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 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.

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.

A Decade of Pathogenesis Advances in Non-Type 2 Inflammatory Endotypes in Chronic Rhinosinusitis: 2012-2022.

Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by localized inflammation of the upper airways. CRS includes two main phenotypes, namely, CRS with nasal polyps and CRS without nasal polyps. The phenotype-based classification method cannot reflect the pathological mechanism. The endotype-based classification method has been paid more and more attention by researchers. It is mainly divided into type 2 and non-type 2 endotypes. The mechanism driving the pathogenesis of non-type 2 inflammation is currently unknown. In this review, the PubMed and Web of Science databases were searched to conduct a critical analysis of representative literature works on the pathogenesis of non-type 2 inflammation in CRS published in the past decade. This review summarizes the latest evidence that may lead to the pathogenesis of non-type 2 inflammation. It is the main method that analyzing the pathogenesis from the perspective of immunology. Genomics and proteomics technique provide new approaches to the study of the pathogenesis. Due to differences in race, environment, geography, and living habits, there are differences in the occurrence of non-type 2 inflammation, which increase the difficulty of understanding the pathogenesis of non-type 2 inflammation in CRS. Studies have confirmed that non-type 2 endotype is more common in Asian patients. The emergence of overlap and unclassified endotypes has promoted the study of heterogeneity in CRS. In addition, as the source of inflammatory cells and the initiation site of the inflammatory response, microvessels and microlymphatic vessels in the nasal mucosal subepithelial tissue participate in the inflammatory response and tissue remodeling. It is uncertain whether CRS patients affect the risk of infection with SARS-CoV-2. In addition, the pathophysiological mechanism of non-type 2 CRS combined with COVID-19 remains to be further studied, and it is worth considering how to select the befitting biologics for CRS patients with non-type 2 inflammation.

A Knowledge Map of the Relationship between Diabetes and Stroke: A Bibliometric Analysis Study.

INTRODUCTION: The correlation between diabetes and stroke has been studied extensively in epidemiological research. Here we used bibliometric software to visualize and analyze the literature related to diabetic stroke to provide an overview of the current state of research, hot spots, and future trends in the field. METHODS: Based on the Web of Science Core Collection(WoSCC) database, we collected studies related to diabetic stroke from 2007 to May 2022. We used CiteSpace (version 6.1.R5), VOSviewer, and Sci-mago Graphica to create knowledge maps and conduct visual analyses on authors, countries, in-stitutions, cited references, and keywords, and Origin for statistical analysis. RESULTS: We included a total of 5171 papers on diabetic stroke from the WoSCC database. Overall, there was a steady increase in the number of publications, with a high number of emerging scientists. The United States was the most productive and influential country, which dominated national col-laborations. The most common subject category was "neurology". In total, 12 major clusters were generated from the cited references. Keywords analysis showed that keywords related to post-stroke injury and treatment are those with the highest burst intensity and latest burst time. CONCLUSIONS: Individual disease treatment remains a hot topic and how to balance acute stroke treatment and glycemic control is currently a difficult clinical problem. At the same time, the mechanism of their interaction and the prevention and treatment of related causative factors remain a hot topic of current and future research.

Elevation of the head of bed reduces splanchnic blood flow in patients with intra-abdominal hypertension.

