Epithelial Na + Channels Function as Extracellular Sensors.

The epithelial Na + channel (ENaC) resides on the apical surfaces of specific epithelia in vertebrates and plays a critical role in extracellular fluid homeostasis. Evidence that ENaC senses the external environment emerged well before the molecular identity of the channel was reported three decades ago. This article discusses progress toward elucidating the mechanisms through which specific external factors regulate ENaC function, highlighting insights gained from structural studies of ENaC and related family members. It also reviews our understanding of the role of ENaC regulation by the extracellular environment in physiology and disease. After familiarizing the reader with the channel's physiological roles and structure, we describe the central role protein allostery plays in ENaC's sensitivity to the external environment. We then discuss each of the extracellular factors that directly regulate the channel: proteases, cations and anions, shear stress, and other regulators specific to particular extracellular compartments. For each regulator, we discuss the initial observations that led to discovery, studies investigating molecular mechanism, and the physiological and pathophysiological implications of regulation. © 2024 American Physiological Society. Compr Physiol 14:5407-5447, 2024.

Beta-blocker drives the conjugative transfer of multidrug resistance genes in pure and complex biological systems.

Drug resistance poses a high risk to human health. Extensive use of non-antibiotic drugs contributes to antibiotic resistance genes (ARGs) transfer. However, how they affect the spread of broad-host plasmids in complex biological systems remains unknown. This study investigated the effect of metoprolol on the transfer frequency and host range of ARGs in both intrageneric and intergeneric pure culture systems, as well as in anammox microbiome. The results showed that environmental concentrations of metoprolol significantly promoted the intrageneric and intergeneric conjugative transfer. Initially, metoprolol induced excessive oxidative stress, resulting in high cell membrane permeability and bacterial SOS response. Meanwhile, more pili formation increased the adhesion and contact between bacteria, and the abundance of conjugation-related genes also increased significantly. Activation of the electron transport chain provided more ATP for this energy-consuming process. The underlying mechanism was further verified in the complex anammox conjugative system. Metoprolol induced the enrichment of ARGs and mobile genetic elements. The enhanced bacterial interaction and energy generation facilitated the high conjugative transfer frequency of ARGs. In addition, plasmid-borne ARGs tended to transfer to opportunistic pathogens. This work raises public concerns about the health and ecological risks of non-antibiotic drugs.

Varying Selection Pressure for a Na+ Sensing Site in Epithelial Na+ Channel Subunits Reflect Divergent Roles in Na+ Homeostasis.

The epithelial Na+ channel (ENaC) emerged early in vertebrates and has played a role in Na+ and fluid homeostasis throughout vertebrate evolution. We previously showed that proteolytic activation of the channel evolved at the water-to-land transition of vertebrates. Sensitivity to extracellular Na+, known as Na+ self-inhibition, reduces ENaC function when Na+ concentrations are high and is a distinctive feature of the channel. A fourth ENaC subunit, δ, emerged in jawed fishes from an α subunit gene duplication. Here, we analyzed 849 α and δ subunit sequences and found that a key Asp in a postulated Na+ binding site was nearly always present in the α subunit, but frequently lost in the δ subunit (e.g. human). Analysis of site evolution and codon substitution rates provide evidence that the ancestral α subunit had the site and that purifying selection for the site relaxed in the δ subunit after its divergence from the α subunit, coinciding with a loss of δ subunit expression in renal tissues. We also show that the proposed Na+ binding site in the α subunit is a bona fide site by conferring novel function to channels comprising human δ subunits. Together, our findings provide evidence that ENaC Na+ self-inhibition improves fitness through its role in Na+ homeostasis in vertebrates.

Quorum sensing mediated response mechanism of anammox consortia to anionic surfactant: Molecular simulation and molecular evidence.

The widespread use of surfactants raise challenges to biological wastewater treatment. Anaerobic ammonium oxidation (anammox) process has the potential to treat wastewater containing anionic surfactants, but the response of anammox consortia at the molecular level under long-term exposure is unclear. Using high-throughput sequencing and gene quantification, combined with molecular docking, the effect of sodium dodecyl sulfonate (SDS) on anammox consortia were investigated. Levels of reactive oxygen species (ROS) might be lower than the threshold of oxidative damage, while the increase of lactate dehydrogenase (LDH) represented the cell membrane damage. Decreased abundance of functional genes (hdh, hzsA and nirS) indicated the decrease of the anammox bacterial abundance. Trace amounts of N-acyl homoserine lactone (AHL, C6-HSL, C8-HSL and C12-HSL) contained in influent could induce endogenous quorum sensing (QS), which could regulate the correlation between functional bacteria to optimize the microbial community and strengthen the resistance of anammox consortia to SDS. In addition, the proliferation of disinfectant resistance genes might increase the environmental pathogenicity of sewage discharge. This work highlights the potential response mechanism of anammox consortium to surfactants and provides a universal microbial-friendly bioenhancement strategy based on QS.

