Risk factors for recurrence of common bile duct stones after surgical treatment and effect of ursodeoxycholic acid intervention

BACKGROUND Endoscopic retrograde cholangiopancreatography(ERCP)is an accurate diagnostic method for choledocholithiasis and treatment option for stone removal.Additionally,ursodeoxycholic acid(UDCA)can dissolve cholesterol stones and prevent their development and reappearance by lowering the cholesterol concen-tration in bile.Despite these treatment options,there are still patients who experience stone recurrence.The clinical data of 100 patients with choledochal stones who were hospitalized at the Yixing People’s Hospital and underwent ERCP for successful stone extraction between June 2020 and December 2022 were retrospectively collected.According to the post-ERCP treatment plan,100 patients were classified into UDCA(n=47)and control(n=53)groups.We aimed to assess the clinical efficacy and rate of relapse in the two patient populations.We then collected information(basic demographic data,clinical characteristics,and serum biochemical indicators)and determined the factors contributing to relapse using logistic regression analysis.Our secondary goal was to determine the effects of UDCA on liver function after ERCP.Compared to the control group,the UDCA group demonstrated a higher clinical effectiveness rate of 92.45%vs 78.72%(P<0.05).No significant differences were observed in liver function indices,including total bilirubin,direct bilirubin,gamma-glutamyl transpeptidase,alanine aminotransferase,alkaline phosphatase,and aspartate aminotransferase,between the two groups before treatment.After treatment,all liver function indices were significantly reduced.Comparing the control vs UDCA groups,the UDCA group exhibited significantly lower levels of all indices(55.39±6.53 vs 77.31±8.52,32.10±4.62 vs 45.39±5.69,142.32±14.21 vs 189.63±16.87,112.52±14.25 vs 149.36±15.36,122.61±16.00 vs 171.33±22.09,96.98±10.44 vs 121.35±11.57,respectively,all P<0.05).The stone recurrence rate was lower in the UDCA group(13.21%)in contrast with the control group(44.68%).Periampullary diverticula(OR:6.00,95%CI:1.69-21.30),maximum stone diameter(OR:1.69,95%CI:1.01-2.85),stone quantity>3(OR:4.23,95%CI:1.17-15.26),and positive bile culture(OR:7.61,95%CI:2.07-27.91)were independent factors that influenced the relapse of common bile duct stones after ERCP(P<0.05).Furthermore,postoperative UDCA was identified as a preventive factor(OR:0.07;95%CI:0.08-0.09).CONCLUSION The intervention effect of UDCA after ERCP for common bile duct stones is adequate,providing new research directions and references for the prevention and treatment of stone recurrence.

Identifying the best common factor model via exploratory eactor analysis

Currently,there is no solid criterion for judging the quality of the estimators in factor analysis.This paper presents a new evaluation method for exploratory factor analysis that pinpoints an appropriate number of factors along with the best method for factor extraction.The proposed technique consists of two steps:testing the normality of the residuals from the fitted model via the Shapiro-Wilk test and using an empirical quantified index to judge the quality of the factor model.Examples are presented to demonstrate how the method is implemented and to verify its effectiveness.

Examining the Hypothesis of Common Factors Shared by Different Addictive Behaviors and Gender Effects on Propensity to Addiction Type

Background: From the two facts reported by previous research: 1) frequent co-occurrence of more than one addictive behavior, 2) childhood adversities identified as origins of different types of addictive behaviors, it is assumed that all types of addictive behaviors, regardless of substance, behavioral, or relationship, share common factors which have not yet been proven by epidemiological research. The Shorter PROMIS Questionnaire (SPQ) was previously developed to assess 16 types of addictive behaviors. Its factor structure, however, has not been fully investigated. Confirming the factor structure will enable us to hypothesize the common factor(s) shared by all, or if not all, most types of addictive behaviors. Aims: This study aimed at 1) examining the factor structure of the SPQ, 2) confirming the reliability of the questionnaire, and 3) examining the impacts of gender and age on each addictive behavior. Methods: Data obtained from 232 Japanese adults who completed all items of the SPQ were used for the analyses. After confirming the one-factor structure model for each of the 16 subscales, the validity of the one-factor structure of the SPQ was evaluated using Confirmatory Factor Analysis (CFA), by adapting 16 subscale scores as observed variables. If its validity was not confirmed, another model which showed better compatibility to the data was explored. The reliability of the SPQ as well as that of all 16 subscales was evaluated. Also, the impacts of gender and age on each subscale score were examined. Results: The one-factor structure for each of the 16 subscales was confirmed. The compatibility of the SPQ one-factor model was not acceptable. The best fit model was a bi-factor model in which one main factor was shared by all 16 subscales, and three factors were shared by some specific addictive behaviors. Male respondents were more likely than female respondents to show high scores in Alcohol, Tobacco, Gambling, Sex, and Recreational Drugs, and low scores only in Shopping. Respondents’ age did not impact any of the 16 subscale scores. Conclusion: It was demonstrated that there are common factors shared by all different types, as well as selected types of addictive behaviors, by conducting CFAs of the SPQ. Reliability was proven for the SPQ and for all 16 subscales. Male respondents were more likely to show physically hedonic addictive behaviors.

Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.

Functions of nuclear factor Y in nervous system development,function and health

Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and enhancers.Over the last 30 years,research has revealed that the nuclear factor Y complex controls many aspects of brain development,including differentiation,axon guidance,homeostasis,disease,and most recently regeneration.However,a complete understanding of transcriptional regulatory networks,including how the nuclear factor Y complex binds to specific CCAAT boxes to perform its function remains elusive.In this review,we explore the nuclear factor Y complex’s role and mode of action during brain development,as well as how genomic technologies may expand understanding of this key regulator of gene expression.

The effects of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents:a meta-analysis

Brain-derived neurotrophic factor is a crucial neurotrophic factor that plays a significant role in brain health. Although the vast majority of meta-analyses have confirmed that exercise interventions can increase brain-derived neurotrophic factor levels in children and adolescents, the effects of specific types of exercise on brain-derived neurotrophic factor levels are still controversial. To address this issue, we used meta-analytic methods to quantitatively evaluate, analyze, and integrate relevant studies. Our goals were to formulate general conclusions regarding the use of exercise interventions, explore the physiological mechanisms by which exercise improves brain health and cognitive ability in children and adolescents, and provide a reliable foundation for follow-up research. We used the Pub Med, Web of Science, Science Direct, Springer, Wiley Online Library, Weipu, Wanfang, and China National Knowledge Infrastructure databases to search for randomized controlled trials examining the influences of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents. The extracted data were analyzed using Review Manager 5.3. According to the inclusion criteria, we assessed randomized controlled trials in which the samples were mainly children and adolescents, and the outcome indicators were measured before and after the intervention. We excluded animal experiments, studies that lacked a control group, and those that did not report quantitative results. The mean difference(MD;before versus after intervention) was used to evaluate the effect of exercise on brain-derived neurotrophic factor levels in children and adolescents. Overall, 531 participants(60 children and 471 adolescents, 10.9–16.1 years) were included from 13 randomized controlled trials. Heterogeneity was evaluated using the Q statistic and I^(2) test provided by Review Manager software. The meta-analysis showed that there was no heterogeneity among the studies(P = 0.67, I^(2) = 0.00%). The combined effect of the interventions was significant(MD = 2.88, 95% CI: 1.53–4.22, P < 0.0001), indicating that the brain-derived neurotrophic factor levels of the children and adolescents in the exercise group were significantly higher than those in the control group. In conclusion, different types of exercise interventions significantly increased brain-derived neurotrophic factor levels in children and adolescents. However, because of the small sample size of this meta-analysis, more high-quality research is needed to verify our conclusions. This metaanalysis was registered at PROSPERO(registration ID: CRD42023439408).

Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish:unveiling the role of vascular endothelial growth factor signaling and microglia

After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.

Age-related driving mechanisms of retinal diseases and neuroprotection by transcription factor EB-targeted therapy

Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.

Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination

During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.

The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson's disease

Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.

