Aberrant functional connectivity associated with drug response in patients with newly diagnosed epilepsy.

OBJECTIVE: To analyze the local functional activity and connectivity features of the brain associated with drug response inpatients newly diagnosed with epilepsy (NDE) who are naïve to anti-seizure medication (ASM). METHODS: Recruited patients, underwent functional magnetic resonance imaging at baseline, and were assigned to the well-controlled (WC, n = 28) or uncontrolled (UC, n = 11) groups based on their response to ASM. Healthy participants were included in the control group (HC, n = 29). The amplitudes of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) were used to measure local functional activity, and voxel-wise degree centrality (DC) and seed-based functional connectivity (FC) were used to evaluate the connecting intensity of the brain areas. RESULTS: Compared to the HC and WC groups, the UC group had higher ALFF values in the left posterior central gyrus (PoCG.L) and left inferior temporal gyrus (ITG.L) and higher DC in the bilateral PoCG (Gaussian random field correction, voxel-level P < 0.001, and cluster-level P < 0.05). Both PoCG and ITG.L in the UC group showed stronger FC with multiple brain regions, mainly located in the occipital and temporal lobes, compared to the HC or WC group, while the WC group showed decreased or similar FC compared to the HC group. INTERPRETATION: Excessive enhancement of brain functional activity or connecting intensity in ASM-naïve patients with NDE may be associated with a higher risk of poor drug response.

Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials.

Objective: Several clinical trials have suggested that fenfluramine (FFA) is effective for the treatment of epilepsy in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). However, the exploration of its optimal target dose is ongoing. This study aimed to summarize the best evidence to inform this clinical issue. Materials and methods: We searched PubMed, Embase (via Ovid), and Web of Science for relevant literature published before December 1st, 2023. Randomized, double-blind, placebo-controlled studies that evaluated the efficacy, safety, and tolerability of FFA in DS and LGS were identified and meta-analysis was performed according to doses. The study was registered with PROSPERO (CRD42023392454). Results: Six hundred and twelve patients from four randomized controlled trials were enrolled. The results demonstrated that FFA at 0.2, 0.4, or 0.7 mg/kg/d showed significantly greater efficacy compared to placebo in terms of at least 50% reduction (p < 0.001, p < 0.001, p < 0.001) and at least 75% reduction (p < 0.001, p = 0.007, p < 0.001) in monthly seizure frequency from baseline. Moreover, significantly more patients receiving FFA than placebo were rated as much improved or very much improved in CGI-I by both caregivers/parents and investigators (p < 0.001). The most common treatment-emergent adverse events were decreased appetite, diarrhea, fatigue, and weight loss, with no valvular heart disease or pulmonary hypertension observed in any participant. For dose comparison, 0.7 mg/kg/d group presented higher efficacy on at least 75% reduction in seizure (p = 0.006) but not on at least 50% reduction. Weight loss (p = 0.002), decreased appetite (p = 0.04), and all-cause withdrawal (p = 0.036) were more common in 0.7 mg/kg/d group than 0.2 mg/kg/d. There was no statistical difference in other safety parameters between these two groups. Conclusion: The higher range of the licensed dose achieves the optimal balance between efficacy, safety, and tolerability in patients with DS and LGS. Clinical trial registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023392454.

Diagnostic value of bedside lung ultrasound and 12-zone score in the 65 cases of neonatal respiratory distress syndrome and its severity.

