 60 years old on ICU admission were included. The primary outcome was DVT during the ICU stay. The secondary outcomes were the 28- and 60-day survival rates, duration of stay in ICU, length of hospitalization, pulmonary embolism, incidence of bleeding events, and 60-day coagulopathy. RESULTS: A total of 650 patients were finally included. DVT occurred in 44 (2.3%) patients. The multivariable logistic regression analysis showed that age (≥75 vs 60-74 years old, odds ratio (OR) = 2.091, 95% confidence interval (CI): 1.308-2.846, P = 0.001), the use of analgesic/sedative/muscarinic drugs (OR = 2.451, 95%CI: 1.814-7.385, P = 0.011), D-dimer level (OR = 1.937, 95%CI: 1.511-3.063, P = 0.006), high Caprini risk score (OR = 2.862, 95%CI: 1.321-2.318, P = 0.039), basic prophylaxis (OR = 0.111, 95%CI: 0.029-0.430, P = 0.001), and physical prophylaxis (OR = 0.322, 95%CI: 0.109-0.954, P = 0.041) were independently associated with DVT. There were no significant differences in 28- and 60-day survival rates, duration of stay in ICU, total length of hospitalization, 60-day pulmonary embolism, and coagulation dysfunction between the two groups, while the DVT group had a higher incidence of bleeding events (2.6% vs. 8.9%, P < 0.001). CONCLUSION: In critically ill older adult patients, basic prophylaxis and physical prophylaxis were found as independent protective factors for DVT. Age (≥75 years old), the use of analgesic/sedative/muscarinic drugs, D-dimer level, and high Caprini risk score were noted as independent risk factors for DVT. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900024956).URL: http://www.chictr.org.cn/listbycreater.aspx .

Glibenclamide Alleviates LPS-Induced Acute Lung Injury through NLRP3 Inflammasome Signaling Pathway.

Glibenclamide displays an anti-inflammatory response in various pulmonary diseases, but its exact role in lipopolysaccharide- (LPS-) induced acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) remains unknown. Herein, we aimed to explore the effect of glibenclamide in vivo and in vitro on the development of LPS-induced ALI in a mouse model. LPS stimulation resulted in increases in lung injury score, wet/dry ratio, and capillary permeability in lungs, as well as in total protein concentration, inflammatory cells, and inflammatory cytokines including IL-1ß, IL-18 in bronchoalveolar lavage fluid (BALF), and lung tissues, whereas glibenclamide treatment reduced these changes. Meanwhile, the increased proteins of NLRP3 and Caspase-1/p20 after LPS instillation in lungs were downregulated by glibenclamide. Similarly, in vitro experiments also found that glibenclamide administration inhibited the LPS-induced upregulations in cytokine secretions of IL-1ß and IL-18, as well as in the expression of components in NLRP3 inflammasome in mouse peritoneal macrophages. Of note, glibenclamide had no effect on the secretion of TNF-α in vivo nor in vitro, implicating that its anti-inflammatory effect is relatively specific to NLRP3 inflammasome. In conclusion, glibenclamide alleviates the development of LPS-induced ALI in a mouse model via inhibiting the NLRP3/Caspase-1/IL-1ß signaling pathway, which might provide a new strategy for the treatment of LPS-induced ALI.

Pharmacokinetics of cefoperazone/sulbactam in critically Ill thrombotic thrombocytopenic purpura patients undergoing therapeutic plasma exchange.

WHAT IS KNOWN AND OBJECTIVES: The aim of this study was to investigate the pharmacokinetics (PK) of cefoperazone (CFP) and sulbactam (SUL) in critically ill thrombotic thrombocytopenic purpura (TTP) patients undergoing therapeutic plasma exchange (TPE). METHODS: Critically ill TTP patients receiving a dose of 3 g CFP/SUL (2.0 g/1.0 g) intravenously every 8 h were included in the study. TPE session began 10 min after the end of CFP/SUL infusion. Serial blood samples were collected at 0, 1, 2, 3, 4, 6 and 8 h at the fourth infusion with TPE and the sixth infusion without TPE. Effluent samples were collected at the effluent port of plasma eliminated at the end of TPE. Concentrations of CFP and SUL in plasma and effluent were measured using LC-MS/MS. PK parameters were calculated based on two-compartment open model. RESULTS: Five critically ill TTP patients receiving CFP/SUL monotherapy were enrolled. T1/2α of CFP and SUL with TPE was 0.62 and 1.30 h, respectively. For CFP, T1/2ß with TPE were significantly higher than those without TPE (5.85 ± 3.16 vs. 4.41 ± 2.74, p = 0.016). Vss with TPE were significantly higher than those without TPE (7.23 ± 0.89 vs. 5.24 ± 0.80 L, p = 0.024). AUC0-8 with TPE were significantly lower compared with those without TPE (1380.98 ± 411.99 vs. 1581.61 ± 500.22 mg*h/L, p = 0.011). Relatively, CLt with TPE were significantly higher than those without TPE (1.56 ± 0.46 vs. 1.37 ± 0.44 L/h, p = 0.010). For SUL, Vss and CLt were higher significantly with TPE than those without TPE (28.11 ± 8.42 vs. 18.87 ± 6.45 L, p = 0.002; 10.74 ± 2.01 vs. 8.60 ± 2.10 L/h, p = 0.048). Mean QPE of CFP and SUL were 344.42 ± 55.37 and 34.65 ± 10.09 mg, respectively. Mean fe% of CFP and SUL were 17.22 ± 2.77% and 3.46 ± 1.01%, respectively. WHAT IS NEW AND CONCLUSION: TPE enhances the clearance of CFP and SUL in critically ill TTP patients. CFP is more likely to be removed than SUL due to its a low V and high Pb. TPE is suggested to begin 1-2 h after the end of CFP/SUL infusion. Plasma concentration monitoring is advised when CFP/SUL must be administered during TPE.