SGLT2-independent effects of canagliflozin on NHE3 and mitochondrial complex I activity inhibit proximal tubule fluid transport and albumin uptake.

Beyond glycemic control, SGLT2 inhibitors (SGLT2is) have protective effects on cardiorenal function. Renoprotection has been suggested to involve inhibition of NHE3 leading to reduced ATP-dependent tubular workload and mitochondrial oxygen consumption. NHE3 activity is also important for regulation of endosomal pH, but the effects of SGLT2i on endocytosis are unknown. We used a highly differentiated cell culture model of proximal tubule (PT) cells to determine the direct effects of SGLT2i on Na+-dependent fluid transport and endocytic uptake in this nephron segment. Strikingly, canagliflozin but not empagliflozin reduced fluid transport across cell monolayers and dramatically inhibited endocytic uptake of albumin. These effects were independent of glucose and occurred at clinically relevant concentrations of drug. Canagliflozin acutely inhibited surface NHE3 activity, consistent with a direct effect, but did not affect endosomal pH or NHE3 phosphorylation. In addition, canagliflozin rapidly and selectively inhibited mitochondrial complex I activity. Inhibition of mitochondrial complex I by metformin recapitulated the effects of canagliflozin on endocytosis and fluid transport, whereas modulation of downstream effectors AMPK and mTOR did not. Mice given a single dose of canagliflozin excreted twice as much urine over 24 h compared with empagliflozin-treated mice despite similar water intake. We conclude that canagliflozin selectively suppresses Na+-dependent fluid transport and albumin uptake in PT cells via direct inhibition of NHE3 and of mitochondrial function upstream of the AMPK/mTOR axis. These additional targets of canagliflozin contribute significantly to reduced PT Na+-dependent fluid transport in vivo.NEW & NOTEWORTHY Reduced NHE3-mediated Na+ transport has been suggested to underlie the cardiorenal protection provided by SGLT2 inhibitors. We found that canagliflozin, but not empagliflozin, reduced NHE3-dependent fluid transport and endocytic uptake in cultured proximal tubule cells. These effects were independent of SGLT2 activity and resulted from inhibition of mitochondrial complex I and NHE3. Studies in mice are consistent with greater effects of canagliflozin versus empagliflozin on fluid transport. Our data suggest that these selective effects of canagliflozin contribute to reduced Na+-dependent transport in proximal tubule cells.

Multi-omics provide insights into the regulation of DNA methylation in pear fruit metabolism.

BACKGROUND: Extensive research has been conducted on fruit development in crops, but the metabolic regulatory networks underlying perennial fruit trees remain poorly understood. To address this knowledge gap, we conduct a comprehensive analysis of the metabolome, proteome, transcriptome, DNA methylome, and small RNAome profiles of pear fruit flesh at 11 developing stages, spanning from fruitlet to ripening. Here, we systematically investigate the metabolic landscape and regulatory network involved. RESULTS: We generate an association database consisting of 439 metabolites and 14,399 genes to elucidate the gene regulatory network of pear flesh metabolism. Interestingly, we detect increased DNA methylation in the promoters of most genes within the database during pear flesh development. Application of a DNA methylation inhibitor to the developing fruit represses chlorophyll degradation in the pericarp and promotes xanthophyll, ß-carotene, and abscisic acid (ABA) accumulation in the flesh. We find the gradual increase in ABA production during pear flesh development is correlated with the expression of several carotenoid pathway genes and multiple transcription factors. Of these transcription factors, the zinc finger protein PbZFP1 is identified as a positive mediator of ABA biosynthesis in pear flesh. Most ABA pathway genes and transcription factors are modified by DNA methylation in the promoters, although some are induced by the DNA methylation inhibitor. These results suggest that DNA methylation inhibits ABA accumulation, which may delay fruit ripening. CONCLUSION: Our findings provide insights into epigenetic regulation of metabolic regulatory networks during pear flesh development, particularly with regard to DNA methylation.

Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice.

Sodium and fluid retention in liver disease is classically thought to result from reduced effective circulating volume and stimulation of the renin-angiotensin-aldosterone system (RAAS). Aldosterone dives Na+ retention by activating the mineralocorticoid receptor and promoting the maturation and apical surface expression of the epithelial Na+ channel (ENaC), found in the aldosterone-sensitive distal nephron. However, evidence of fluid retention without RAAS activation suggests the involvement of additional mechanisms. Liver disease can greatly increase plasma and urinary bile acid concentrations and have been shown to activate ENaC in vitro. We hypothesize that elevated bile acids in liver disease activate ENaC and drive fluid retention independent of RAAS. We therefore increased circulating bile acids in mice through bile duct ligation (BDL) and measured effects on urine and body composition, while using spironolactone to antagonize the mineralocorticoid receptor. We found BDL lowered blood [K+] and hematocrit, and increased benzamil-sensitive natriuresis compared to sham, consistent with ENaC activation. BDL mice also gained significantly more body water. Blocking ENaC reversed fluid gains in BDL mice but had no effect in shams. In isolated collecting ducts from rabbits, taurocholic acid stimulated net Na+ absorption but had no effect on K+ secretion or flow-dependent ion fluxes. Our results provide experimental evidence for a novel aldosterone-independent mechanism for sodium and fluid retention in liver disease which may provide additional therapeutic options for liver disease patients.

Multiple TMA-aided CRISPR/Cas13a platform for highly sensitive detection of IL-15 to predict immunotherapeutic response in nasopharyngeal carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs)-based treatments have been recommended as the first line for refractory recurrent and/or metastatic nasopharyngeal carcinoma (NPC) patients, yet responses vary, and predictive biomarkers are urgently needed. We selected serum interleukin-15 (sIL-15) out of four interleukins as a candidate biomarker, while most patients' sIL-15 levels were too low to be detected by conventional methods, so it was necessary to construct a highly sensitive method to detect sIL-15 in order to select NPC patients who would benefit most or least from ICIs. METHODS: Combining a primer exchange reaction (PER), transcription-mediated amplification (TMA), and a immuno-PER-TMA-CRISPR/Cas13a system, we developed a novel multiple signal amplification platform with a detection limit of 32 fg/mL, making it 153-fold more sensitive than ELISA. RESULTS: This platform demonstrated high specificity, repeatability, and versatility. When applied to two independent cohorts of 130 NPC sera, the predictive value of sIL-15 was accurate in both cohorts (area under the curve: training, 0.882; validation, 0.898). Additionally, lower sIL-15 levels were correlated with poorer progression-free survival (training, HR: 0.080, p<0.0001; validation, HR: 0.053, p<0.0001). CONCLUSION: This work proposes a simple and sensitive approach for sIL-15 detection to provide insights for personalized immunotherapy of NPC patients.

Prevalence and risk factors for colonisation and infection with carbapenem-resistant Enterobacterales in intensive care units: A prospective multicentre study.

OBJECTIVES: This study aimed to investigate the prevalence and risk factors for carbapenem-resistant Enterobacterales colonisation/infection at admission and acquisition among patients admitted to the intensive care unit. RESEARCH METHODOLOGY/DESIGN: A prospective and multicentre study. SETTING: This study was conducted in 24 intensive care units in Anhui, China. MAIN OUTCOME MEASURES: Demographic and clinical data were collected, and rectal carbapenem-resistant Enterobacterales colonisation was detected by active screening. Multivariate logistic regression models were used to analyse factors associated with colonisation/infection with carbapenem-resistant Enterobacterales at admission and acquisition during the intensive care unit stay. RESULTS: There were 1133 intensive care unit patients included in this study. In total, 5.9% of patients with carbapenem-resistant Enterobacterales colonisation/infection at admission, and of which 56.7% were colonisations. Besides, 8.5% of patients acquired carbapenem-resistant Enterobacterales colonisation/infection during the intensive care stay, and of which 67.6% were colonisations. At admission, transfer from another hospital, admission to an intensive care unit within one year, colonisation/infection/epidemiological link with carbapenem-resistant Enterobacterales within one year, and exposure to any antibiotics within three months were risk factors for colonisation/infection with carbapenem-resistant Enterobacterales. During the intensive care stay, renal disease, an epidemiological link with carbapenem-resistant Enterobacterales, exposure to carbapenems and beta-lactams/beta-lactamase inhibitors, and intensive care stay of three weeks or longer were associated with acquisition. CONCLUSION: The prevalence of colonisation/infection with carbapenem-resistant Enterobacterales in intensive care units is of great concern and should be monitored systematically. Particularly for the 8.5% prevalence of carbapenem-resistant Enterobacterales acquisition during the intensive care stay needs enhanced infection prevention and control measures in these setting. Surveillance of colonisation/infection with carbapenem-resistant Enterobacterales at admission and during the patient's stay represents an early identification tool to prevent further transmission of carbapenem-resistant Enterobacterales. IMPLICATIONS FOR CLINICAL PRACTICE: Carbapenem-resistant Enterobacterales colonization screening at admission and during the patient's stay is an important tool to control carbapenem-resistant Enterobacterales spread in intensive care units.