OBJECTIVE: To explore the predictive value of bedside lung ultrasound score in the severity of neonatal respiratory distress syndrome (NRDS) and mechanical ventilation and extubation. METHODS: The clinical data of 65 neonates with NRDS and invasive mechanical ventilation diagnosed in the neonatal intensive care unit of our hospital from July 2021 to July 2022 were retrospectively analyzed. 65 neonates were included in the NRDS group, and 40 neonates with other common lung diseases were selected as the other lung disease groups. All neonates underwent lung ultrasound and X-ray examination. The correlation between lung ultrasound scores and arterial blood gas indexes was analyzed by Pearson. The efficacy of successful evacuation of mechanical ventilation was evaluated by lung ultrasound analysis by ROC curve analysis. RESULTS: The positive rates of lung consolidation and white lung in NRDS group were higher than the other lung disease groups (P < 0.05). The positive rates of bronchial inflation sign and double lung points were lower than these in the other lung disease groups (P < 0.05). The ultrasound scores of both lungs, left lung, right lung, bilateral lung and double basal lung in the NRDS group were significantly higher than those in the other lung disease groups (P < 0.05). There was a significant positive correlation between lung ultrasound score and X-ray grade (r = 0.841, P < 0.001). The area under the curve (AUC) of lung ultrasound score for the differential diagnosis of NRDS and common lung diseases was 0.907. The AUC of lung ultrasound score in the differential diagnosis of mild and moderate, and moderate and severe NRDS were 0.914 and 0.933, respectively, which had high clinical value. The lung ultrasound score was positively correlated with the level of PaCO2 (r = 0.254, P = 0.041), and negatively correlated with the levels of SpO2 and PaO2 (r = - 0.459, - 0.362, P = 0.001, 0.003). The AUC of successful mechanical ventilation withdrawal predicted by the pulmonary ultrasound score before extubation was 0.954 (95% CI 0.907-1.000). The predictive value of successful extubation was 10 points of the pulmonary ultrasound score, with a sensitivity of 93.33% and a specificity of 88.00%. CONCLUSION: The bedside lung ultrasound score can intuitively reflect the respiratory status of neonates, which provides clinicians with an important basis for disease evaluation.

Construction of Nanofibrillar Networked Wood Aerogels Derived from Typical Softwood and Hardwood: A Comparative Study on the In Situ Formation Mechanism of Nanofibrillar Networks.

The construction of networks within natural wood (NW) lumens to produce porous wood aerogels (WAs) with fascinating characteristics of being lightweight, flexible, and porous is significant for the high value-added utilization of wood. Nonetheless, how wood species affect the structure and properties of WAs has not been comprehensively investigated. Herein, typical softwood of fir and hardwoods of poplar and balsa are employed to fabricate WAs with abundant nanofibrillar networks using the method of lignin removal and nanofibril's in situ regeneration. Benefiting from the avoidance of xylem ray restriction and the exposure of the cellulose framework, hardwood has a stronger tendency to form nanofibrillar networks compared to softwood. Specifically, a larger and more evenly distributed network structure is displayed in the lumens of balsa WAs (WA-3) with a low density (59 kg m-3), a high porosity (96%), and high compressive properties (strain = 40%; maximum stress = 0.42 MPa; height retention = 100%) because of the unique structure and properties of WA-3. Comparatively, the specific surface area (SSA) exhibits 25-, 27-, and 34-fold increments in the cases of fir WAs (WA-1), poplar WAs (WA-2), and WA-3. The formation of nanofibrillar networks depends on the low-density and thin cell walls of hardwood. This work offers a foundation for investigating the formation mechanisms of nanonetworks and for expanding the potential applications of WAs.

Metabolomics comparison of metabolites and functional pathways in the SH-SY5Y cell model of Parkinson's disease under PEMF exposure.

