Background and objectives: Chronic musculoskeletal (MS) pain is common in chronic kidney disease (CKD) patients. The association of chronic MS pain and CKD progression has not yet been established.Method: We conducted a prospective cohort study to evaluate the association of chronic MS pain and CKD progression of pre-dialysis CKD patients.Result: A total of 53.2% of pre-dialysis CKD patients had chronic MS pain. Patients classified as progression and non-progression had a similar prevalence of chronic MS pain at baseline, and similar baseline use of NSAIDs and Chinese herbal medicines. Univariate Cox analysis indicated that chronic MS pain and baseline NSAID or Chinese herbal medicine use were not significantly associated with progression of CKD. But multivariate Cox regression found chronic MS pain was independently significantly associated with all-cause mortality . However, serum levels of hs-CRP were similar between those chronic MS pain patients and without chronic MS pain patients .Conclusion: The CKD patients with chronic MS pain was independently and significantly associated with all-cause mortality, but not independently and significantly associated with CKD progression and composite endpoints. The inflammatory marker-hs-CRP was similar between CKD patients with and without chronic MS pain. The incidence of chronic kidney disease (CKD) is still increasing worldwide despite integrative care and timely referral . CKD patPatients with CKD often suffer from chronic pain ,4. For ePain was considered as an important symptom in CKD patients ,9. In ad2 [determined by the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation] in 2 separate measurements within an interval of 3 months [Pre-dialysis CKD patients who visited an outpatient clinic at the Nephrology Department of Chang Gung Memorial Hospital at Keelung from March 2006 to July 2007 were recruited for the study. Patients satisfying the following criteria were included in this study consecutively: age >18–<80 years and with stable CKD in the 3 months before the start of the study. CKD was defined as the presence of persistent proteinuria or a decreased estimated glomerular filtration rate (eGFR) of <90 mL/min per 1.73 m3 months . A totalThe study evaluated the association between chronic MS pain and renal prognosis in CKD patients. All eligible patients were carefully interviewed to identify primary disease and current medications. Chronic MS pain was evaluated by using the Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) questionnaire . All eliFor patients with MS pain, pain was assessed using a visual analog scale (VAS), on a range of 0 mm (no pain) to 100 mm (very painful), after which the patients were examined by a rheumatologist to confirm the information and characterize MS pain symptoms. For the calculation of prevalence and for all other analyses, chronic MS pain was defined as non-traumatic MS pain for over 3 months with a VAS score of >1 .Basic demographic data were collected, including information on age, gender, nutrition status – body mass index (BMI), history of smoking, current use of NSAIDs or Chinese herbal medicines, and the presence of diabetes, hypertension, coronary artery disease (CAD), and hyperuricemia. Baseline hematological and biochemical data of these patients were also collected. Current use of NSAIDs was defined by self-reported use of ibuprofen, naproxen, sulindac, piroxicam, indomethacin, tolmetin, or diclofenac, COX (cyclooxygenase)-2 inhibitor (with brand names and combination formulas identified) daily or nearly every day for the last 30 days. Current use of Chinese herb was defined by self-reported use of any Chinese herb daily or nearly every day for the last 30 days. Full laboratory profiles were obtained. The laboratory parameters included levels of blood urea nitrogen, serum creatinine (Scr), hemoglobin, albumin, high-sensitivity C-reactive protein (hs-CRP), calcium (Ca) and phosphate (P). Serum creatinine levels were assessed by spectrophotometric analysis using a modified kinetic Jaffe reaction.t-test or the Mann–Whitney U-test was used to compare the means of continuous variables and the Chi-square test was used to compare categorical data. Kaplan–Meier curves were used to assess renal survival in patients. Adjusted risk estimates for progression to the endpoint were calculated using univariate regression, followed by multivariate Cox proportional hazard regression. Co-variants selection based on univariate analysis with variables with p < .05 was selected. All statistical tests were two-tailed, and a p value less than .05 was considered statistically significant. Data were analyzed using the SPSS 23.0 for Windows .Descriptive statistics are expressed as means ± standard deviations or as medians and ranges or percentages, as appropriate. Student’s 2. A total of 243 patients (53.3%) had chronic MS pain. At baseline, 36 patients (7.8%) reported the use of an NSAID and 44 patients (9.6%) reported the use of a Chinese herbal medicine. Those patients with male, higher BMI, co-morbidity of hyperuricemia, higher levels of systolic blood pressure, lower levels of proteinuria, higher serum levels of hemoglobin and product of serum calcium and phosphate levels, and less co-morbidity of diabetes-prone to associated with chronic MS pain. In our study patients, the prevalence of mild