Single-cell transcriptome profiling of sepsis identifies HLA-DR^(low)S100A^(high)monocytes with immunosuppressive function

Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.

Combination of ablative fractional carbon dioxide laser and platelet-rich plasma treatment to improve hypertrophic scars:a retrospective clinical observational study

Background:Hypertrophic scars are one of the main complications that affect the quality of life of patients after burns.Many methods have been shown to be effective in the treatment of hypertrophic scars,such as ablative fractional CO_(2) laser(AFCL)and platelet-rich plasma(PRP).However,there are few studies on the effect of the combined application of these measures.The purpose of this study was to explore the therapeutic effect of AFCL combined with PRP on hypertrophic burn scars.Methods:A retrospective clinical observation study was conducted on 50 patients with hypertrophic burn scars.The AFCL+PRP group included 31 patients who received AFCL combined with PRP treatment;the AFCL group included 19 patients who received AFCL treatment only.The University of North Carolina 4P Scar Scale(UNC4P)and the Vancouver Scar Scale(VSS)scores that were collected before each treatment were used as indicators of the effectiveness of the previous treatment.The scores recorded at the second,fourth and seventh months were analysed.Results:The demographic data of the 2 groups were not significantly different.Before treatment,therewas no difference in the UNC4P and VSS scores between the 2 groups.Therewas a significant decline in the UNC4P and VSS total scores over 6 months in both groups(p<0.05)and scores in the 2 groups were comparable after 3 and 6 months(p<0.05).UNC4P scores in the AFCL+PRP group decreased from a mean of 8.26 to 2.61(p<0.05)with a concomitant drop in VSS scores from a mean of 11.74 to 6.06(p<0.01).In the AFCL group UNC4P and VSS scores decreased from 7.68 to 4.63(p<0.05)and from 10.89 to 8.16(p<0.05),respectively.The sub-items of these 2 assessments were analysed and the results suggest that AFCL combined with PRP can comprehensively improve scarring.Conclusions:This study shows that PRP is an effective adjunct for AFCL in the treatment of hypertrophic burn scars and that the combination of PRP and AFCL proved to be more useful than AFCL alone.This combination may be a new and effective clinical practice for the treatment of scars.However,larger and higher-level clinical studies are still needed to determine its efficacy and possible mechanisms.

Efficacy and safety of external tissue expansion technique in the treatment of soft tissue defects:a systematic review and meta-analysis of outcomes and complication rates

Background:Currently,various external tissue expansion devices are becoming widely used.Considering the scarcity of relevant application standards,this systematic review was performed to explore the effectiveness and safety of external tissue expansion techniques for the reconstruction of soft tissue defects.Method:A systematic review and meta-analysis on the efficacy and safety of external tissue expansion technique was conducted.A comprehensive search was performed in the following electronic databases:PubMed/Medline,Embase,Cochrane Library(Wiley Online Library),andWeb of Science.Studies reporting patients with soft tissue defects under the treatment of external tissue expansion technique were included.Results:A total of 66 studies with 22 different types of external tissue expansion devices met the inclusion criteria.We performed a descriptive analysis of different kinds of devices.A single-arm meta-analysis was performed to evaluate the efficacy and safety of the external tissue expansion technique for different aetiologies.The pooled mean wound healing time among patients with defects after fasciotomy was 10.548 days[95%confidence interval(CI)=5.796-15.299].The pooled median wound healing times of patients with defects after excisional surgery,trauma,chronic ulcers and abdominal defects were 11.218 days(95%CI=6.183-16.253),11.561 days(95%CI=7.062-16.060),15.956 days(95%CI=11.916-19.996)and 12.853 days(95%CI=9.444-16.227),respectively.The pooled wound healing rates of patients with defects after fasciotomy,excisional surgery,trauma,chronic ulcers and abdominal defects were 93.8%(95%CI=87.1-98.2%),97.2%(95%CI=92.2-99.7%),97.0%(95%CI=91.2-99.8%),99.5%(95%CI=97.6-100%),and 96.8%(95%CI=79.2-100%),respectively.We performed a subgroup analysis in patients with diabetic ulcers and open abdominal wounds.The pooled median wound healing time of patients with diabetic ulcers was 11.730 days(95%CI=10.334-13.125).The pooled median wound healing time of patients with open abdomen defects was 48.810 days(95%CI=35.557-62.063)and the pooled successful healing rate was 68.8%(95%CI=45.9-88.1%).A total of 1686 patients were included,265(15.7%)of whom experienced complications.The most common complication was dehiscence(n=53,3.14%).Conclusions:Our systematic review is the first to demonstrate the efficacy and safety of external tissue expansion in the management of soft tissue defects.However,we must interpret the meta-analysis results with caution considering the limitations of this review.Large-scale randomized controlled trials and long-term follow-up studies are still needed to confirm the effectiveness and evaluate the quality of healing.

