Establishing delivery route-dependent safety and efficacy of living biodrug mesenchymal stem cells in heart failure patients

BACKGROUND Mesenchymal stem cells(MSCs)as living biopharmaceuticals with unique properties,i.e.,stemness,viability,phenotypes,paracrine activity,etc.,need to be administered such that they reach the target site,maintaining these properties unchanged and are retained at the injury site to participate in the repair process.Route of delivery(RoD)remains one of the critical determinants of safety and efficacy.This study elucidates the safety and effectiveness of different RoDs of MSC treatment in heart failure(HF)based on phase II randomized clinical trials(RCTs).We hypothesize that the RoD modulates the safety and efficacy of MSCbased therapy and determines the outcome of the intervention.AIM To investigate the effect of RoD of MSCs on safety and efficacy in HF patients.METHODS RCTs were retrieved from six databases.Safety endpoints included mortality and serious adverse events(SAEs),while efficacy outcomes encompassed changes in left ventricular ejection fraction(LVEF),6-minute walk distance(6MWD),and pro-B-type natriuretic peptide(pro-BNP).Subgroup analyses on RoD were performed for all study endpoints.RESULTS Twelve RCTs were included.Overall,MSC therapy demonstrated a significant decrease in mortality[relative risk(RR):0.55,95%confidence interval(95%CI):0.33-0.92,P=0.02]compared to control,while SAE outcomes showed no significant difference(RR:0.84,95%CI:0.66-1.05,P=0.11).RoD subgroup analysis revealed a significant difference in SAE among the transendocardial(TESI)injection subgroup(RR=0.71,95%CI:0.54-0.95,P=0.04).The pooled weighted mean difference(WMD)demonstrated an overall significant improvement of LVEF by 2.44%(WMD:2.44%,95%CI:0.80-4.29,P value≤0.001),with only intracoronary(IC)subgroup showing significant improvement(WMD:7.26%,95%CI:5.61-8.92,P≤0.001).Furthermore,the IC delivery route significantly improved 6MWD by 115 m(WMD=114.99 m,95%CI:91.48-138.50),respectively.In biochemical efficacy outcomes,only the IC subgroup showed a significant reduction in pro-BNP by-860.64 pg/mL(WMD:-860.64 pg/Ml,95%CI:-944.02 to-777.26,P=0.001).CONCLUSION Our study concluded that all delivery methods of MSC-based therapy are safe.Despite the overall benefits in efficacy,the TESI and IC routes provided better outcomes than other methods.Larger-scale trials are warranted before implementing MSC-based therapy in routine clinical practice.

Survival outcomes of right-lobe living donor liver transplantation for patients with high Model for End-stage Liver Disease scores

BACKGROUND: Controversy exists over whether living donor liver transplantation (LDLT) should be offered to patients with high Model for End-stage Liver Disease (MELD) scores. This study tried to determine whether a high MELD score would result in inferior outcomes of right-lobe LDLT. METHODS: Among 411 consecutive patients who received right-lobe LDLT at our center, 143 were included in this study. The patients were divided into two groups according to their MELD scores: a high-score group (MELD score ≥25; n=75) and a low-score group (MELD score 【25; n=68). Their demographic data and perioperative conditions were compared. Univariable and multivariable analyses were performed to identify risk factors affecting patient survival. RESULTS: In the high-score group, more patients required preoperative intensive care unit admission (49.3% vs 2.9%; P【0.001), mechanical ventilation (21.3% vs 0%; P【0.001), or hemodialysis (13.3% vs 0%; P=0.005); the waiting time before LDLT was shorter (4 vs 66 days; P【0.001); more blood was transfused during operation (7 vs 2 units; P【0.001); patients stayed longer in the intensive care unit (6 vs 3 days; P【0.001) and hospital (21 vs 15 days; P=0.015) after transplantation;more patients developed early postoperative complications (69.3% vs 50.0%; P=0.018); and values of postoperative peak blood parameters were higher. However, the two groups had comparable hospital mortality. Graft survival and patient overall survival at one year (94.7% vs 95.6%; 95.9% vs 96.9%), three years (91.9% vs 92.6%; 93.2% vs 95.3%), and five years (90.2% vs 90.2%; 93.2% vs 95.3%) were also similar between the groups. CONCLUSIONS: Although the high-score group had signifi-cantly more early postoperative complications, the two groups had comparable hospital mortality and similar satisfactory rates of graft survival and patient overall survival. Therefore, a high MELD score should not be a contraindication to right-lobe LDLT if donor risk and recipient benefit are taken into full account.