Objective: PEMF is an emerging technique in the treatment of Parkinson's disease (PD) due to its potential improvement of movement speed. The aim of this study was to investigate the metabolic profiles of pulsed electromagnetic fields (PEMFs) in an SH-SY5Y cell model of PD. Methods: The SH-SY5Y cell model of PD was induced by 1-methyl-4-phenylpyridinium (MPP+). Liquid chromatography mass spectrometry (LC‒MS)-based untargeted metabolomics was performed to examine changes in the PD cell model with or without PEMF exposure. We conducted KEGG pathway enrichment analysis to explore the potentially related pathways of the differentially expressed metabolites. Results: A total of 275 metabolites were annotated, and 27 significantly different metabolites were found between the PEMF treatment and control groups (VIP >1, P < 0.05), mainly including 4 amino acids and peptides, 4 fatty acid esters, 2 glycerophosphoethanolamines, 2 ceramides and 2 monoradylglycerols; among them, 12 metabolites were upregulated, and 15 were downregulated. The increased expression levels of glutamine, adenosine monophosphate and taurine were highly associated with PEMF stimulation in the PD model. The enrichment results of differentially abundant metabolite functional pathways showed that biological processes such as the mTOR signaling pathway, PI3K-Akt signaling pathway, and cAMP signaling pathway were significantly affected. Conclusion: PEMFs affected glutamine, adenosine monophosphate and taurine as well as their functional pathways in an in vitro model of PD. Further functional studies regarding the biological effect of these changes are required to evaluate the clinical efficacy and safety of PEMF treatment in PD.

A lipid droplet-associated protein Nem1 regulates appressorium function for infection of Magnaporthe oryzae.

Lipid droplets are important storages in fungal conidia and can be used by plant pathogenic fungi for infection. However, the regulatory mechanism of lipid droplets formation and the utilization during fungal development and infection are largely unknown. Here, in Magnaporthe oryzae, we identified a lipid droplet-associated protein Nem1 that played a key role in lipid droplets biogenesis and utilization. Nem1 was highly expressed in conidia, but lowly expressed in appressoria, and its encoded protein was localized to lipid droplets. Deletion of NEM1 resulted in reduced numbers of lipid droplets and decreased content of diacylglycerol (DAG) or triacylglycerol (TAG). NEM1 was required for asexual development especially conidia production. The Δnem1 mutant was nearly loss of virulence to host plants due to defects in appressorial penetration and invasive growth. Remarkably, Nem1 was regulated by the TOR signaling pathway and involved in the autophagy process. The Ser303 residue of Nem1 could be phosphorylated by the cAMP-PKA signaling pathway and was important for biological function of Nem1. Together, our study revealed a regulatory mechanism of lipid biogenesis and metabolism during the conidium and appressorium formation of the rice blast fungus. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-023-00098-5.

Histone Deacetylase 3-Directed PROTACs Have Anti-inflammatory Potential by Blocking Polarization of M0-like into M1-like Macrophages.

Macrophage polarization plays a crucial role in inflammatory processes. The histone deacetylase 3 (HDAC3) has a deacetylase-independent function that can activate pro-inflammatory gene expression in lipopolysaccharide-stimulated M1-like macrophages and cannot be blocked by traditional small-molecule HDAC3 inhibitors. Here we employed the proteolysis targeting chimera (PROTAC) technology to target the deacetylase-independent function of HDAC3. We developed a potent and selective HDAC3-directed PROTAC, P7, which induces nearly complete HDAC3 degradation at low micromolar concentrations in both THP-1 cells and human primary macrophages. P7 increases the anti-inflammatory cytokine secretion in THP-1-derived M1-like macrophages. Importantly, P7 decreases the secretion of pro-inflammatory cytokines in M1-like macrophages derived from human primary macrophages. This can be explained by the observed inhibition of macrophage polarization from M0-like into M1-like macrophage. In conclusion, we demonstrate that the HDAC3-directed PROTAC P7 has anti-inflammatory activity and blocks macrophage polarization, demonstrating that this molecular mechanism can be targeted with small molecule therapeutics.

Advances in attractive therapeutic approach for macrophage activation syndrome in COVID-19.