BACKGROUND: Elevation of the head of bed (HOB) increases intra-abdominal pressure (IAP), but the effect of body position on abdominal splanchnic perfusion is not clear. The current study aimed to evaluate the effect of body position on the superior mesenteric artery (SMA) and the celiac artery (CA) blood flow by Doppler ultrasound in mechanically ventilated patients with intra-abdominal hypertension (IAH). METHODS: This prospective cohort study included 53 mechanically ventilated patients with IAH. IAP, hemodynamic variables, and Doppler parameters of the SMA and CA were measured in the supine position. The measurements were repeated after the HOB angle was raised to 15° for 5 min and similarly at HOB angles of 30° and 45°. Finally, the patient was returned to the supine and these variables were re-measured. RESULTS: The median (interquartile range, IQR) superior mesenteric artery blood flow (SMABF) decreased from 269 (244-322) to 204 (183-234) mL/min and the median (IQR) celiac artery blood flow (CABF) from 424 (368-483) to 376 (332-472) mL/min (both p<0.0001) while median (IQR) IAP increased from 14(13-16) to 16(14-18) mmHg (p<0.0001) when the HOB angle was changed from 0° to 15°. However, SMABF and CABF were maintained at similar levels from 15° to 30°, despite median (IQR) IAP increased to 17(15-18) mmHg (p = 0.0002). Elevation from 30° to 45° further reduced median (IQR) SMABF from 200(169-244) to 164(139-212) mL/min and CABF from 389(310-438) to 291(241-383) mL/min (both p<0.0001), Meanwhile, median (IQR) IAP increased to 19(18-21) mmHg (p<0.0001). CONCLUSIONS: In mechanically ventilated patients with IAH, progressive elevation of the HOB from a supine to semi-recumbent position was associated with a gradual reduction in splanchnic blood flow. However, the results indicate that splanchnic blood flow is not further reduced when the HOB is elevated from 15° to 30°.This study confirms the influence of head-up angle on blood flow of the splanchnic organs and may contribute to the selection of the optimal position in patients with abdominal hypertension.

Efficacy of Levosimendan in the Treatment of Patients With Severe Septic Cardiomyopathy.

OBJECTIVE: This study was designed to compare the effects of levosimendan and dobutamine on hemodynamics and clinical efficacy in patients with severe septic cardiomyopathy (left ventricular ejection fraction [LVEF] ≤35%). DESIGN: A prospective, single-blind, randomized controlled study. SETTING: In Baoding, China. PARTICIPANTS: Thirty patients with severe septic cardiomyopathy treated in the authors' hospital's Department of Critical Medicine from September 2018 to September 2021 were enrolled in this study. INTERVENTIONS: These patients were divided randomly into the levosimendan group and dobutamine group. The LVEF, cardiac index (CI), stroke volume index (SVI), systemic vascular resistance index, heart rate, norepinephrine dose, and lactate at the time of enrollment and the 24th hour were compared, along with myocardial injury markers on the third day, C-reactive protein, mechanical ventilation time, length of intensive care unit (ICU) stay, cost, and 28-day mortality. The primary outcome was 28-day mortality. MEASUREMENTS AND MAIN RESULTS: At the 24th hour after treatment, CI, LVEF, SVI, and fluid volume were found to be higher in the levosimendan group than in the dobutamine group, whereas the dose of norepinephrine was lower in the former rather than the latter group. On the third day of treatment, cardiac troponin I in the levosimendan group was lower than that in the dobutamine group. Although the differences in 28-day mortality, ICU stay, and ICU treatment cost between the groups were not statistically significant, the ventilator application time of the levosimendan group was significantly shorter than that of the dobutamine group. CONCLUSIONS: Compared with dobutamine, levosimendan was more effective at improving cardiac function, reducing myocardial injury, and reducing mechanical ventilation time in patients with severe septic cardiomyopathy.

The Role and Mechanism of Hydrogen-Rich Water in the Cucumis sativus Response to Chilling Stress.

Cucumber is a warm climate vegetable that is sensitive to chilling reactions. Chilling can occur at any period of cucumber growth and development and seriously affects the yield and quality of cucumber. Hydrogen (H2) is a type of antioxidant that plays a critical role in plant development and the response to stress. Hydrogen-rich water (HRW) is the main way to use exogenous hydrogen. This study explored the role and mechanism of HRW in the cucumber defense response to chilling stress. The research results showed that applying 50% saturated HRW to the roots of cucumber seedlings relieved the damage caused by chilling stress. The growth and development indicators, such as plant height, stem diameter, leaf area, dry weight, fresh weight, and root length, increased under the HRW treatment. Photosynthetic efficiency, chlorophyll content, and Fv/Fm also improved and reduced energy dissipation. In addition, after HRW treatment, the REC and MDA content were decreased, and membrane lipid damage was reduced. NBT and DAB staining results showed that the color was lighter, and the area was smaller under HRW treatment. Additionally, the contents of O2- and H2O2 also decreased. Under chilling stress, the application of HRW increased the activity of the antioxidases SOD, CAT, POD, GR, and APX and improved the expression of the SOD, CAT, POD, GR, and APX antioxidase genes. The GSSG content was reduced, and the GSH content was increased. In addition, the ASA content also increased. Therefore, exogenous HRW is an effective measure for cucumber to respond to chilling stress.