Risk factors for the development of post-endoscopic retrograde cholangiopancreatography pancreatitis in patients with asymptomatic common bile duct stones

BACKGROUND Previous studies have revealed that patients with asymptomatic common bile duct(CBD)stones are at a high risk of developing post-endoscopic retrograde cholangiopancreatography(ERCP)pancreatitis(PEP).However,no studies to date have addressed the risk factors for PEP in patients with asymptomatic CBD stones.AIM To examine the risk factors for PEP in patients with asymptomatic CBD stones.METHODS Using medical records of three institutions in Japan for 6 years,we identified a total of 1135 patients with choledocholithiasis including 967 symptomatic patients and 168 asymptomatic patients with native papilla who underwent therapeutic ERCP.We performed univariate and multivariate analyses to examine the risk factors for PEP in the 168 patients with asymptomatic CBD stones.RESULTS The overall incidence rate of PEP in all the patients with during study period was 4.7%(53/1135).Of the 168 patients with asymptomatic CBD stones,24(14.3%)developed PEP.In univariate analysis,precut sphincterotomy(P=0.009)and biliary balloon sphincter dilation(P=0.043)were significant risk factors for PEP.In multivariate analysis,precut sphincterotomy(P=0.002,95%CI:2.2-27.8,odds ratio=7.7),biliary balloon sphincter dilation(P=0.015,95%CI:1.4-17.3,odds ratio=4.9),and trainee endoscopists(P=0.048,95%CI:1.01-8.1,odds ratio=2.9)were significant risk factors for PEP.CONCLUSION ERCP for asymptomatic CBD stones should be performed by experienced endoscopists.When performing precut sphincterotomy or biliary balloon sphincter dilation in patients with asymptomatic CBD stones,the placement of a prophylactic pancreatic stent is strongly recommended to prevent PEP.

Restoration of common bile duct diameter within 2 weeks after endoscopic stone retraction is a preventive factor for stone recurrence

Background： Little information is available about the relationship between restoration of common bileduct （CBD） diameter after endoscopic stone retraction and recurrence of CBD stones in elderly patients.The present study was to determine whether restoration of CBD diameter is a preventive factor for CBDstone recurrence in elderly patients who underwent endoscopic retrograde cholangiopancreatography（ERCP）.

Acute distal common bile duct angle is risk factor for postendoscopic retrograde cholangiopancreatography pancreatitis in beginner endoscopist

BACKGROUND Post-endoscopic retrograde cholangiopancreatography(ERCP) pancreatitis(PEP)is a critical and poorly managed complication of ERCP. Endoscopists need to understand the risk factors for PEP. However, the majority of studies investigating ERCP-related risk factors have included well-trained endoscopists,with the issue of endoscopist experience on PEP incidence not having been systematically evaluated.AIM To explore the risk factors for PEP in beginner endoscopists without supervision.METHODS We performed a retrospective analysis of 293 patients, with na?ve papilla and no history of pancreatitis, treated using bile duct cannulation. Patients were classified according to the endoscopist’s experience(beginner vs expert). The angle of the distal common bile duct(CBD) was measured as the angle between the lower wall of the bile duct and a vertical line extending to the lower wall of the bile duct on coronal view computed tomography.RESULTS After propensity matching, there were no differences between patients treated by the expert and beginner endoscopist with regard to age, sex, mean bile duct dilatation, and ratio of benign disease. The distal CBD angle was classified as acute(> 30o) or obtuse(≤ 30o), based on the mean angle of 29.9o for the group. An acute distal CBD angle was a significant risk factor for PEP for beginner(P =0.049), but not expert.CONCLUSION For beginner endoscopists first performing unsupervised ERCP, cases with an obtuse distal CBD angle may be more appropriate to lower the risk of PEP.

Complications of common bile duct stones: A risk factors analysis

Background: The latest guidelines recommended that common bile duct stones(CBDSs) should be removed, preferably endoscopically, regardless of the presence of symptoms or complications. However, the removal of CBDSs may not be feasible in very old patients or those with co-morbidities. In these cases, it is important to understand the risk factors for the development of CBDSs-related complications to decide whether or not to treat high-risk patients. Herein, we aimed to identify the risk factors for the development of complications after the diagnosis of CBDSs. Methods: The medical records of patients with CBDSs between October 2005 and September 2019 were retrospectively analyzed. All patients with radiologically-diagnosed CBDSs, including those who received treatment and those who did not, were analyzed. Results: A total of 634 patients were included and 95(15.0%) patients had CBDS-related complications during the mean follow-up period of 32.6 months. Forty-four(6.9%) high-risk patients remained asymptomatic and did not receive treatment during the follow-up period. In multivariate analyses, size of CBDSs ≥ 5 mm and no treatment within 30 days were independent risk factors for the development of complications. The spontaneous passage of CBDSs was proved radiologically in 9 out of 81(11.1%) patients within 30 days. Conclusions: It is recommended treating CBDSs within 30 days from the diagnosis, even in high-risk patients, especially if the size is larger than 5 mm.