Nowadays, people have relaxed their vigilance against COVID-19 due to its declining infection numbers and attenuated virulence. However, COVID-19 still needs to be concern due to its emerging variants, the relaxation of restrictions as well as breakthrough infections. During the period of the COVID-19 infection, the imbalanced and hyper-responsive immune system plays a critical role in its pathogenesis. Macrophage Activation Syndrome (MAS) is a fatal complication of immune system disease, which is caused by the excessive activation and proliferation of macrophages and cytotoxic T cells (CTL). COVID-19-related hyperinflammation shares common clinical features with the above MAS symptoms, such as hypercytokinemia, hyperferritinemia, and coagulopathy. In MAS, immune exhaustion or defective anti-viral responses leads to the inadequate cytolytic capacity of CTL which contributes to prolonged interaction between CTL, APCs and macrophages. It is possible that the same process also occurred in COVID-19 patients, and further led to a cytokine storm confined to the lungs. It is associated with the poor prognosis of severe patients such as multiple organ failure and even death. The main difference of cytokine storm is that in COVID-19 pneumonia is mainly the specific damage of the lung, while in MAS is easy to develop into a systemic. The attractive therapeutic approach to prevent MAS in COVID-19 mainly includes antiviral, antibiotics, convalescent plasma (CP) therapy and hemadsorption, extensive immunosuppressive agents, and cytokine-targeted therapies. Here, we discuss the role of the therapeutic approaches mentioned above in the two diseases. And we found that the treatment effect of the same therapeutic approach is different.

Safety and efficacy of rapid withdrawal of anti-seizure medication during long-term video-EEG monitoring.

Objective: Anti-seizure medications (ASMs) are often withdrawn during long-term video-EEG monitoring (LTM) to allow pre-surgical evaluation. Herein, we evaluated the safety and efficacy of ultra-rapid withdrawal (URW) and rapid withdrawal (RW) of ASMs in an epilepsy monitoring unit (EMU). Methods: This retrospective study examined all consecutive patients admitted to our EMU between May 2021 and October 2022. Patients were classified into the URW and RW groups according to the way ASMs were withdrawn. We compared the efficacy and safety of the procedures used in the groups in terms of duration of LTM, latency to the first seizure, and incidence of focal to bilateral tonic-clonic seizures (FBTCS), seizure clusters (SC), and status epilepticus (SE). Results: Overall, 110 patients (38 women) were included. The mean age of patients at the time of LTM was 29 years. All medications were stopped on admission for monitoring in the URW group (n = 75), while in the RW group (n = 35) ASMs were withdrawn within 1 day. In both groups, the duration of LTM was approximately 3 days: URW group (2.9 ± 0.5 days) and RW group (3.1 ± 0.8 days). The latency to the first seizure was significantly different between the two groups; however, there were no differences between the two groups in terms of the distribution of FBTCS, SC, or SE, number of seizures, and the requirement for intravenous rescue medication was low. Conclusion: The rapid withdrawal of ASMs to provoke seizures during monitoring for pre-surgical evaluation following the URW protocol was as effective and safe as with RW. Ultra-rapid ASM withdrawal has the benefits of reducing LTM duration and shortening the time to first seizure compared to rapid medication tapering.

Allosteric Inhibitors of Macrophage Migration Inhibitory Factor (MIF) Interfere with Apoptosis-Inducing Factor (AIF) Co-Localization to Prevent Parthanatos.

Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and essential signaling protein associated with inflammation and cancers. One of the newly described roles of MIF is binding to apoptosis-inducing factor (AIF) that "brings" cells to death in pathological conditions. The interaction between MIF and AIF and their nuclear translocation stands as a central event in parthanatos. However, classical competitive MIF tautomerase inhibitors do not interfere with MIF functions in parthanatos. In this study, we employed a pharmacophore-switch to provide allosteric MIF tautomerase inhibitors that interfere with the MIF/AIF co-localization. Synthesis and screening of a focused compound collection around the 1,2,3-triazole core enabled identification of the allosteric tautomerase MIF inhibitor 6y with low micromolar potency (IC50 = 1.7 ± 0.1 µM). This inhibitor prevented MIF/AIF nuclear translocation and protects cells from parthanatos. These findings indicate that alternative modes to target MIF hold promise to investigate MIF function in parthanatos-mediated diseases.

Protocol of the Double-Click Seq Method to Evaluate the Deposition Bias of Chromatin Proteins.