Saikosaponin A and Its Epimers Alleviate LPS-Induced Acute Lung Injury in Mice.

The purpose of this work was to illustrate the effect of processing with vinegar on saikosaponins of Bupleurum chinense DC. (BC) and the protective effects of saikosaponin A (SSA), saikosaponin b1 (SSb1), saikosaponin b2 (SSb2), and saikosaponin D (SSD) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice. We comprehensively evaluated the anti-inflammatory effects and potential mechanisms of SSA, SSb1, SSb2, and SSD through an LPS-induced ALI model using intratracheal injection. The results showed that SSA, SSb1, SSb2, and SSD significantly decreased pulmonary edema; reduced the levels of IL-6, TNF-α, and IL-1ß in serum and lung tissues; alleviated pulmonary pathological damage; and decreased the levels of the IL-6, TNF-α, and IL-1ß genes and the expression of NF-κB/TLR4-related proteins. Interestingly, they were similar in structure, but SSb2 had a better anti-inflammatory effect at the same dose, according to a principal component analysis. These findings indicated that it may not have been comprehensive to only use SSA and SSD as indicators to evaluate the quality of BC, especially as the contents of SSb1 and SSb2 in vinegar-processed BC were significantly increased.

Metabolomics and Lipidomics Study Unveils the Impact of Tauroursodeoxycholic Acid on Hyperlipidemic Mice.

Bear bile powder is an essential, traditional and valuable Chinese herbal medicine that clears heat, calms the liver, and improves eyesight. Early studies have shown that bear bile powder has lipid-lowering activity, but due to the scarcity of natural bear bile powder resources, it has yet to be used on a large scale. Researchers have found that tauroursodeoxycholic acid (TUDCA) is the primary characteristic bioactive substance of bear bile powder. This study aimed to investigate the therapeutic effect of TUDCA on high-fat diet (HFD)-induced hyperlipidemia. A hyperlipidemia model was established by feeding mice high-fat chow, following the intervention of different concentrations of TUDCA (25/50/100 mg/kg) orally, the hallmark biochemical indexes (total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)), histopathological examination (hematoxylin-eosin (HE) staining and oil red O (ORO) staining), and metabolomic analysis of serum and liver. The results showed that TUDCA could downregulate total TC, TG, LDL-C, upregulate HDL-C, reduce fat deposition in hepatocytes, reverse hepatocyte steatosis, and exhibit prominent lipid-lowering activity. In addition, it may play a therapeutic role by regulating glycerophospholipid metabolism.

The traditional herb Polygonum hydropiper from China: a comprehensive review on phytochemistry, pharmacological activities and applications.

CONTEXT: Polygonum hydropiper L. (Polygonaceae) (PH) is a traditional Chinese traditional medicine with a pungent flavor and mild drug properties. PH is mainly distributed in the channel tropism in the stomach and large intestine. PH has multiple uses and can be used to treat a variety of diseases for a long time. OBJECTIVE: This review summarizes the phytochemical and pharmacological activities, and applications of PH from 1980 to 2022. We also provide suggestions for promoting further research and developing additional applications of PH. METHODS: The data and information on PH from 1980 to 2022 reviewed in this article were obtained from scientific databases, including Science Direct, PubMed, Science Citation Index, SciFinder Scholar (SciFinder), Springer, American Chemical Society (ACS) Publications, and China National Knowledge Infrastructure (CNKI), etc. Some information was obtained from classic literature on traditional Chinese medicines. The search terms were Polygonum hydropiper, phytochemistry compositions of Polygonum hydropiper, pharmacological activities of Polygonum hydropiper, and applications of Polygonum hydropiper. RESULTS: The comprehensive analysis of the literature resulted in 324 compounds being isolated, identified, and reported from PH. Regarding traditional uses, the majority of phytochemical and pharmacological studies have indicated the diverse bioactivities of PH extracts, flavonoids, and volatile oil elements, including antibacterial, antifungal, insecticidal, antioxidant, and anti-inflammatory. CONCLUSIONS: PH has a long history of diversified medicinal uses, some of which have been verified in modern pharmacological studies. Further detailed studies are required to establish scientific and reasonable quality evaluation standards and action mechanisms of active constituents from PH.

Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: A substantial proportion of patients with unresectable stage III non-small-cell lung cancer (NSCLC) cannot either tolerate or access concurrent chemoradiotherapy, so sequential chemoradiotherapy is commonly used. We assessed the efficacy and safety of sugemalimab, an anti-PD-L1 antibody, in patients with stage III NSCLC whose disease had not progressed after concurrent or sequential chemoradiotherapy. METHODS: GEMSTONE-301 is a randomised, double-blind, placebo-controlled, phase 3 trial in patients with locally advanced, unresectable, stage III NSCLC, done at 50 hospitals or academic research centres in China. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had not progressed after concurrent or sequential chemoradiotherapy. We randomly assigned patients (2:1, using an interactive voice-web response system) to receive sugemalimab 1200 mg or matching placebo, intravenously every 3 weeks for up to 24 months. Stratification factors were ECOG performance status, previous chemoradiotherapy, and total radiotherapy dose. The investigators, trial coordination staff, patients, and study sponsor were masked to treatment allocation. The primary endpoint was progression-free survival as assessed by blinded independent central review (BICR) in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of assigned study treatment. The study has completed enrolment and the results of a preplanned analysis of the primary endpoint are reported here. The trial is registered with ClinicalTrials.gov, NCT03728556. FINDINGS: Between Aug 30, 2018 and Dec 30, 2020, we screened 564 patients of whom 381 were eligible. Study treatment was received by all patients randomly assigned to sugemalimab (n=255) and to placebo (n=126). At data cutoff (March 8, 2021), median follow-up was 14·3 months (IQR 6·4-19·4) for patients in the sugemalimab group and 13·7 months (7·1-18·4) for patients in the placebo group. Progression-free survival assessed by BICR was significantly longer with sugemalimab than with placebo (median 9·0 months [95% CI 8·1-14·1] vs 5·8 months [95% CI 4·2-6·6]; stratified hazard ratio 0·64 [95% CI 0·48-0·85], p=0·0026). Grade 3 or 4 treatment-related adverse events occurred in 22 (9%) of 255 patients in the sugemalimab group versus seven (6%) of 126 patients in the placebo group, the most common being pneumonitis or immune-mediated pneumonitis (seven [3%] of 255 patients in the sugemalimab group vs one [<1%] of 126 in the placebo group). Treatment-related serious adverse events occurred in 38 (15%) patients in the sugemalimab group and 12 (10%) in the placebo group. Treatment-related deaths were reported in four (2%) of 255 patients (pneumonia in two patients, pneumonia with immune-mediated pneumonitis in one patient, and acute hepatic failure in one patient) in the sugemalimab group and none in the placebo group. INTERPRETATION: Sugemalimab after definitive concurrent or sequential chemoradiotherapy could be an effective consolidation therapy for patients with stage III NSCLC whose disease has not progressed after sequential or concurrent chemoradiotherapy. Longer follow-up is needed to confirm this conclusion. FUNDING: CStone Pharmaceuticals and the National Key Research and Development Program of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

mTOR pathway mediates endoplasmic reticulum stress-induced CD4+ T cell apoptosis in septic mice.