pain, moderate pain and severe pain are 15.6% (n = 38/243), 28.4% (n = 69/243) and 58% (n = 141/243), respectively. About the CKD stage and chronic MS pain severity, severe chronic MS pain was found in 54.2% (n = 64/118) of CKD patients with stage 1–2 disease, 54.9% (n = 62/113) of CKD patients with stage 3–4 disease and 83.3% (n = 10/12) of CKD patients with stage 5 disease (p < .001). About the cause of chronic MS pain, we found 71% of those chronic MS pain had co-morbidity of gout, 0.4% had co-morbidity of rheumatoid arthritis, 1.2% had co-morbidity of spine osteoarthritis, 19.8% had co-morbidity of back pain. In our study with follow-up of about 6 years, there were 13 patients drop out, 31 patients died, 36 patients initiated hemodialysis, 10 patients initiated peritoneal dialysis at the end of the study.The mean age was 63.3 ± 14.1 years and 194 patients (42.5%) were male . The meap = .857), use of NSAID , and use of a Chinese herbal medicine .A total of 82 patients (17.9%) experienced renal progression with a mean follow-up time of 44.6 ± 12.8 months. Among these 82 patients, 36 patients had eGFR less than 50% of baseline and 46 patients progressed to ESRD . Patientp < .001), hypertension , lower eGFR , low serum levels of hemoglobin , low serum levels of albumin , low serum levels of calcium , high serum levels of phosphate , high product of serum levels of calcium and phosphate , higher serum levels of uric acid , higher systolic blood pressure , higher levels of proteinuria  were significantly associated with renal progression (p = .984) (p = .446) (p < .001), low BMI , low levels of eGFR , high levels of hs-CRP , high levels of uric acid , low levels of diastolic blood pressure , higher levels of proteinuria  were significantly associated with all-cause mortality. But those CKD patients with chronic MS pain were not significantly associated with higher all-cause mortality  (p < .001), low eGFR , low serum levels of hemoglobin , low serum levels of albumin , high serum levels of hs-CRP , low serum levels of calcium , high serum levels of phosphate , high serum levels of uric acid , high levels of systolic blood pressure , low levels of diastolic blood pressure , and higher levels of proteinuria  were significantly associated with composite endpoints. Furthermore, those CKD patients with chronic MS pain were not significantly associated with composite endpoints   . The eGF = .446) . About a = .903) . In addi = .774) . In addip = .233) and composite endpoints  (p = .049) after adjustment of age, gender, co-morbidity of diabetes, hypertension, baseline eGFR, serum hemoglobin, albumin, hs-CRP, calcium, phosphate, Ca × P, and proteinuria. Besides, co-morbidity of diabetes mellitus  and proteinuria  were also significantly independently associated with renal progression. And proteinuria was independently significantly associated with composite endpoints . However, baseline NSAID or Chinese herbal medicine use was also not independently significantly associated with primary and composite endpoints. The study also showed increased uric acid level is significantly associated with renal progression, all-cause mortality, and composite endpoints . But the association between uric acid level and renal progression, all-cause mortality and composite endpoints  loss significance after adjustment in the multivariate cox-regression analysis.The analysis of multivariate Cox regression was also performed to evaluate the exact association between chronic MS pain and other factors, and primary and composite endpoints. The results indicated that the presence of chronic MS pain was not independently significantly associated with renal progression  . But theNumerous factors underlie the progression of CKD. The present study enrolled pre-dialysis CKD patients and evaluated the effect of chronic MS pain on CKD progression. The present study was a prospective follow-up study of patients and considered numerous measurable risk factors for CKD progression, including the presence of chronic MS pain, use of an NSAID, and use of a Chinese herbal medicine. The main results found that those patients with and without chronic MS pain had similar risk for CKD progression. But patients with chronic MS pain had independently significantly higher all-cause mortality than those patients without chronic MS pain. However, the inflammatory marker-hs-CRP was similar between CKD patients with and without chronic MS pain.Our predialysis CKD patients had a high prevalence of chronic MS pain (53.3%) and our results indicate that male patients, high BMI, and co-morbidity of hyperuricemia, and a Ca × P imbalance were significantly associated with this symptom. However, we were surprised to find that patients with and without chronic MS pain used NSAIDs and Chinese herbal medicines at similar levels, had similar levels of inflammatory markers (hs-CRP), and had similar levels of serum albumin. Our long-term follow-up of about 6 years indicated that patients with chronic MS pain had similar risk of CKD progression as those without chronic MS pain. Pain and inflammation are nearly always associated with each other. Hyper-inflammation was associated with CKD progression ,18. The p values=.074). One study showed that chronic MS pain was prevalence in advanced CKD patients  [p values=.377). So, the result suggested that CKD stages