Research advances in application of mainstream anammox processes: Roles of quorum sensing and microbial metabolism.

Anaerobic ammonium oxidation (anammox) is a low-carbon biological nitrogen removal process, that has been widely applied to treat high-strength wastewater. However, the practical application of mainstream anammox treatment is limited due to the slow growth rate of anammox bacteria (AnAOB). Therefore, it is important to provide a comprehensive summary of the potential impacts and regulatory strategies for system stability. This article systematically reviewed the effects of environmental fluctuations on anammox systems, summarizing the bacterial metabolisms and the relationship between metabolite and microbial functional effects. To address the shortcoming of mainstream anammox process, molecular strategies based on quorum sensing (QS) were proposed. Sludge granulation, gel encapsulation and carrier-based biofilm technologies were adopted to enhance the QS function in microbial aggregation and reduction of biomass loss. Furthermore, this article discussed the application and progress of anammox-coupled processes. Valuable insights were provided for the stable operation and development of mainstream anammox process from the perspectives of QS and microbial metabolism.

Bile acids regulate the epithelial Na+ channel in native tissues through direct binding at multiple sites.

Bile acids, originally known to emulsify dietary lipids, are now established signalling molecules that regulate physiological processes. Signalling targets several proteins that include the ion channels involved in regulating intestinal motility and bile viscosity. Studies show that bile acids regulate the epithelial sodium channel (ENaC) in cultured cell models and heterologous expression systems. ENaC plays both local and systemic roles in regulating extracellular fluids. Here we investigated whether bile acids regulate ENaC expressed in native tissues. We found that taurocholic acid and taurohyodeoxycholic acid regulated ENaC in both the distal nephron and distal colon. We also tested the hypothesis that regulation occurs through direct binding. Using photoaffinity labelling, we found evidence for specific binding to both the ß and γ subunits of the channel. In functional experiments, we found that the α subunit was sufficient for regulation. We also found that regulation by at least one bile acid was voltage-sensitive, suggesting that one binding site may be closely associated with the pore-forming helices of the channel. Our data provide evidence that bile acids regulate ENaC by binding to multiple sites to influence the open probability of the channel. KEY POINTS: Recent studies have shown that bile acids regulate the epithelial sodium channel (ENaC) in vitro. Here we investigated whether bile acids regulate ENaC in native tissues and whether bile acids directly bind the channel. We found that bile acids regulate ENaC expressed in the mouse cortical collecting duct and mouse colon by modulating open probability. Photoaffinity labelling experiments showed specific binding to the ß and γ subunits of the channel, while channels comprising only α subunits were sensitive to taurocholic acid in functional experiments using Xenopus oocytes. Taurocholic acid regulation of ENaC was voltage-dependent, providing evidence for binding to pore-forming helices. Our data indicate that bile acids are ENaC regulatory effectors that may have a role in the physiology and pathophysiology of several systems.

Activation by cleavage of the epithelial Na+ channel α and γ subunits independently coevolved with the vertebrate terrestrial migration.