Endoplasmic reticulum stress (ERS) has been well documented to participate in the pathophysiological processes of apoptosis in many diseases. Inhibition of ERS ameliorates pathological organ injury. However, the upstream signaling pathways and molecular regulatory mechanisms of which are still unknown. mTOR, an evolutionarily conserved protein kinase, is a key regulator of apoptosis. Hence, in this study, a classical cecal ligation and puncture (CLP) sepsis model was constructed by using the T cell-specific knockout mTOR and TSC1 (Tuberous Sclerosis Complex, the inhibitor of mTOR signaling pathway) mice to explore the underlying signaling pathway and molecular mechanism of host immune imbalance caused by apoptosis in sepsis. We found that mTOR may modulate septic T cell apoptosis by regulating Akt-IRE1-JNK pathway. To further clarify the possible mechanism, the specific inhibitors of PI3K-Akt and IRE1-JNK were used to intervene in mice before/after CLP, respectively. By analyzing the proteins of mTOR-ERS signaling pathway and the expression of apoptosis-related proteins and genes, we found that mTOR mediated the ER stress induced CD4+ T cell apoptosis in Septic mice by negatively regulating the Akt-IRE1-JNK-Caspase 3 signaling cascades. These results indicate that mTOR-Akt-IRE1α-JNK signaling pathway mediated the Endoplasmic reticulum stress induced CD4+ T cell apoptosis in Septic mice.

mTOR deletion ameliorates CD4 + T cell apoptosis during sepsis by improving autophagosome-lysosome fusion.

Autophagy dysfunction contributes to CD4 + T cell apoptosis during sepsis leading to impairment of adaptive immunity. However, the underlying mechanism is unclear. The mammalian target of rapamycin (mTOR) pathway modulates CD4 + T cell survival during sepsis through mechanisms that are not fully understood. We developed a mouse model of sepsis through cecal ligation and puncture (CLP) to investigate dynamic changes in autophagy in CD4 + T cells. We used T cell specific-mTOR/tuberous sclerosis complex 1 (TSC1)-knockout mice to explore the roles of the mTOR pathway in modulating autophagy during sepsis. We observed reduced fusion of autophagosomes with lysosomes in the CD4 + T cells of CLP mice, which may represent a characteristic feature of autophagy dysfunction. Deletion of mTOR relieved autophagosome-lysosome fusion dysfunction and ameliorated apoptosis of CD4 + T cells in CLP mice, but this rescued phenotype was abolished by treatment with bafilomycin A1, a specific A-L fusion inhibitor. We further explored the underlying molecular mechanism and found that phosphorylation levels of transcription factor EB were significant higher in CLP mice and that expression of A-L fusion protein SNAREs were restricted, both of which were ameliorated by mTOR deletion. Taken together, these results suggest that the mTOR pathway plays a critical role in regulation of CD4 + T-cell apoptosis during sepsis, partly through regulation of A-L fusion-related protein transcription.

T-lymphocyte subtyping: an early warning and a potential prognostic indicator of active cytomegalovirus infection in patients with sepsis.

Cytomegalovirus (CMV) infection is very common in patients suffering from sepsis and may cause poor prognosis. To explore the relationship between immune status of patients with sepsis and CMV infection, we assessed T lymphocyte subtyping and other commonly used clinical parameters in patients with sepsis upon admission to the intensive care unit (ICU) and evaluated their potential impact on diagnosis and outcomes of active CMV infection. In our study, 82 of 599 patients with sepsis were diagnosed with active CMV infection. The 28-day mortality was higher in active CMV-infected than nonactive CMV-infected patients (20.7% versus 9.9%); 51of 82 active CMV-infected patients with sepsis were assessed to have CMV-DNA-negative conversion, while 31 were persistently positive for CMV DNA. Higher CD8+ CD28+ T-cell counts at presentation were associated with CMV-DNA-negative conversion and lower 28-day mortality. The CMV-DNA-negative conversion and 28-day mortality of active CMV-infected patients with sepsis could be predicted using cutoff values of 151 (74.5% sensitivity and 87.1% specificity) and 64.5 (52.9% sensitivity and 92.3% specificity) CD8+ CD28+ T cells mL-1 at ICU admission, respectively. Higher CD8+ CD28+ T-cell count was significantly associated with active CMV infection, higher CMV-DNA-negative conversion and lower 28-day mortality, which may be a potential marker for early warning of active CMV infection and outcome prediction.