Symmetrical deposition of parental and newly synthesized chromatin proteins over both sister chromatids is important for the maintenance of epigenetic integrity. However, the mechanisms to maintain equal distribution of parental and newly synthesized chromatid proteins over sister chromatids remains largely unknown. Here, we describe the protocol for the recently developed double-click seq method that enables mapping of asymmetry in the deposition of parental and newly synthesized chromatin proteins on both sister chromatids in DNA replication. The method involved metabolic labeling of new chromatin proteins with l-Azidohomoalanine (AHA) and newly synthesized DNA with Ethynyl-2'-deoxyuridine (EdU) followed by two subsequent click reactions for biotinylation and subsequently by corresponding separation steps. This enables isolation of parental DNA that was bound to nucleosomes containing new chromatin proteins. Sequencing of these DNA samples and mapping around origins of replication in the cellular DNA enables estimation of the asymmetry in deposition of chromatin proteins over the leading and lagging strand in DNA replication. Altogether, this method contributes to the toolbox to understand histone deposition in DNA replication. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Metabolic labeling with AHA and EdU and isolation of nuclei Basic Protocol 2: First click reaction, MNase digestion and streptavidin enrichment of labeled nucleosomes Basic Protocol 3: Second click reaction, Replication-Enriched Nucleosome Sequencing (RENS) Protocol.

ADAM metallopeptidase with thrombospondin type 1 motif 16 is a potential marker for prognosis in clear cell renal cell carcinoma.

The mortality rate of clear cell renal cell carcinoma (ccRCC) remains high. Immunohistochemical staining, Western blotting and real-time quantitative polymerase chain reaction were employed to evaluate ADAM (a disintegrin and metalloproteinase) metallopeptidase with thrombospondin type 1 motif 16 (ADAMTS16) levels in ccRCC tissues and paired normal tissues, and all tissues were obtained from clinical samples of 46 cases of ccRCC patients. Moreover, we analyzed the role ADAMTS16 in the progression of ccRCC using Cell Counting Kit-8 assay and flow cytometry. ADAMTS16 levels in ccRCC tissues were markedly low, relative to normal tissues, and ADAMTS16 level closely correlated with tumor stage, lymph node metastasis as well as pathological grade. Patients with elevated ADAMTS16 expressions have a more favorable survival outcome, relative to patients with low expression of ADAMTS16. In vitro study showed ADAMTS16 expression markedly decreased in ccRCC cells and acted as a tumor suppressor compared with the normal cells. The expression of ADAMTS16 is down-regulated in ccRCC tissues, relative to normal tissues, and it may inhibit the malignancies of ccRCC. Such inhibitory effect may be ascribed to the involvement of AKT/mammalian target of rapamycin signaling. Hence, the present study of ADAMTS16 will provide new insight into the underlying biological mechanisms of ccRCC.

Discovery of highly potent HDAC8 PROTACs with anti-tumor activity.

Various diseases are deeply associated with aberrations in HDAC8 functions. These aberrations can be assigned to either structural functions or catalytic functions of HDAC8. Therefore, development of HDAC8 degradation inducers might be more promising than HDAC8 inhibitors. We employed the proteolysis targeting chimera (PROTAC) strategy to develop a selective and potent HDAC8 degradation inducer CT-4 with single-digit nanomolar DC50 values and over 95% Dmax in both triple-negative breast cancer MDA-MB-231 cells and T-cell leukemia cells. Notably, CT-4 demonstrated potent anti-migration activity and limited anti-proliferative activity in MDA-MB-231 cells. In contrast, CT-4 effectively induced apototic cell death in Jurkat cells, as assessed by a caspase 3/7 activity assay and flow cytometry. Our findings suggest that the development of HDAC8 degradation inducers holds great potential for the treatment of HDAC8-related diseases.

Suicidality and epilepsy: A systematic review and meta-analysis.