Ballistic limit velocity of small caliber projectiles against SS400 steel plates:Live fire experiments and empirical models

This study presents the ballistic limit velocity of small caliber projectiles against SS400 steel plate derived from live-fire ballistic experiments. Four different small caliber projectiles were tested against SS400 steel plates of 9 mm, 10 mm, and 12 mm thicknesses. The ballistic limit velocity was calculated using two standard methods, MIL-STD-662F and NIJ-STD-0101.06, and additionally using a support vector machine algorithm. The results show a linear relationship between the plate thickness and ballistic limit velocity. Further, the relative penetration performance among five different small caliber projectiles was analyzed using the Penetration Performance Ratio(PPR) introduced in this study, which suggests the potential of PPR to predict the ballistic limit velocity of other untested materials and/or different projectiles.

Factors Influencing Mode of Delivery: A Case-Control Study

The primary objective of this investigation was to scrutinize the prepregnancy conditions and lifestyles of 2046 women residing in Liuzhou City, with the aim of delineating the determinants of delivery methods. Evidently, the study unearthed substantial correlations between prepregnancy body mass index, educational attainment, exposure to passive smoking, medical history, and other variables with the mode of delivery. Furthermore, a predictive nomogram model was formulated to accurately forecast the likelihood of cesarean section. These discernments equip pertinent authorities with the means to institute targeted screening and supportive measures for women contemplating pregnancy based on these identified factors. Moreover, provision of services such as prepregnancy counseling and clinical risk assessments could be instrumental in curbing the incidence of cesarean section.

Living donor liver transplantation for high model for endstage liver disease score:What have we learned?

AIM: To assess the impact of model for end-stage liver disease(MELD) score on patient survival and morbidity post living donor liver transplantation(LDLT). METHODS: A retrospective study was performed on 80 adult patients who had LDLT from 2011-2013. Nine patients were excluded and 71 patients were divided into two groups; Group 1 included 38 patients with a MELD score < 20, and Group 2 included 33 patients with a MELD score > 20. Comparison between both groups was done regarding operative time, intra-operative blood requirement, intensive care unit(ICU) and hospital stay, infection, and patient survival.RESULTS: Eleven patients died(15.5%); 3/38(7.9%)patients in Group 1 and 8/33(24.2%) in Group 2 with significant difference(P = 0.02). Mean operative time, duration of hospital stay, and ICU stay were similar in both groups. Mean volume of blood transfusion and cell saver re-transfusion were 8 ± 4 units and 1668 ± 202 m L, respectively, in Group 1 in comparison to 10 ± 6 units and 1910 ± 679 m L, respectively, in Group 2 with no significant difference(P = 0.09 and 0.167, respectively). The rates of infection and systemic complications(renal, respiratory, cardiovascular and neurological complications) were similar in both groups. CONCLUSION: A MELD score > 20 may predict mortality after LDLT.