Technological Innovation: A Primary Driver to Promote Global Urban Common Prosperity——An Analysis of Factors Influencing the Competitiveness of 1,007 Cities around the World

Common prosperity,an important goal of human development,increasingly has to be achieved through the common prosperity of cities.The research into and discovery of the determinants which create differences in urban economic competitiveness is of great signi ficance as,thereby,the research and expected discovery can help with the formulation of relevant policies for development,competition,and cooperation to promote win-win conditions among cities.However,such research is still rare.Based on the economic competitiveness data of 1,007 cities,this paper uses OLS regression and Shapley-value based decompositions regression to analyze factors affecting the economic competitiveness of global cities and differences that the cities made.Combined with quantile regression,studying the law of changing of each factor's effect on cities with different levels of economic competitiveness is of theoretical and practical signi ficance.The study findings are as follows.(1)The variability of global urban economic competitiveness is quite large.Cities in North America and Europe are still the benchmarks of global urban economic prosperity.(2)Financial services,technological innovation,industrial system,business environment,institutional environment,infrastructure,among other factors,have signi ficant impacts on the economic competitiveness of cities.(3)The primary factor that in fluenced the variability in economic competitiveness is technological innovation.(4)The ranking of the main in fluencing factors varied slightly between cities at different levels of economic competitiveness.These indicate that the international community should promote innovation in and diffusion of science and technology to achieve common prosperity by narrowing the gap between cities.The relevant decision-making departments,e.g.urban planning departments with strong economic and finance expertise of the cities in different development zones should adopt different measures in accordance with their actual situations.

Risk factors for small intestinal adenocarcinomas that are common in the proximal small intestine

The frequency of primary small intestinal adenocarcinoma is increasing but is still low.Its frequency is approximately 3%of that of colorectal adenocarcinoma.Considering that the small intestine occupies 90%of the surface area of the gastrointestinal tract,small intestinal adenocarcinoma is very rare.The main site of small intestinal adenocarcinoma is the proximal small intestine.Based on this characteristic,dietary animal proteins/lipids and bile concentrations are implicated and reported to be involved in carcinogenesis.Since most nutrients are absorbed in the proximal small intestine,the effect of absorbable intestinal content is a suitable explanation for why small intestinal adenocarcinoma is more common in the proximal small intestine.The proportion of aerobic bacteria is high in the proximal small intestine,but the absolute number of bacteria is low.In addition,the length and density of villi are greater in the proximal small intestine.However,the involvement of villi is considered to be low because the number of small intestinal adenocarcinomas is much smaller than that of colorectal adenocarcinomas.On the other hand,the reason for the low incidence of small intestinal adenocarcinoma in the distal small intestine may be that immune organs reside there.Genetic and disease factors increase the likelihood of small intestinal adenocarcinoma.In carcinogenesis experiments in which the positions of the small and large intestines were exchanged,tumors still occurred in the large intestinal mucosa more often.In other words,the influence of the intestinal contents is small,and there is a large difference in epithelial properties between the small intestine and the large intestine.In conclusion,small intestinal adenocarcinoma is rare compared to large intestinal adenocarcinoma due to the nature of the epithelium.It is reasonable to assume that diet is a trigger for small intestinal adenocarcinoma.

Significant risk factors for intensive care unit-acquired weakness:A processing strategy based on repeated machine learning