Vertebrates evolved mechanisms for sodium conservation and gas exchange in conjunction with migration from aquatic to terrestrial habitats. Epithelial Na+ channel (ENaC) function is critical to systems responsible for extracellular fluid homeostasis and gas exchange. ENaC is activated by cleavage at multiple specific extracellular polybasic sites, releasing inhibitory tracts from the channel's α and γ subunits. We found that proximal and distal polybasic tracts in ENaC subunits coevolved, consistent with the dual cleavage requirement for activation observed in mammals. Polybasic tract pairs evolved with the terrestrial migration and the appearance of lungs, coincident with the ENaC activator aldosterone, and appeared independently in the α and γ subunits. In summary, sites within ENaC for protease activation developed in vertebrates when renal Na+ conservation and alveolar gas exchange were required for terrestrial survival.

Development and external validation of a predictive nomogram model of posttraumatic epilepsy: A retrospective analysis.

OBJECTIVE: We aimed to develop and validate a predictive model of posttraumatic epilepsy (PTE). METHODS: The training cohort was patients registered at West China Hospital and diagnosed as traumatic brain injury (TBI) between January 1, 2011, and December 31, 2017. On the basis of multivariable cox proportional hazards model using a forward stepwise method, the nomogram was generated. We externally validated this instrument in 834 participants from two independent cohorts to assess its performance. RESULTS: The nomogram was built based on the results of multivariable cox proportional hazards regression analysis of 1301patients from West China Hospital. The prevalence of PTE was 12.8% (95% confidence interval [CI], 10.9-14.6%) in training cohort, 10.5% (95% CI, 7.5-13.4%) in the testing 1 cohort, and 6.1% (95% CI, 3.7-8.4%) in the testing 2 cohort. 7 independent predictors of PTE composed the nomogram (sex, time of loss of consciousness, subdural hemorrhage, contusion sites, early posttraumatic seizures, TBI severity, and treatment). The C-index was 0.846 (95% CI, 0.817-0.876), and the corresponding sensitivity and specificity were 0.867 and 0.738. External validations showed good discrimination in overall testing cohorts with a C-index of 0.895 (95% CI, 0.859-0.930), in the testing 1 cohort (C-index 0.897, 95% CI, 0.855-0.938) and testing 2 cohort (C-index, 0.883, 95% CI, 0.814-0.952). Calibration of this model was also good since the calibration plots were close to the ideal line. CONCLUSIONS: This nomogram was developed and validated in a large cohort for individualized prediction of PTE, which can identify individuals at high risk of epilepsy and help us find preventive drugs based on these targeted population.

[Inpatient Care Expenditure of Terminally Ill Patients in the Geriatric Ward of Peking Union Medical College Hospital].

Objective To describe the inpatient care expenditure of the terminally ill patients in the geriatric ward of Peking Union Medical College Hospital and facilitate future research on the economic outcomes of hospice and palliative care.Methods The histories of patients admitted to the Department of Geriatrics of Peking Union Medical College Hospital during 2018 were reviewed by trained doctors.According to the diagnosis and overall health state,terminally ill patients were selected and enrolled in the study.Demographics,health and disease information,prescriptions,and expenditure details were retrieved from the HIS system.Results In 2018,35 patients were terminally ill and eligible for hospice care,including 20 males and 15 females,with the average age of(78±8)years(59-91 years),the average age-adjusted Charlson Comorbidity Index of 10±3,and the median Barthel index of 40(10,70).These patients had malignant tumor(23 cases),heart failure(4 cases),end-stage renal disease(1 case),end-stage liver disease(2 cases),dementia(4 cases)and other severe diseases(3 cases).The patients received standard care within the scope of internal medicine and geriatrics.Finally,8 patients died during hospitalization,and 27 were discharged alive.The 35 patients had the median length of stay of 15(12,23)days,the median inpatient expenditure of CNY 21 500(13 800,37 600),and the median daily expenditure of CNY 1425(970,2503).The percentage of expenditure was(28.5±12.3)% for medication,(33.2±18.0)% for tests and examinations,and 11.5%(6.4%,15.8%)for accommodation and medical services.The medications for symptom control costed CNY(77±58)per day on average,accounting for(5.2±3.5)% of the total expenditure.Conclusions The inpatient expenditure for terminally ill patients in the tertiary grade A hospital was higher than that reported in community hospitals providing hospice care.In terms of expenditure constitution,the money spent on medications and tests/examinations were similar,and the percentage of expenditure on medications for symptom control was low.There is a need for further research on the economic impact of hospice and palliative care among terminally ill patients in China.

Prevalence and associated factors of sharps injuries and other blood/body fluid exposures among healthcare workers: A multicenter study.