Impact of Delivery Mode on Morbidity in Preterm Infants with Very Low Birth Weights (<1500 Grams)

The mode of delivery and gestational age for very-low-birth-weight (VLBW) preterm infants are not yet well established and are constant topics of debate. Objective: To analyze the impact of delivery mode on morbidity in preterm infants weighing less than 1500 g. Results: Among 21,957 births, 81 were analyzed;53 were delivered vaginally, and 28 were delivered by cesarean section. The median maternal age, gestational age and body mass index among those delivered vaginally and by cesarean section were 20 years and 22.5 years, 27.6 weeks and 30.1 weeks, and 26.0 kg/m2 and 27.8 kg/m2, respectively. With respect to neonatal blood gas parameters, for those born vaginally and by cesarean section, the median pH was 7.32 and 7.24, the pCO2 was 41.5 mmHg and 51.1 mmHg, and the pO2 was 22.3 mmHg and 16 mmHg. The median fetal weight among those born by cesarean section and vaginally were 1180 g and 955 g, respectively. The median Apgar scores at the first and fifth minutes among those born by cesarean section and vaginally were 5.00 and 8.00 and 4.50 and 7.00, respectively. Conclusion: There was no significant difference between the results of vaginal and cesarean delivery for VLBW infants. Thus, further studies on this subject are needed.

Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus

BACKGROUND The prevalence of metabolic-associated fatty liver disease(MAFLD)is a growing public health issue in people living with human immunodeficiency virus(PLWH).However,the pathophysiology of MAFLD is still unknown,and the role of genetic variables is only now becoming evident.AIM To evaluate the associations of gene-polymorphism-related MAFLD in PLWH.METHODS The study employed transient elastography with a controlled attenuation parameter≥248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central Thailand.Candidate single-nucleotide polymorphisms(SNPs)were genotyped using TaqMan®MGB probe 5'nuclease assays for seven MAFLD-related genes.Statistical analyses included SNP frequency analysis,Fisher's Exact and Chi-square tests,odds ratio calculations,and multivariable logistic regression.RESULTS The G-allele carriers of PNPLA3(rs738409)exhibited a two-fold rise in MAFLD,increasing by 2.5 times in MAFLD with human immunodeficiency virus infection.The clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times(P=0.001)more significant chance of developing aberrant triglyceride among PLWH.CONCLUSION The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.

In vivo imaging and computational modeling of nonlinear shear waves in living skeletal muscles

How the state of living muscles modulates the features of nonlinear elastic waves generated by external dynamic loads remains unclear because of the challenge of directly observing and modeling nonlinear elastic waves in skeletal muscles in vivo,considering their active deformation behavior.Here,this important issue is addressed by combining experiments performed with an ultrafast ultrasound imaging system to track nonlinear shear waves(shear shock waves)in muscles in vivo and finite element analysis relying on a physically motivated constitutive model to study the effect of muscle activation level.Skeletal muscle was loaded with a deep muscle stimulator to generate shear shock waves(SSWs).The particle velocities,second and third harmonics,and group velocities of the SSWs in living muscles under both passive and active states were measured in vivo.Our experimental results reveal,for the first time,that muscle states have a pronounced effect on wave features;a low level of activation may facilitate the occurrence of both the second and third harmonics,whereas a high level of activation may inhibit the third harmonic.Finite element analysis was further carried out to quantitatively explore the effect of active muscle deformation behavior on the generation and propagation of SSWs.The simulation results at different muscle activation levels confirmed the experimental findings.The ability to reveal the effects of muscle state on the features of SSWs may be helpful in elucidating the unique dynamic deformation mechanism of living skeletal muscles,quantitatively characterizing diverse shock wave-based therapy instruments,and guiding the design of muscle-mimicking soft materials.

A Study on the Factors Influencing Consumer Purchase Decision Under the Live-Streaming Sales Model

In recent years,with the rapid development and popularization of Internet information technology,many new media platforms have risen rapidly,and major e-commerce companies have begun to explore the mode of livestreaming.Especially during the COVID-19 pandemic,due to the lockdown,live-streaming has become an important means of economic development in many places.Owing to its remarkable characteristics of timeliness,entertainment,and interactivity,it has become the latest and trendiest sales mode of e-commerce channels,reflecting huge economic potential and commercial value.This article analyzes two models and their characteristics of live-streaming sales from a practical perspective.Based on this,it outlines consumer purchasing decisions and the factors that affect consumer purchasing decisions under the live-streaming sales model.Finally,it discusses targeted suggestions for using the live-streaming sales model to expand the consumer market,hoping to promote the healthy and steady development of the live-streaming sales industry.