BACKGROUND Intensive care unit-acquired weakness(ICU-AW)is a common complication that significantly impacts the patient's recovery process,even leading to adverse outcomes.Currently,there is a lack of effective preventive measures.AIM To identify significant risk factors for ICU-AW through iterative machine learning techniques and offer recommendations for its prevention and treatment.METHODS Patients were categorized into ICU-AW and non-ICU-AW groups on the 14th day post-ICU admission.Relevant data from the initial 14 d of ICU stay,such as age,comorbidities,sedative dosage,vasopressor dosage,duration of mechanical ventilation,length of ICU stay,and rehabilitation therapy,were gathered.The relationships between these variables and ICU-AW were examined.Utilizing iterative machine learning techniques,a multilayer perceptron neural network model was developed,and its predictive performance for ICU-AW was assessed using the receiver operating characteristic curve.RESULTS Within the ICU-AW group,age,duration of mechanical ventilation,lorazepam dosage,adrenaline dosage,and length of ICU stay were significantly higher than in the non-ICU-AW group.Additionally,sepsis,multiple organ dysfunction syndrome,hypoalbuminemia,acute heart failure,respiratory failure,acute kidney injury,anemia,stress-related gastrointestinal bleeding,shock,hypertension,coronary artery disease,malignant tumors,and rehabilitation therapy ratios were significantly higher in the ICU-AW group,demonstrating statistical significance.The most influential factors contributing to ICU-AW were identified as the length of ICU stay(100.0%)and the duration of mechanical ventilation(54.9%).The neural network model predicted ICU-AW with an area under the curve of 0.941,sensitivity of 92.2%,and specificity of 82.7%.CONCLUSION The main factors influencing ICU-AW are the length of ICU stay and the duration of mechanical ventilation.A primary preventive strategy,when feasible,involves minimizing both ICU stay and mechanical ventilation duration.

Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor?

Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor.Therefore,while,based on the current knowledge,the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reve rse the disease pathology per se,promoting brainderived neurotrophic factor/tro pomyosin receptor kinase B signaling still has a very high therapeutic relevance.

Hepatocyte growth factor promotes retinal pigment epithelium cell activity through MET/AKT signaling pathway

AIM:To explore the effects of hepatocyte growth factor(HGF)on retinal pigment epithelium(RPE)cell behaviors.METHODS:The human adult retinal pigment epithelial cell line-19(ARPE-19)were treated by HGF or mesenchymalepithelial transition factor(MET)inhibitor SU11274 in vitro.Cell viability was detected by a Cell Counting Kit-8 assay.Cell proliferation and motility was detected by a bromodeoxyuridine incorporation assay and a wound healing assay,respectively.The expression levels of MET,phosphorylated MET,protein kinase B(AKT),and phosphorylated AKT proteins were determined by Western blot assay.The MET and phosphorylated MET proteins were also determined by immunofluorescence assay.RESULTS:HGF increased ARPE-19 cells’viability,proliferation and migration,and induced an increase of phosphorylated MET and phosphorylated AKT proteins.SU11274 significantly reduced cell viability,proliferation,and migration and decreased the expression of MET and AKT proteins.SU11274 suppressed HGF-induced increase of viability,proliferation,and migration in ARPE-19 cells.Additionally,SU11274 also blocked HGF-induced phosphorylation of MET and AKT proteins.CONCLUSION:HGF enhances cellular viability,proliferation,and migration in RPE cells through the MET/AKT signaling pathway,whereas this enhancement is suppressed by the MET inhibitor SU11274.HGF-induced MET/AKT signaling might be a vital contributor of RPE cells survival.

The roles of macrophage migration inhibitory factor in retinal diseases

Macrophage migration inhibitory factor(MIF),a multifunctional cytokine,is secreted by various cells and participates in inflammatory reactions,including innate and adaptive immunity.There are some evidences that MIF is involved in many vitreoretinal diseases.For example,MIF can exacerbate many types of uveitis;measurements of MIF levels can be used to monitor the effectiveness of uveitis treatment.MIF also alleviates trauma-induced and glaucoma-induced optic nerve damage.Furthermore,MIF is critical for retinal/choroidal neovascularization,especially complex neovascularization.MIF exacerbates retinal degeneration;thus,anti-MIF therapy may help to mitigate retinal degeneration.MIF protects uveal melanoma from attacks by natural killer cells.The mechanism underlying the effects of MIF in these diseases has been demonstrated:it binds to cluster of differentiation 74,inhibits the c-Jun N-terminal kinase pathway,and triggers mitogen-activated protein kinases,extracellular signal-regulated kinase-1/2,and the phosphoinositide-3-kinase/Akt pathway.MIF also upregulates Toll-like receptor 4 and activates the nuclear factor kappa-B signaling pathway.This review focuses on the structure and function of MIF and its receptors,including the effects of MIF on uveal inflammation,retinal degeneration,optic neuropathy,retinal/choroidal neovascularization,and uveal melanoma.