Utility of paired plasma and drainage fluid mNGS in diagnosing acute intra-abdominal infections with sepsis.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) has been increasingly applied in sepsis. We aimed to evaluate the diagnostic and therapeutic utility of mNGS of paired plasma and peritoneal drainage (PD) fluid samples in comparison to culture-based microbiological tests (CMTs) among critically ill patients with suspected acute intra-abdominal infections (IAIs). METHODS: We conducted a prospective study from October 2021 to December 2022 enrolling septic patients with suspected IAIs (n = 111). Pairwise CMTs and mNGS of plasma and PD fluid were sent for pathogen detection. The mNGS group underwent therapeutic regimen adjustment based on mNGS results for better treatment. The microbial community structure, clinical features, antibiotic use and prognoses of the patients were analyzed. RESULTS: Higher positivity rates were observed with mNGS versus CMTs for both PD fluid (90.0% vs. 48.3%, p < 0.005) and plasma (76.7% vs. 1.6%, p < 0.005). 90% of enrolled patients had clues of suspected pathogens combining mNGS and CMT methods. Gram-negative pathogens consist of most intra-abdominal pathogens, including a great variety of anaerobes represented by Bacteroides and Clostridium. Patients with matched plasma- and PD-mNGS results had higher mortality and sepsis severity. Reduced usage of carbapenem (30.0% vs. 49.4%, p < 0.05) and duration of anti-MRSA treatment (5.1 ± 3.3 vs. 7.0 ± 8.4 days, p < 0.05) was shown in the mNGS group in our study. CONCLUSIONS: Pairwise plasma and PD fluid mNGS improves microbiological diagnosis compared to CMTs for acute IAI. Combining plasma and PD mNGS could predict poor prognosis. mNGS may enable optimize empirical antibiotic use.

Effect of Improved Nursing Strategy on Prognosis of Immunosuppressed Patients With Pneumonia and Sepsis: A Prospective Cohort Study.

Objectives: To investigate the effect of our improved nursing strategy on prognosis in immunosuppressed patients with pneumonia and sepsis. Methods: Immunosuppressed patients (absolute lymphocyte count <1000 cells/mm3) with pneumonia and sepsis were enrolled and divided into a control group and treatment group. The treatment group received the improved nursing strategy. The primary outcome in this study was 28-day mortality. Results: In accordance with the study criteria, 1019 patients were finally enrolled. Compared with patients in the control group, those in the treatment group had significantly fewer days on mechanical ventilation [5 (4, 7) versus 5 (4, 7) days, P = .03] and lower intensive care unit (ICU) mortality [21.1% (132 of 627) vs 28.8% (113 of 392); P = .005] and 28-day mortality [22.2% (139 of 627) vs 29.8% (117 of 392); P = .006]. The treatment group also had a shorter duration of ICU stay [9 (5, 15) vs 11 (6, 22) days, P = .0001] than the control group. The improved nursing strategy acted as an independent protective factor in 28-day mortality: odds ratio 0.645, 95% confidence interval: 0.449-0.927, P = .018. Conclusion: Our improved nursing strategy shortened the duration of mechanical ventilation and the ICU stay and decreased ICU mortality and 28-day mortality in immunosuppressed patients with pneumonia and sepsis. Trial registration: ChiCTR.org.cn, ChiCTR-ROC-17010750. Registered 28 February 2017.

Chikusetsu Saponin IVa liposomes modified with a retro-enantio peptide penetrating the blood-brain barrier to suppress pyroptosis in acute ischemic stroke rats.

BACKGROUND: The therapeutic strategies for acute ischemic stroke were faced with substantial constraints, emphasizing the necessity to safeguard neuronal cells during cerebral ischemia to reduce neurological impairments and enhance recovery outcomes. Despite its potential as a neuroprotective agent in stroke treatment, Chikusetsu saponin IVa encounters numerous challenges in clinical application. RESULT: Brain-targeted liposomes modified with THRre peptides showed substantial uptake by bEnd. 3 and PC-12 cells and demonstrated the ability to cross an in vitro blood-brain barrier model, subsequently accumulating in PC-12 cells. In vivo, they could significantly accumulate in rat brain. Treatment with C-IVa-LPs-THRre notably reduced the expression of proteins in the P2RX7/NLRP3/Caspase-1 pathway and inflammatory factors. This was evidenced by decreased cerebral infarct size and improved neurological function in MCAO rats. CONCLUSION: The findings indicate that C-IVa-LPs-THRre could serve as a promising strategy for targeting cerebral ischemia. This approach enhances drug concentration in the brain, mitigates pyroptosis, and improves the neuroinflammatory response associated with stroke.

Protective effect of alirocumab, a PCSK9 inhibitor, on the sciatic nerve of rats with diabetic peripheral neuropathy.