and also advanced CKD were not associated with chronic MS pain. Caravaca et al. enrolled advanced CKD patients and found chronic MS pain was associated with higher inflammation and poor prognosis, but the association was not significant after adjustment of the demographic factor. In our study patients, we found chronic MS pain was significantly associated with all-cause mortality after adjustment. But we cannot find the association between chronic MS pain and inflammation. It may be due to chronic MS pain in some patients may not link to inflammation. Chronic MS pain caused by inflammation is more likely to be associated with advanced CKD patients. Due to the recruited patients, CKD with different stages and the number of our advanced CKD patients was not enough, we cannot find this association in our study patients.In this study, we found that CKD stages were not significantly different between chronic MS pain and no chronic MS pain  . BecauseThe focus of this study was to examine CKD patients with chronic MS pain and CKD progression. We found that those with chronic MS pain and baseline use of a NSAID or Chinese herbal medicine had similar risk of CKD progression as those without chronic MS pain and use of a NSAID or Chinese herbal medicine. Besides, the inflammatory marker-hs-CRP serum levels were similar between those CKD patients with and without chronic MS pain. Our study has some limitation. The use of NSAID and Chinese herb agents was based on a self-reported questionnaire and the prevalence of NSAID and Chinese herb use was not recorded during the follow-up period. Besides, we did not collect acute kidney injury outcome data. Also, we did not collect the information on opioid use. Opioid is related to proteinuria. Those patients with chronic MS pain may use opioid instead of NSAID or CHM for pain relief. Due to lacking information about opioid use, the study cannot conclude NSAIDs or Chinese herb agents do not associate with CKD progression. In addition, a sample size of NSAIDs or CHM user is too low to detect this association. However, our results found the presence of chronic MS pain was independently significantly associated with increased all-cause mortality.In summary, our study demonstrated that CKD patients with chronic MS pain were independently and significantly associated with all-cause mortality, but not independently and significantly associated with CKD progression and composite endpoints. The inflammatory marker-hs-CRP was similar between CKD patients with and without chronic MS pain.


The aim of this study is to find the better treatment for gastric cancer by comparing robotic gastrectomy, laparoscopic gastrectomy, and open gastrectomy using Bayesian network meta-analysis.We will search PubMed, Embase, and the Cochrane Library for eligible studies published before 1 September 2018. There will be no language restrictions. Randomized clinical trials that compare robotic gastrectomy, laparoscopic gastrectomy, or open gastrectomy for patients with gastric cancer will be included. The risk of bias of included studies will be assessed by the Cochrane Collaboration's tool for assessing risk of bias in randomized trial. The outcomes of the study include operation time, estimated blood loss, time of ambulation, times to first flatus, time of oral intake, hospitalization, and the occurrence of complication. If sufficient data is collected and adequate clinical homogeneity is established among studies, we will conduct pairwise meta-analyses and Bayesian network meta-analyses for all related outcome measures.The study does not involve human subjects and does not need ethical approval and patient consent. The results of the network meta-analysis will be disseminated in a peer-reviewed journal for publication. To overcome the disadvantages of laparoscopy, robotic surgical systems which significantly improve visibility, and manipulation have been introduced.,11 Numerous studies have assessed the efficacy and safety of robotic gastrectomy.,12–16Laparoscopy, however, has some limitations including the restricted device manipulation area, amplification of hand tremor, and 2-dimensional imaging.Currently, the comparative effectiveness and safety of minimally invasive and open gastrectomy for gastric cancer are still unknown because of the limited number of head-to-head trials. On the other hand, pairwise meta-analyses could only combine direct evidence. Network meta-analyses which could synthesize both the direct evidence and indirect evidence simultaneously is a potential solution to the problems. Therefore, in the present study, we will evaluate the comparative efficacy and safety of robotic gastrectomy, laparoscopic gastrectomy, and open gastrectomy on gastric cancer using a Bayesian network meta-analysis to find the best treatment for gastric cancer.2 The network meta-analysis will be conducted in accordance with PRISMA for Network Meta-Analyses guidelines. The study has been registered in PROSPERO (CRD42018108687). The study does not involve human subjects and does not need ethical approval and patient consent.The protocol adheres to preferred reporting items for systematic review and meta-analysis protocol (PRISMA-P) checklist.2.12.1.1We will include studies focusing on patients with gastric cancer. Comparisons of laparoscopic gastrectomy, robotic gastrectomy, or open