A multicenter study of sharps injuries (SIs) and other blood or body fluid (OBBF) exposures was conducted among 33,156 healthcare workers (HCWs) from 175 hospitals in Anhui, China. In total, 12,178 HCWs (36.7%) had experienced at least 1 SI in the previous 12 months and 8,116 HCWs (24.5%) had experienced at least 1 OBBF exposure during the previous 12 months.

Validation of the predictive model for seizure recurrence after withdrawal of antiepileptic drugs.

PURPOSE: The purpose of this study was to validate the practicability of Lamberink's prediction model in risk assessment of antiepileptic drug (AED) withdrawal in a real, seizure-free population and to find a practical cutoff value to guide clinical withdrawal. METHODS: A group of seizure-free patients from West China Hospital was recruited. Each patient had been seizure-free for at least two years. The seizure recurrence risk among the patients was calculated by an online AED withdrawal risk calculator. The predictive ability of Lamberink's model was assessed by analyzing discrimination and calibration with receiver operating characteristic (ROC) curves and calibration plots, respectively. RESULTS: A total of 184 seizure-free patients received risk evaluation, all of whom were followed up for at least two years or had an earlier report of seizure relapse. Of these patients, 128 patients were followed up for at least five years or had an earlier report of relapse within five years. Sixty-two of 184 (33.7%) patients relapsed within two years, while 81 of 184 (44.0%) patients relapsed within five years after the start of AEDs' withdrawal. Cox regression analyses showed that seizure duration before remission and the age of seizure onset were independent predictors of relapse at two years. For predictors of recurrence at five years, seizure duration before remission, age at onset, and withdrawal were significant. For discrimination, ROC curve analysis showed that the area under the curve (AUC) for the seizure recurrence within two and five years was 0.605 (95% confidence interval [CI]: 0.518-0.692, p = 0.02) and 0.656 (95% CI: 0.563-0.749, p = 0.003), respectively. For calibration, it was poor in two-year prediction; the observed number was considerably lower than the predicted number. However, the calibration plot showed good calibration with the five-year prediction except for the second, fourth, and eighth deciles. With a cutoff two-year recurrence risk of 47%, the model had a sensitivity of 0.758 and a specificity of 0.410; the largest Youden index was 1.168. With a cutoff five-year recurrence risk of 77%, the model had a sensitivity of 0.358 and a specificity of 0.979; the largest Youden index was 1.337. CONCLUSIONS: Lamberink's prediction model has a general discrimination ability. The model overestimated the actual recurrence events when predicting the two-year recurrence risk, but it showed relatively good calibration with five-year prediction. The cutoff value found in this study may be used to guide patients and clinicians towards a decision regarding the withdrawal of AEDs. The model appears to be a useful tool for predicting seizure recurrence for the five-year recurrence risk.

Epidemiology of traumatic brain injury-associated epilepsy in western China: An analysis of multicenter data.

OBJECTIVES: This study aims to explore the probability of developing posttraumatic epilepsy (PTE) in the following 8 years after traumatic brain injury (TBI), the risk factors associated with PTE and its cumulative prevalence. METHODS: This is a retrospective follow-up study of patients with traumatic brain injury (TBI) discharged from the West China Hospital between January 1, 2011 and December 31, 2017, Chengdu Shang Jin Nan Fu Hospital and Sichuan Provincial People's Hospital from January 1, 2013 to March 1, 2015. We used forward stepwise method to build the final multivariate cox proportional hazard regression model to obtain estimates of hazard ratio (HR) of PTE and 95% confidence intervals (CI). We also conducted Kaplan-Meier survival analysis to investigate the cumulative prevalence of PTE. RESULTS: The cumulative incidence of PTE rose from 6.2% in one year to 10.6% in eight years. There were more male patients in PTE group and generally older. Besides, patients with PTE tended to have abnormal CT scan results. The risk factors of PTE were male (HR = 1.6, 95% CI: 1.1-2.2, P = 0.009), early posttraumatic seizures (HR = 2.9, 95% CI: 2.2-4.1, P < 0.001), TBI severity (moderate TBI: HR = 3.0, 95% CI: 1.8-5.0, P = 0.001; severe TBI: HR = 4.3, 95% CI: 2.3-7.6, P < 0.029), loss of consciousness (LOC) more than 30 min (30 min-24 h: HR = 1.8, 95% CI: 1.02-3.1, P = 0.041; >24 h: HR = 2.4, 95% CI: 1.4-2.4, P = 0.001), subdural hematoma (SDH) (HR = 1.9, 95% CI: 1.4-2.5, P < 0.001), brain contusion sites (frontal-temporal lobe: HR = 2.7, 95% CI: 1.9-3.9, P < 0.001; other sites: HR = 1.5, 95% CI: 1.01-2.3, P = 0.042) and cranial surgery (HR = 1.7, 95% CI: 1.3-2.3, P < 0.001). SIGNIFICANCE: The probability of developing PTE increased during the study period. In addition, the risk of developing PTE was significantly associated with gender, EPTS, LOC time, SDH, brain contusion sites, surgery and TBI severity. However, further researches may be needed to predict the risk of PTE in combination with quantitative factors.