Background: We aimed to evaluate the association between epilepsy and suicidality, including suicidal ideation, attempts and completed suicide. Methods: We systematically searched PubMed, Embase, Cochrane Online Library, and Clinicaltrials.gov from 1946 to June 21, 2021 and assessed the quality of the studies using the Newcastle-Ottawa Scale. We calculated the pooled OR and the crude rate for suicidal ideation, suicide attempts and completed suicide in patients with epilepsy (PWE). Results: We screened 2,786 studies and included 88 articles with 1,178,401 PWE and 6,900,657 participants as controls. Search terms included epilepsy and suicide. The pooled rates of suicidal ideation, suicide attempts and completed suicide in PWE were 19.73% (95% CI: 17.00-22.62%), 5.96% (95% CI: 4.82-7.20%), and 0.24% (95% CI: 0.11-0.42%), respectively. Compared to the control group, PWE were at a significantly higher risk of total suicidality (pooled OR, 2.60; 95%: 2.13-3.18), including suicidal ideation (pooled OR, 2.70; 95% CI, 2.21-3.30), suicide attempts (pooled OR, 2.74; 95% CI, 2.08-3.61) and completed suicide (pooled OR, 2.36; 95% CI, 1.45-3.83). Subgroup analyses showed significant differences in the subgroups of the measurement of suicidality. Conclusion: The rate of suicidal ideation, suicide attempts and completed suicide in PWE were about 19.73, 5.96, and 0.24%. And there was an increased risk of suicidality in PWE especially temporal lobe epilepsy and drug-resistant epilepsy. Clinicians need to be aware of this risk in PWE with early identification and prevention at the time of diagnosis.Protocol Registration: PROSPERO CRD42021278220.

Anomalous concentrations of rare earth elements in acid mine drainage and implications for rare earth resources from late Permian coal seams in northern Guizhou.

Rare earth elements (REEs) have attracted much attention in recent decades due to their growing applications in high-tech industries. Coal and acid mine drainage (AMD) are considered promising alternative sources due to their high concentrations of REEs. Here, AMD with anomalous REEs concentrations was reported in a coal-mine area in northern Guizhou, China. The AMD had a total concentration as high as 22.3 mg/l, suggesting that regional coal seams may be enriched with REEs. Five segments from borehole samples, which contained coal, rocks from the roof and floor of the coal seam were collected from the coal mine site to investigate the abundance, enrichment, and occurrence of REE-bearing minerals. Elemental analysis showed that the REE contents in the coal, mudstone and limestone from the coal seam roof, and claystone from the floor (all dating to the late Permian) varied greatly, with averages of 388, 549, 60.1 mg/kg and 2030 mg/kg, respectively. Encouragingly, the REEs content in the claystone is over an order of magnitude higher than the average content reported in most other coal-based materials. The enrichment of REEs resources in regional coal seams is particularly associated with the contribution of REEs in the claystone that comprises the coal seam floor, rather than just the coal, as considered in previous studies. The minerals in these claystone samples were dominated by kaolinite, pyrite, quartz and anatase. Two types of REE-bearing minerals, bastnaesite and monazite, were detected in the claystone samples by SEM-EDS analysis, and they were found to be adsorbed by a large amount of clay minerals, mainly kaolinite. Additionally, the results of chemical sequential extraction also confirmed that the majority of the REEs in the claystone samples are mainly in their ion-exchangeable, metal oxide and acid-soluble forms, which are viable prospects for REE extraction. Therefore, the anomalous concentrations of REEs and most of them are in extractable phases, which demonstrates that the claystone from the floor of the late Permian coal seam should be a potential secondary source of REEs. Future studies will further consider the extraction model and the economic benefits of REEs from the floor claystone samples.

Venous Thrombus Embolism in Polytrauma: Special Attention to Patients with Traumatic Brain Injury.