gastrectomy will be included. No further restrictions will be made on age, ethnic distribution, and gender.2.1.2The outcomes of the study include operation time, estimated blood loss, time of ambulation, times to first flatus, time of oral intake, hospitalization, and the occurrence of complication.2.1.3Study designs of interest will include only published RCTs comparing laparoscopic gastrectomy or robotic gastrectomy or open gastrectomy. There is no language restriction.2.2We will search the following databases: PubMed, Embase, and the Cochrane library. All databases will be systematically searched from implementation to 1 September 2018.Search strategy of PubMed was as follows:#1 ((“stomach neoplasms”[MeSH Terms] or (“stomach”[All Fields] and “neoplasms”[All Fields]) or “stomach neoplasms”[All Fields] or (“gastric”[All Fields] and “cancer”[All Fields]) or “gastric cancer”[All Fields])) or “stomach cancer”#2 (“robotics”[MeSH Terms] or “robotics”[All Fields] or “robotic”[All Fields]) and (“gastrectomy”[MeSH Terms] or “gastrectomy”[All Fields])#3 (“laparoscopy”[MeSH Terms] or “laparoscopy”[All Fields] or “laparoscopic”[All Fields]) and (“gastrectomy”[MeSH Terms] or “gastrectomy”[All Fields])#4 #2 or #3#5 RCT[Publication Type] or randomized[Title/Abstract] or placebo[Title/Abstract]#6 #1 and #4 and #52.3Two independent reviewers will complete study selection and data management. Reviewers will evaluate the study titles and abstracts to include articles that meet the inclusion criteria. Disagreements will be resolved by discussion.For studies that meet the eligibility criteria, we will extract data from articles into a standardized form. The data includes characteristics of the study , baseline characteristics of participants  and outcomes. Moreover, follow-up information and survival data will be collected.P value. If the effect size cannot be calculated, we will contact the authors to obtain additional data. If there is no response, we will send 2 email reminders to study authors.If standard deviations (SDs) or standard errors were not reported for continuous outcomes, we will first calculate effect size in Review Manager version 5.3 based on the reported data such as 95% confidence intervals (CIs) or 2.4 Assessment of the risk of bias will be based on following domains: sequence generation, allocation concealment, blinding of participants and researchers, incomplete outcome data, selective reporting, and other bias random. Disagreements will be resolved through discussion.The risk of bias in individual studies will be assessed by 2 independent researchers in accordance with Cochrane Collaboration's tool for assessing risk of bias in randomized trials.2.52.5.1P <.05 can be assumed if 95% CrIs do not include 0 at conventional levels of statistical significance. We will assess heterogeneity using chi-square test and I2 statistic. Chi-square test with the significance set P <.10 or I2 >50% indicates statistical heterogeneity.We will calculate continuous data using the weighted mean difference (WMD) with 95% credible intervals (CrIs) and dichotomous variables using odd ratio (OR) with 95% CrIs. We can interpret CrIs as CIs, and a 2-sided 2.5.2 for every head-to-head comparison involving at least 2 RCTs. Then, we will conduct a network meta-analysis with a Bayesian random-effects model. Apart from pooled WMDs or odds ratios (ORs) with 95% CrIs, relative ranking probability of different types of gastrectomy will be presented through surface under cumulative ranking curve (SUCRA) values. SUCRA values will be expressed as percentages of efficacy or safety of each intervention, and a larger the SUCRA value indicate the better the rank. For each analysis, we will assess the inconsistencies between direct and indirect evidence in the network using node splitting method. Comparison-adjusted funnel plots will be drawn to estimate publication bias in the network meta-analysis. We will draw network plots to present the geometry of the network meta-analyses.First, we will perform traditional pairwise meta-analyses with random-effects model2.5.3All analyses involved will be performed using R v3.5.0 (gemtc package and rjags package), and Stata version 14.3To date, no network meta-analysis has been carried out to provide comprehensive quantitative synthesis of robotic gastrectomy, laparoscopic gastrectomy, and open gastrectomy. In this systematic review and Bayesian network meta-analysis, we will summarize direct and indirect evidence and evaluate comparative the efficacy and safety of minimally invasive and open gastrectomy for gastric cancer. Our study will rank robotic gastrectomy, laparoscopic gastrectomy, and open gastrectomy for gastric cancer based on the relevant outcomes. The results of this study may be beneficial for patients with gastric cancer, gastrointestinal surgeons and policy-makers.Xixiong Wang conceived the concept and designed the study protocol. Zhiqiang Li and Meizhu Chen tested the feasibility of the study. Chenming Wu, Yexiang Fu wrote the manuscript. Xixiong Wang provided methodological advice, polished and revised the manuscript. All authors saw and approved the final version of the paper.Conceptualization: Xixiong Wang.Investigation: Zhiqiang Li, Meizhu Chen.Methodology: Xixiong Wang.Writing – original draft: Chenming Wu, Yexiang Fu.Writing – review & editing: Xixiong Wang.