Interannual variability of boreal summer intraseasonal oscillation over the northwestern Pacific influenced by the Pacific Meridional Mode

During the boreal summer,intraseasonal oscillations exhibit significant interannual variations in intensity over two key regions:the central-western equatorial Pacific(5°S-5°N,150°E-150°W)and the subtropical Northwestern Pacific(10°-20°N,130°E-175°W).The former is well-documented and considered to be influenced by the ENSO,while the latter has received comparatively less attention and is likely influenced by the Pacific Meridional Mode(PMM),as suggested by partial correlation analysis results.To elucidate the physical processes responsible for the enhanced(weakened)intraseasonal convection over the subtropical northwestern Pacific during warm(cold)PMM years,the authors employed a moisture budget analysis.The findings reveal that during warm PMM years,there is an increase in summer-mean moisture over the subtropical northwestern Pacific.This increase interacts with intensified vertical motion perturbations in the region,leading to greater vertical moisture advection in the lower troposphere and consequently resulting in convective instability.Such a process is pivotal in amplifying intraseasonal convection anomalies.The observational findings were further verified by model experiments forced by PMM-like sea surface temperature patterns.

Study on the Design of Modern Living Environment in China

Three development stages of living environment design in China were summarized,characteristics in different stages introduced,and suggestions given in view of specific problems.It was proposed that design of modern living environment should be harmonious with the whole environment,innovative spirits and creative designs should be highlighted in the living environment,and regional characteristics,historic and cultural succession should be valued.

越南非洲猪瘟疫苗AVAC ASF LIVE(ASFV-G-ΔMGF)研究工作分析与思考

非洲猪瘟(Afcrian swine fever,ASF)是由非洲猪瘟病毒(African swine fever virus,ASFV)感染引起的烈性传染病。近日,越南正式将经临床试验验证的非洲猪瘟弱毒疫苗AVAC ASF LIVE(ASFV-G-ΔMGF)在其全国推广使用。本文对越南非洲猪瘟弱毒疫苗ASFV-G-ΔMGF相关研究数据进行了总结分析,分别从ASFVG-ΔMGF株攻毒保护能力评价、传代细胞培养株临床动物实验、野猪口服接种试验、毒力返强验证等方面,结合国内相关ASFV基因缺失株试验数据进行了分析。总结分析发现:越南上市的ASFV-G-ΔMGF疫苗株,二次免疫接种后攻毒保护效果更好,但在对野猪的口服接种评价中,其口鼻接种效果存在不确定性;随着疫苗株在动物体内的不断传代,其存在毒力返强和毒株变异风险,导致接种猪只临床症状明显;ASFV-G-ΔMGF株虽然有较好的攻毒保护能力和可靠的生产优势,但仍缺乏相关研究数据,特别是在垂直传播、交叉保护、基因突变等方面。后续仍需对ASFV-G-ΔMGF株的临床应用效果进一步评价。

Vascular complications after adult living donor liver transplantation:Evaluation with ultrasonography

Living donor liver transplantation(LDLT) has beenwidely used to treat end-stage liver disease with improvement in surgical technology and the application of new immunosuppressants. Vascular complications after liver transplantation remain a major threat to the survival of recipients. LDLT recipients are more likely to develop vascular complications because of their complex vascular reconstruction and the slender vessels. Early diagnosis and treatment are critical for the survival of graft and recipients. As a non-invasive, cost-effective and non-radioactive method with bedside availability, conventional gray-scale and Doppler ultrasonography play important roles in identifying vascular complications in the early postoperative period and during the follow-up. Recently, with the detailed vascular tracing and perfusion visualization, contrastenhanced ultrasound(CEUS) has significantly improved the diagnosis of postoperative vascular complications. This review focuses on the role of conventional grayscale ultrasound, Doppler ultrasound and CEUS for early diagnosis of vascular complications after adult LDLT.