Therapeutic effect of intravenous levetiracetam in status epilepticus: A meta-analysis and systematic review.

PURPOSE: We performed this analysis to evaluate the efficacy and safety of intravenous levetiracetam (IV LEV) in patients with status epilepticus. METHOD: Studies were searched in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for available randomized controlled trials(RCTs) comparing the efficacy and/or safety of IV LEV with other antiepileptic drugs (AEDs). Meta-analysis was performed using the random-effects model to calculate risk ratio with the RevMan 5.3 software. RESULTS: Six RCTs with a total of 543 patients were included. There was no significant differences in clinical seizure cessation and hospital mortality, either between IV LEV and IV phenytoin (PHT) or between IV LEV and IV valproate (VPA). Compared with IV PHT, IV LEV had a lower risk of poor neurological outcome. For IV LEV compared with IV lorazepam (LOR), no significant difference in efficacy was found, but IV LEV patients had significantly lower need for ventilatory assistance. Adding IV LEV to clonazepam (CNP), compared with adding placebo showed no significant differences in seizure cessation at 15 min. CONCLUSIONS: Our results suggested that IV LEV was comparable to IV PHT,VPA, or LOR in efficacy, and IV LEV as add-on therapy of CNP had no superiority in seizure cessation than CNP plus placebo. IV LEV may have a better tolerability than other AEDs do. More RCTs are needed to validate the role of IV LEV in status epilepticus.

Serum Apolipoprotein A-I Combined With C-Reactive Protein Serves As A Novel Prognostic Stratification System For Colorectal Cancer.

BACKGROUND AND OBJECTIVE: Noninvasive prognostic tools for colorectal cancer (CRC) are urgently needed. This study was designed to investigate the prognostic value of preoperative serum lipid and lipoprotein concentrations (including ApoA-I, Apo-B, HDL-C, LDL-C, TC and TG) and CRP levels retrospectively in CRC patients. METHODS: Preoperative serum lipid and lipoprotein concentrations (including ApoA-I, Apo-B, HDL-C, LDL-C, TC and TG) and CRP levels were analyzed retrospectively in 250 patients with CRC. The prognostic significance of these indexes was determined by univariate and multivariate Cox hazard models. RESULTS: CRC patients with higher levels of ApoA-I and HDL-C and lower levels of CRP had significantly longer overall survival (OS, log rank test, p<0.05). Based on univariate analysis, ApoA-I levels (p=0.002), CRP levels (p=0.007), HDL-C levels (p=0.005), pT classification (p=0.005), pN classification (p<0.001), pM classification (p<0.001) and pTNM stage (p<0.001) were significantly associated with OS. Multivariate Cox proportional hazards regression analysis indicated that ApoA-I levels (HR: 1.52, p=0.023), CRP levels (HR: 1.85, p=0.035) and pTNM stage (HR: 2.53, p< 0.001) were independent predictors of CRC survival. The included patients were then stratified into three tiers based on the ApoA-I and CRP levels. In the whole cohort, the OS and disease-free survival differed significantly between the low-risk (ApoA-I≥1.08 mg/dL and CRP<3.04 mg/dL), medium-risk (ApoA-I≥1.08 mg/dL or CRP<3.04 mg/dL), and high-risk (ApoA-I<1.08 mg/dL and CRP ≥3.04 mg/dL) groups (p=0.001 and p=0.004). CONCLUSION: Decreased levels of ApoA-I and HDL-C and increased levels of CRP were predictive of poor prognosis among patients with CRC. In addition, the combination of ApoA-I and CRP can serve as a novel prognostic stratification system for more accurate clinical staging of CRC.