Venous thrombus embolism (VTE) is common after polytrauma, both of which are considered significant contributors to poor outcomes and mortality. Traumatic brain injury (TBI) is recognized as an independent risk factor for VTE and one of the most common components of polytraumatic injuries. Few studies have assessed the impact of TBI on the development of VTE in polytrauma patients. This study sought to determine whether TBI further increases the risk for VTE in polytrauma patients. A retrospective, multi-center trial was performed from May 2020 to December 2021. The occurrence of venous thrombosis and pulmonary embolism from injury to 28 days after injury was observed. Of 847 enrolled patients, 220 (26%) developed DVT. The incidence of DVT was 31.9% (122/383) in patients with polytrauma with TBI (PT + TBI group), 22.0% (54/246) in patients with polytrauma without TBI (PT group), and 20.2% (44/218) in patients with isolated TBI (TBI group). Despite similar Glasgow Coma Scale scores, the incidence of DVT in the PT + TBI group was significantly higher than in the TBI group (31.9% vs. 20.2%, p < 0.01). Similarly, despite no difference in Injury Severity Scores between the PT + TBI and PT groups, the DVT rate was significantly higher in the PT + TBI group than in the PT group (31.9% vs. 22.0%, p < 0.01). Delayed anticoagulant therapy, delayed mechanical prophylaxis, older age, and higher D-dimer levels were independent predictive risk factors for DVT occurrence in the PT + TBI group. The incidence of PE within the whole population was 6.9% (59/847). Most patients with PE were in the PT + TBI group (64.4%, 38/59), and the PE rate was significantly higher in the PT + TBI group compared to the PT (p < 0.01) or TBI (p < 0.05) group. In conclusion, this study characterizes polytrauma patients at high risk for VTE occurrence and emphasizes that TBI markedly increases the incidence of DVT and PE in polytrauma patients. Delayed anticoagulant therapy and delayed mechanical prophylaxis were identified as the major risk factors for a higher incidence of VTE in polytrauma patients with TBI.

Immune checkpoint molecule Tim-3 promotes NKT cell apoptosis and predicts poorer prognosis in Sepsis.

BACKGROUND: Sepsis is a leading cause of death among critically ill patients, which is defined as life-threatening organ dysfunction caused by a deregulated host immune response to infection. Immune checkpoint molecule Tim-3 plays important and complex roles in regulating immune responses and in inducing immune tolerance. Although immune checkpoint blockade would be expected as a promising therapeutic strategy for sepsis, but the underlying mechanism remain unknown, especially under clinical conditions. METHODS: Tim-3 expression and apoptosis in NKT cells were compared in septic patients (27 patients with sepsis and 28 patients with septic shock). Phenotypic and functional characterization of Tim-3+ NKT cells were analysed, and then the relationship between Tim-3 + NKT cells and clinical prognosis were investigated in septic patients. α-lactose (Tim-3/Galectin-9 signalling inhibitor) and Tim-3 mutant mice (targeting mutation of the Tim-3 cytoplasmic domain) were utilized to evaluate the protective effect of Tim-3 signalling blockade following septic challenge. RESULTS: There is a close correlation between Tim-3 expression and the functional status of NKT cells in septic patients, Upregulated Tim-3 expression promoted NKT cell activation and apoptosis during the early stage of sepsis, and it was associated with worse disease severity and poorer prognosis in septic patients. Blockade of the Tim-3/Galectin-9 signal axis using α-lactose inhibited in vitro apoptosis of NKT cells isolated from septic patients. Impaired activity of Tim-3 protected mice following septic challenge. CONCLUSIONS: Overall, these findings demonstrated that immune checkpoint molecule Tim-3 in NKT cells plays a critical role in the immunopathogenesis of septic patients. Blockade of immune checkpoint molecule Tim-3 may be a promising immunomodulatory strategy in future clinical practice for the management of sepsis.

Two nucleotide sugar transporters are important for cell wall integrity and full virulence of Magnaporthe oryzae.