Dyslipidemia has been considered a risk factor for diabetic peripheral neuropathy. Proprotein convertase subtilisin-like/Kexin 9 inhibitor (PCSK9) inhibitors are a new type of lipid-lowering drug currently in clinical use. The role of PCSK9 in diabetic peripheral neuropathy is still unclear. In this study, the effect of alirocumab, a PCSK9 inhibitor, on the sciatic nerve in rats with diabetic peripheral neuropathy and its underlying mechanisms were investigated. The diabetic peripheral neuropathy rat model was established by using a high-fat diet combined with streptozotocin injection, and experimental subjects were divided into normal, diabetic peripheral neuropathy, and alirocumab groups. The results showed that Alirocumab improved nerve conduction, morphological changes, and small fiber deficits in rats with DPN, possibly related to its amelioration of oxidative stress and the inflammatory response.

The level of partial pressure of carbon dioxide affects organ perfusion in respiratory failure patients undergoing pressure support ventilation with venovenous extracorporeal membrane oxygenation: a prospective study.

BACKGROUND: We evaluated the influence of different partial carbon dioxide pressure (PaCO2) levels on organ perfusion in patients with respiratory failure receiving pressure-support ventilation with veno-venous extracorporeal membrane oxygenation (V-V ECMO). METHODS: In this twelve patients prospective study, ECMO gas-flow was decreased from baseline (PaCO2 < 40 mmHg) until PaCO2 increased by 5-10 mmHg (High-CO2 phase). Resistance indices of gut, spleen, and snuffbox artery, the peripheral perfusion index (PPI), and heart rate variability were measured at baseline and High-CO2 phase. RESULTS: When PaCO2 increased from 36 (36-37) mmHg at baseline to 42 (41-43) mmHg in the High-CO2 phase (p < 0.001), PPI decreased significantly (p = 0.026). The snuffbox artery (p = 0.022), superior mesenteric artery (p = 0.042), and spleen (p = 0.012) resistance indices increased significantly. The root mean square of successive differences (RMSSD) decreased from 19.5(18.1-22.7) to 15.9(14.4-18.6) ms (p = 0.034), and the ratio of low-frequency to high-frequency components(LF/HF) increased from 0.47 ± 0.23 to 0.70 ± 0.38 (p = 0.013). CONCLUSIONS: High PaCO2 might cause decreased peripheral tissue and visceral organ perfusion through autonomic nervous system in patients with respiratory failure undergoing PSV with V-V ECMO.

The level of partial pressure of carbon dioxide affects respiratory effort in COVID-19 patients undergoing pressure support ventilation with extracorporeal membrane oxygenation.

BACKGROUND: Patients with COVID-19 undergoing pressure support ventilation (PSV) with extracorporeal membrane oxygenation (ECMO) commonly had high respiratory drive, which could cause self-inflicted lung injury. The aim of this study was to evaluate the influence of different levels of partial pressure of carbon dioxide(PaCO2) on respiratory effort in COVID-19 patients undergoing PSV with ECMO. METHODS: ECMO gas flow was downregulated from baseline (respiratory rate < 25 bpm, peak airway pressure < 25 cm H2O, tidal volume < 6 mL/kg, PaCO2 < 40 mmHg) until PaCO2 increased by 5 - 10 mmHg. The pressure muscle index (PMI) and airway pressure swing during occlusion (ΔPOCC) were used to monitor respiratory effort, and they were measured before and after enforcement of the regulations. RESULTS: Ten patients with COVID-19 who had undergone ECMO were enrolled in this prospective study. When the PaCO2 increased from 36 (36 - 37) to 42 (41-43) mmHg (p = 0.0020), there was a significant increase in ΔPOCC [from 5.6 (4.7-8.0) to 11.1 (8.5-13.1) cm H2O, p = 0.0020] and PMI [from 3.0 ± 1.4 to 6.5 ± 2.1 cm H2O, p < 0.0001]. Meanwhile, increased inspiratory effort determined by elevated PaCO2 levels led to enhancement of tidal volume from 4.1 ± 1.2 mL/kg to 5.3 ± 1.5 mL/kg (p = 0.0003) and respiratory rate from 13 ± 2 to 15 ± 2 bpm (p = 0.0266). In addition, the increase in PaCO2 was linearly correlated with changes in ΔPOCC and PMI (R2 = 0.7293, p = 0.0003 and R2 = 0.4105, p = 0.0460, respectively). CONCLUSIONS: In patients with COVID-19 undergoing PSV with ECMO, an increase of PaCO2 could increase the inspiratory effort.

mTOR Deletion Alleviates CD4+ T-Cell Dysfunction in Sepsis through Reducing CTLA4 Accumulation Mediated by Rescuing Autophagy.