Living-donor vs deceased-donor liver transplantation for patients with hepatocellular carcinoma

With the increasing prevalence of living-donor liver transplantation(LDLT) for patients with hepatocellular carcinoma(HCC),some authors have reported a potential increase in the HCC recurrence rates among LDLT recipients compared to deceased-donor liver transplantation(DDLT) recipients.The aim of this review is to encompass current opinions and clinical reports regarding differences in the outcome,especially the recurrence of HCC,between LDLT and DDLT.While some studies report impaired recurrence- free survival and increased recurrence rates among LDLT recipients,others,including large database studies,report comparable recurrence- free survival and recurrence rates between LDLT and DDLT.Studies supporting the increased recurrence in LDLT have linked graft regeneration to tumor progression,but we found no association between graft regeneration/initial graft volume and tumor recurrence among our 125 consecutive LDLTs for HCC cases.In the absence of a prospective study regarding the use of LDLT vs DDLT for HCC patients,there is no evidence to support the higher HCC recurrence after LDLT than DDLT,and LDLT remains a reasonable treatment option for HCC patients with cirrhosis.

Current diagnosis and treatment of benign biliary stricturesafter living donor liver transplantation

Despite advances in surgical techniques, benign biliary strictures after living donor liver transplantation(LDLT) remain a significant biliary complication and play an important role in graft and patient survival. Benign biliary strictures after transplantation are classified into anastomotic or non-anastomotic strictures. These two types differ in presentation, outcome, and response to therapy. The leading causes of biliary strictures include impaired blood supply, technical errors during surgery, and biliary anomalies. Because patients usually have non-specific symptoms, a high index of suspicion should be maintained. Magnetic resonance cholangiography has gained widespread acceptance as a reliable noninvasive tool for detecting biliary complications. Endoscopy has played an increasingly prominent role in the diagnosis and treatment of biliary strictures after LDLT. Endoscopic management in LDLT recipients may be more challenging than in deceased donor liver transplantation patients because of the complex nature of the duct-to-duct reconstruction. Repeated aggressive endoscopic treatment with dilation and the placement of multiple plastic stents is considered the first-line treatment for biliary strictures. Percutaneous and surgical treatments are now reserved for patients for whom endoscopic management fails and for those with multiple, inaccessible intrahepatic strictures or Roux-en-Y anastomoses. Recent advances in enteroscopy enable treatment, even in these latter cases. Direct cholangioscopy, another advanced form of endoscopy, allows direct visualization of the inner wall of the biliary tree and is expected to facilitate stenting or stone extraction. Rendezvous techniques can be a good option when the endoscopic approach to the biliary stricture is unfeasible. These developments have resulted in almost all patients being managed by the endoscopic approach.

基于LIVE2D技术的博物馆动态形象设计实践研究

探索以Live2D技术作为新的设计手段,进一步提升二维平面形象设计的表现力和影响力,寻找塑造新颖的博物馆动态形象的可行性,为博物馆提供适应现代多种媒体渠道传播形式的动态形象设计。以Live2D技术为核心,从文化传承与发展的角度出发,结合博物馆实地调研与文物设计转化,拓宽博物馆形象设计在其馆内的应用范围,将传统平面原画通过2D建模,进而增强二维形象的可动性和真实感,结合符号学语义,实现以山东博物馆“亚丑钺”为例的动态形象设计实践。围绕博物馆藏品为原型,从平面设计图实现二维建模,实现文物藏品转化为角色形象,设计出基于Live2D技术的动态博物馆形象,为观展流程增添吸引力和沉浸感。促进博物馆以文物为原型的形象良性发展,丰富与观众的交互形式,帮助藏品达成创造性转化、创新性发展,从而为山东博物馆以及其他文化机构提供关于形象设计多元化创新的可借鉴新形式。