Cell wall polysaccharides play key roles in fungal development, virulence, and resistance to the plant immune system, and are synthesized from many nucleotide sugars in the endoplasmic reticulum (ER)-Golgi secretory system. Nucleotide sugar transporters (NSTs) are responsible for transporting cytosolic-derived nucleotide sugars to the ER lumen for processing, but their roles in plant-pathogenic fungi remain to be revealed. Here, we identified two important NSTs, NST1 and NST2, in the rice blast fungus Magnaporthe oryzae. Both NSTs were localized in the ER, which was consistent with a function in transporting nucleotide sugar for processing in the ER. Sugar transport property analysis suggested that NST1 is involved in transportation of mannose and glucose, while NST2 is only responsible for mannose transportation. Accordingly, deletion of NSTs resulted in a significant decrease in corresponding soluble saccharides abundance and defect in sugar utilization. Moreover, both NSTs played important roles in cell wall integrity, were involved in asexual development, and were required for full virulence. The NST mutants exhibited decreasing external glycoproteins and exposure of inner chitin, which resulted in activation of the host defence response. Altogether, our results revealed that two sugar transporters are required for fungal cell wall polysaccharides accumulation and full virulence of M. oryzae.

[PACS and Photoshop assisted isosceles triangle osteotomy and Kirschner wire tension buckle fixation in the treatment of cubitus varus in children].

OBJECTIVE: To investigate the clinical efficacy of picture archiving and communication system (PACS) and Photoshop assisted isosceles triangle osteotomy and Kirschner wire fixation with tension band in the treatment of cubitus varus in children. METHODS: The clinic data of 20 children with cubitus varus treated with isosceles triangle osteotomy of distal humerus and Kirschner wire fixation with tension band from October 2014 to October 2019, were retrospectively analyzed. There were 13 males and 7 females, aged from 3.2 to 13.5 years old, the median age was 6.65 years old. PACS system was applied for the osteotomy design preoperatively, simulating and measuring the side length of isosceles triangle osteotomy. Then, Photoshop system was used to simulate the preoperative and postoperative osteotomy graphics, which could guide precise osteotomy during operation. RESULTS: All the 20 patients were followed up for 20 to 24 months, with a median of 22.5 months. At the last follow-up, the carrying angle of the affected limb was 5 ° to 13 °, with a median of 8.3 °. The clinical efficacy was evaluated according to the Flynn elbow function score:excellent in 16 cases, good in 2 cases, and fair in 2 cases. CONCLUSION: The treatment of cubitus varus in children by isosceles triangle osteotomy and Kirschner wire fixation with tension band assisted by PACS and Photoshop system has shown good clinical outcome.

Incidence and association of seizures in stroke patients following endovascular treatment: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Post-stroke seizures (PSSs) are some of the most common complications of stroke and are associated with poor outcomes in patients. Endovascular treatment (EVT) is the standard of care for patients with acute ischaemic stroke related large-vessel occlusion. However, whether EVT increases the risk of PSSs remains controversial; the association between PSSs and EVT is poorly understood. METHODS: PubMed, Embase and the Cochrane Library were searched for relevant studies published from 1995 to 6 December 2021. The overall incidence of PSSs in patients treated with EVT and the separate incidence for all included studies in each subgroup, stratified by the type of treatment or time of onset, were calculated. The pooled odds ratio and confidence interval were calculated to quantify the effects of EVT on PSS occurrence. RESULTS: In all, 946 studies were screened and 16 articles were included, with a total sample size of 12,664 patients; 7836 patients received EVT, of whom 460 had PSS. The pooled incidence of PSS after EVT was 5.8%, which was similar to patients treated with mechanical thrombectomy (5.3%), intra-arterial thrombolysis (6.8%) or bridging therapy (5.4%). The cumulative incidence of post-stroke epilepsy (6.0%) was almost twice that of acute symptomatic seizures (3.6%). The pooled odds ratio for the relationship between EVT and PSS was 1.91 (95% confidence interval 0.98-3.73). CONCLUSIONS: The cumulative incidence of stroke patients treated with EVT who developed seizures was 5.8%, and EVT was non-significantly associated with the occurrence of seizures after stroke.