Sepsis has been the leading cause of death in ICU patients. CD4+ T cells are the mainstay of the body's immune system, and the depletion of CD4+ T cells in sepsis is of great concern. Cytotoxic T lymphocyte-associated protein 4 (CTLA4) is a negative immunomodulator for T cell activation and degradation through the autophagy-lysosome pathway. Mammalian target of rapamycin (mTOR) is the most classical upstream regulator of autophagy. With a mouse model of sepsis through cecal ligation and puncture (CLP), T cell specific-mTOR/tuberous sclerosis complex 1 (TSC1)-knockout mice, and bafilomycin A1, a specific autophagosome-lysosome (A-L) fusion inhibitor, we primarily proved that mTOR could modulate the expression and accumulation of CTLA4 by regulating the onset process of autophagy such as A-L fusion. Given such a regulatory relationship, targeting mTOR could provide new light to improve immune function in sepsis, and the prospect of using rapamycin in the clinic would be worth exploring further.

Template-Guided Hierarchical Multi-View Registration Framework of Unordered Bridge Terrestrial Laser Scanning Data.

The registration of bridge point cloud data (PCD) is an important preprocessing step for tasks such as bridge modeling, deformation detection, and bridge health monitoring. However, most existing research on bridge PCD registration only focused on pairwise registration, and payed insufficient attention to multi-view registration. In addition, to recover the overlaps of unordered multiple scans and obtain the merging order, extensive pairwise matching and the creation of a fully connected graph of all scans are often required, resulting in low efficiency. To address these issues, this paper proposes a marker-free template-guided method to align multiple unordered bridge PCD to a global coordinate system. Firstly, by aligning each scan to a given registration template, the overlaps between all the scans are recovered. Secondly, a fully connected graph is created based on the overlaps and scanning locations, and then a graph-partition algorithm is utilized to construct the scan-blocks. Then, the coarse-to-fine registration is performed within each scan-block, and the transformation matrix of coarse registration is obtained using an intelligent optimization algorithm. Finally, global block-to-block registration is performed to align all scans to a unified coordinate reference system. We tested our framework on different bridge point cloud datasets, including a suspension bridge and a continuous rigid frame bridge, to evaluate its accuracy. Experimental results demonstrate that our method has high accuracy.

α-Synuclein induces deficiency in clathrin-mediated endocytosis through inhibiting synaptojanin1 expression.

Parkinson's disease (PD) is an age-related chronic neurological disorder, mainly characterized by the pathological feature of α-synuclein (α-syn) aggregation, with the exact disease pathogenesis unclear. During the onset and progression of PD, synaptic dysfunction, including dysregulation of axonal transport, impaired exocytosis, and endocytosis are identified as crucial events of PD pathogenesis. It has been reported that over-expression of α-syn impairs clathrin-mediated endocytosis (CME) in the synapses. However, the underlying mechanisms still needs to be explored. In this study, we investigated the molecular events underlying the synaptic dysfunction caused by over-expression of wild-type human α-syn and its mutant form, involving series of proteins participating in CME. We found that excessive human α-syn causes impaired fission and uncoating of clathrin-coated vesicles during synaptic vesicle recycling, leading to reduced clustering of synaptic vesicles near the active zone and increased size of plasma membrane and number of endocytic intermediates. Furthermore, over-expressed human α-syn induced changes of CME-associated proteins, among which synaptojanin1 (SYNJ1) showed significant reduction in various brain regions. Over-expression of SYNJ1 in primary hippocampal neurons from α-syn transgenic mice recovered the synaptic vesicle density, clustering and endocytosis. Using fluorescence-conjugated transferrin, we demonstrated that SYNJ1 re-boosted the CME activity by restoring the phosphatidylinositol-4,5-bisphosphate homeostasis. Our data suggested that over-expression of α-syn disrupts synaptic function through interfering with vesicle recycling, which could be alleviated by re-availing of SYNJ1. Our study unrevealed a molecular mechanism of the synaptic dysfunction in PD pathogenesis and provided a potential therapeutic target for treating PD.

The pivotal role of MYB transcription factors in plant disease resistance.

MAIN CONCLUSION: MYB transcription factors are essential for diverse biology processes in plants. This review has focused on the potential molecular actions of MYB transcription factors in plant immunity. Plants possess a variety of molecules to defend against disease. Transcription factors (TFs) serve as gene connections in the regulatory networks controlling plant growth and defense against various stressors. As one of the largest TF families in plants, MYB TFs coordinate molecular players that modulate plant defense resistance. However, the molecular action of MYB TFs in plant disease resistance lacks a systematic analysis and summary. Here, we describe the structure and function of the MYB family in the plant immune response. Functional characterization revealed that MYB TFs often function either as positive or negative modulators towards different biotic stressors. Moreover, the MYB TF resistance mechanisms are diverse. The potential molecular actions of MYB TFs are being analyzed to uncover functions by controlling the expression of resistance genes, lignin/flavonoids/cuticular wax biosynthesis, polysaccharide signaling, hormone defense signaling, and the hypersensitivity response. MYB TFs have a variety of regulatory modes that fulfill pivotal roles in plant immunity. MYB TFs regulate the expression of multiple defense genes and are, therefore, important for increasing plant disease resistance and promoting agricultural production.