Combination therapy of thiamine,vitamin C and hydrocortisone in treating patients with sepsis and septic shock:a meta-analysis and trial sequential analysis

Background:The objective of this study was to evaluate the clinical efficacy of thiamine and vitamin C with or without hydrocortisone coadministration on the treatment of sepsis and septic shock.Methods:MEDLINE,EMBASE and CENTRAL databases were searched for randomized controlled trials(RCTs)that made a comparative study between the combination therapy of vitamin C and thiamine with or without hydrocortisone and the administration of placebo in patients with sepsis or septic shock.Two reviewers independently performed study selection,data extraction and quality assessment.Both short-term mortality and change in the sequential organ failure assessment(SOFA)score from baseline(delta SOFA)were set as the primary outcomes.Secondary endpoints included intensive care unit(ICU)mortality,new onset of acute kidney injury,total adverse events,ICU and hospital length of stay,duration of vasopressor usage and ventilator-free days.Meanwhile,trial sequential analysis was conducted for primary outcomes.Results:Eight RCTs with 1428 patients were included in the current study.The results showed no significant reduction of short-term mortality in sepsis and septic shock patients who received combination therapy of vitamin C and thiamine with or without hydrocortisone compared to those with placebo{risk ratio(RR),1.02[95%confidence interval(CI),0.87 to 1.20],p=0.81,I2=0%;risk difference(RD),0[95%CI,−0.04 to 0.05]}.Nevertheless,the combination therapy was associated with significant reduction in SOFA score[mean difference(MD),−0.63,(95%CI,−0.96 to−0.29,p<0.001,I^(2)=0%]and vasopressors duration(MD,−22.11[95%CI,−30.46 to−13.77],p<0.001,I2=6%).Additionally,there were no statistical differences in the pooled estimate for other outcomes.Conclusions:In the current meta-analysis,the combination therapy of vitamin C and thiamine,with or without hydrocortisone had no impact on short-term mortality when compared with placebo,but was associated with significant reduction in SOFA score among patients with sepsis and septic shock.

Exosomes derived from human amniotic epithelial cells accelerate diabetic wound healing via PI3K-AKT-mTOR-mediated promotion in angiogenesis and fibroblast function

Background:Diabetic wounds are one of the most common and serious complications of diabetes mellitus,characterized by the dysfunction of wound-healing-related cells in quantity and quality.Our previous studies revealed that human amniotic epithelial cells(hAECs)could promote diabetic wound healing by paracrine action.Interestingly,numerous studies demonstrated that exosomes derived from stem cells are the critical paracrine vehicles for stem cell therapy.However,whether exosomes derived from hAECs(hAECs-Exos)mediate the effects of hAECs on diabetic wound healing remains unclear.This study aimed to investigate the biological effects of hAECs-Exos on diabetic wound healing and preliminarily elucidate the underlying mechanism.Methods:hAECs-Exos were isolated by ultracentrifugation and identified by transmission electron microscopy,dynamic light scattering and flow cytometry.A series of in vitro functional analyses were performed to assess the regulatory effects of hAECs-Exos on human fibroblasts(HFBs)and human umbilical vein endothelial cells(HUVECs)in a high-glycemic microenvironment.Highthroughput sequencing and bioinformatics analyses were conducted to speculate the related mechanisms of actions of hAECs-Exos on HFBs and HUVECs.Subsequently,the role of the candidate signaling pathway of hAECs-Exos in regulating the function of HUVECs and HFBs,as well as in diabetic wound healing,was assessed.Results:hAECs-Exos presented a cup-or sphere-shaped morphology with a mean diameter of 105.89±10.36 nm,were positive for CD63 and TSG101 and could be internalized by HFBs and HUVECs.After that,hAECs-Exos not only significantly promoted the proliferation and migration of HFBs,but also facilitated the angiogenic activity of HUVECs in vitro.High-throughput sequencing revealed enriched miRNAs of hAECs-Exos involved in wound healing.Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses have shown that the target genes of the top 15 miRNAs were highly enriched in the PI3K-AKT pathway.Further functional studies demonstrated that the PI3K-AKT-mTOR pathway was necessary for the induced biological effects of hAECs-Exos on HFBs and HUVECs,as well as on wound healing,in diabetic mice.Conclusions:Our findings demonstrated that hAECs-Exos represent a promising,novel strategy for diabetic wound healing by promoting angiogenesis and fibroblast function via activation of the PI3K-AKT-mTOR pathway.

Comorbidities of scars in China:a national study based on hospitalized cases

Background:Scar comorbidities seriously affect the physical and mental health of patients,but few studies have reported the exact epidemiological characteristics of scar comorbidities in China.This study aimed to investigate the prevalence of scar comorbidities in China.Methods:The data of 177,586 scar cases between 2013 and 2018 were obtained from the Hospital Quality Monitoring System based on the 10th edition of the International Classification of Diseases coding system.The total distribution of scar comorbidities and their relationship with age,aetiology and body regions were analysed.Results:Six comorbidities(contracture,malformation,ocular complications,adhesion,infection and others)were the main focus.In general,male patients outnumbered females and urban areas outnumbered rural areas.The proportion of contractures was the highest at 59,028(33.24%).Students,workers and farmers made up the majority of the occupation.Han Chinese accounted for the majority of the ethnic.The highest proportion of scar contracture occurred at 1–1.9 years of age(58.97%),after which a significant downward trend was observed.However,starting from 50 years of age,ocular complications increased gradually and significantly,eventually reaching a peak of 34.49%in those aged>80 years.Scar contracture was the most common comorbidity according to aetiology,and the highest proportion was observed in patients who were scalded(29.33%).Contractures were also the most frequent comorbidity in hands(10.30%),lower limbs(6.97%),feet(6.80%)and upper limbs(6.02%).The mean and median hospitalization durations were 12.85 and 8 days,respectively.Conclusions:Contractures were the most common comorbidities,and different comorbidities tended to occur at different ages and with different causative factors.