Biliary strictures complicating living donor liver transplantation:Problems,novel insights and solutions

Biliary stricture complicating living donor liver transplantation(LDLT) is a relatively common complication, occurring in most transplant centres across the world. Cases of biliary strictures are more common in LDLT than in deceased donor liver transplantation. Endoscopic management is the mainstay for biliary strictures complicating LDLT and includes endoscopic retrograde cholangiography, sphincterotomy and stent placement(with or without balloon dilatation). The efficacy and safety profiles as well as outcomes of endoscopic management of biliary strictures complicating LDLT is an area that needs to be viewed in isolation, owing to its unique set of problems and attending complications; as such, it merits a tailored approach, which is yet to be well established. The diagnostic criteria applied to these strictures are not uniform and are over-reliant on imaging studies showing an anastomotic narrowing. It has to be kept in mind that in the setting of LDLT, a subjective anastomotic narrowing is present in most cases due to a mismatch in ductal diameters. However, whether this narrowing results in a functionally significant narrowing is a question that needs further study. In addition, wide variation in the endotherapy protocols practised in most centres makes it difficult to interpret the results and hampers our understanding of this topic. The outcome definition for endotherapy is also heterogenous and needs to be standardised to allow for comparison of data in this regard and establish a clinical practice guideline. There have been multiple studies in this area in the last 2 years, with novel findings that have provided solutions to some of these issues. This review endeavours to incorporate these new findings into the wider understanding of endotherapy for biliary strictures complicating LDLT, with specific emphasis on diagnosis of strictures in the LDLT setting, endotherapy protocols and outcome definitions. An attempt is made to present the best management options currently available as well as directions for future research in the area.

Doppler ultrasonography in living donor liver transplantation recipients: Intra- and post-operative vascular complications

Living-donor liver transplantation has provided a solution to the severe lack of cadaver grafts for the replacement of liver afflicted with end-stage cirrhosis, fulminant disease, or inborn errors of metabolism. Vascular complications remain the most serious complications and a common cause for graft failure after hepatic transplantation. Doppler ultrasound remains the primary radiological imaging modality for the diagnosis of such complications. This article presents a brief review of intra- and post-operative living donor liver transplantation anatomy and a synopsis of the role of ultrasonography and color Doppler in evaluating the graft vascular haemodynamics both during surgery and post-operatively in accurately defining the early vascular complications. Intra-operative ultrasonography of the liver graft provides the surgeon with useful real-time diagnostic and staging information that may result in an alteration in the planned surgical approach and corrections of surgical complications during the procedure of vascular anastomoses. The relevant intraoperative anatomy and the spectrum of normal and abnormal findings are described. Ultrasonography and color Doppler also provides the clinicians and surgeons early post-operative potential developmental complications that may occur during hospital stay. Early detection and thus early problem solving can make the difference between graft survival and failure.

Microsurgical reconstruction of hepatic artery in living donor liver transplantation:experiences and lessons

BACKGROUND: Hepatic artery (HA) reconstruction is one of the key steps for living donor liver transplantation (LDLT). The incidence of HA thrombosis has been reduced by the introduction of nucrosurgical techniques under a high resolution microscope or loupe. METHODS: We report our experience in 101 cases of HA reconstruction in LDLTs using the graft-artery-undamp and posterior-wall-first technique. The reconstructions were completed by either a plastic surgeon or a transplant surgeon. RESULTS: The rate of HA thrombosis was 2% (2/101). The risk factors for failed procedures appeared to be reduced by participation of the transplant surgeon compared with the plastic surgeon. For a graft with duplicate arteries, we considered no branches should be discarded even with a positive clamping test. CONCLUSIONS: HA reconstruction without clamping the graft artery is a feasible and simplified technique, which can be mastered by transplant surgeons with considerable microsurgical training.