Evaluation of the Potential Risk of the Emerging Yr5-Virulent Races of Puccinia striiformis f. sp. tritici to 165 Chinese Wheat Cultivars.

In 2017, a new race (TSA-6) of the wheat stripe rust pathogen, Puccinia striiformis f. sp. tritici, virulent to resistance gene Yr5, was detected in China. However, whether Chinese wheat cultivars are resistant to the new race was unknown. In this study, two isolates (TSA-6 and TSA-9) with virulence to Yr5 were tested on other wheat Yr gene lines for their avirulence and virulence patterns and used, together with prevalent races CYR32 and CYR34 without the Yr5 virulence, to evaluate 165 major Chinese wheat cultivars for their reactions. Isolates TSA-6 and TSA-9 had similar but different virulence spectra and therefore should be considered two different races. Their avirulence and virulence patterns were remarkably different from that of CYR34 but quite similar to that of CYR32. Of the 165 wheat cultivars, 21 had all-stage resistance to TSA-6, 34 to TSA-9, and 20 to both races. Adult plant resistance (APR) was detected in 35 cultivars to TSA-6 and 27 to TSA-9, but only three cultivars showed APR to both new races. Slow rusting resistance was observed in 24 cultivars to TSA-6 and 33 to TSA-9. Analysis of variance of disease index indicated a significant difference between cultivars but not between the four races. Based on the molecular marker data, a low percentage of wheat cultivars carried Yr5, Yr7, Yr10, Yr15, Yr26, or YrSP. Because TSA-6 and TSA-9 can be a serious threat to wheat production in China, continual monitoring of TSA-6, TSA-9, and other races is needed.

Clinical characteristics, risk factors and outcomes of mixed Candida albicans/bacterial bloodstream infections.

PURPOSE: The purpose of this study was to explore the clinical features, risk factors, and outcomes of mixed Candida albicans/bacterial bloodstream infections (mixed-CA/B-BSIs) compared with monomicrobial Candida albicans bloodstream infection (mono-CA-BSI) in adult patients in China. METHODS: All hospitalized adults with Candida albicans bloodstream infection (CA-BSI) were recruited for this retrospective observational study from January 1, 2013, to December 31, 2018. RESULTS: Of the 117 patients with CA-BSI, 24 patients (20.5%) had mixed-CA/B-BSIs. The most common copathogens were coagulase-negative Staphylococcus (CNS) (24.0%), followed by Klebsiella pneumoniae (20.0%) and Staphylococcus aureus (16.0%). In the multivariable analysis, a prior ICU stay > 2 days (adjusted odds ratio [OR], 7.445; 95% confidence interval [CI], 1.152-48.132) was an independent risk factor for mixed-CA/B-BSIs. Compared with patients with mono-CA-BSI, patients with mixed-CA/B-BSIs had a prolonged length of mechanical ventilation [17.5 (4.5, 34.8) vs. 3.0 (0.0, 24.5), p = 0.019] and prolonged length of ICU stay [22.0 (14.3, 42.2) vs. 8.0 (0.0, 31.5), p = 0.010]; however, mortality was not significantly different. CONCLUSIONS: There was a high rate of mixed-CA/B-BSIs cases among CA-BSI cases, and CNS was the predominant coexisting species. A prior ICU stay > 2 days was an independent risk factor for mixed -CA/B-BSIs. Although there was no difference in mortality, the outcomes of patients with mixed -CA/B-BSIs, including prolonged length of mechanical ventilation and prolonged length of ICU stay, were worse than those with mono-CA-BSI; this deserves further attention from clinicians.