Staphylococcus pseudintermedius is an important disease-causing bacterium in dogs and is recognized as a growing threat to human health. Due to increasing multidrug resistance, discovery of alternative methods for treatment of these infections is vital. Interference with one target for alternative treatment, the quorum sensing system agr, has demonstrated clinical improvement of infections in S. aureus animal models. In this study, we sequenced and characterized 160 clinical S. pseudintermedius isolates and their agr systems in order to increase understanding of the epidemiology of the agr group and clarify its associations with types of infection and antimicrobial resistance. We found that isolates with agr type II were significantly less common than other agr types in diseased dogs. This provides valuable information to veterinary clinical microbiologists and clinicians, especially as less research has been performed on infection associations of agr and its therapeutic potential in S. pseudintermedius than in S. aureus. Staphylococcus pseudintermedius is an important canine pathogen implicated in an increasing number of human infections. Along with rising levels of methicillin and multidrug resistance, staphylococcal biofilms are a complicating factor for treatment and contribute to device, implant, and surgical infections. Staphylococcal virulence, including biofilm formation, is regulated in part by the quorum sensing accessory gene regulator system (agr). The signal molecule for agr, known as the autoinducing peptide molecule, contains polymorphisms that result in the formation of distinct groups. In S. pseudintermedius, 4 groups  have been identified but not comprehensively examined for associations with infection type, virulence factor carriage, or phylogenetic relationships—all of which have been found to be significant in S. aureus. In this study, 160 clinical canine isolates from Texas, including isolates from healthy dogs (n = 40) and 3 different infection groups , were sequenced. The agr group, biofilm-producing capabilities, toxin gene carriage, antimicrobial resistance, and sequence type (ST) were identified for all isolates. While no significant associations were discovered among the clinical infection types and agr groups, agr II isolates were significantly less common than any other group in diseased dogs. Furthermore, agr II isolates were less likely than other agr groups to be multidrug resistant and to carry toxin genes expA and sec-canine. Fifty-two (33%) of the 160 isolates were methicillin resistant, and the main sequence types  of methicillin-resistant strains of S. pseudintermedius (MRSP) were identified for the geographic region.IMPORTANCEStaphylococcus pseudintermedius is an important disease-causing bacterium in dogs and is recognized as a growing threat to human health. Due to increasing multidrug resistance, discovery of alternative methods for treatment of these infections is vital. Interference with one target for alternative treatment, the quorum sensing system agr, has demonstrated clinical improvement of infections in S. aureus animal models. In this study, we sequenced and characterized 160 clinical S. pseudintermedius isolates and their agr systems in order to increase understanding of the epidemiology of the agr group and clarify its associations with types of infection and antimicrobial resistance. We found that isolates with agr type II were significantly less common than other agr types in diseased dogs. This provides valuable information to veterinary clinical microbiologists and clinicians, especially as less research has been performed on infection associations of agr and its therapeutic potential in S. pseudintermedius than in S. aureus. Staphylococcus pseudintermedius is a canine commensal and opportunistic pathogen responsible for a wide range of infections, including pyoderma, bacteremia, and implant device-related and postsurgical infections. While infections of humans by S. pseudintermedius are less common than infections of dogs, identification of S. pseudintermedius as a human pathogen is being increasing reported (–S. pseudintermedius (MRSP) complicate treatment of these infections. Without the use of matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), it can be difficult to differentiate between S. pseudintermedius and S. aureus. Accurate identification is key because the cefoxitin surrogate for methicillin resistance testing in S. aureus often fails to detect methicillin resistance in S. pseudintermedius , also known as slime, is among the major extracellular polymeric substances found in staphylococcal biofilms that facilitate adherence to host cells and is involved with evasion of the host’s innate immune response. Slime production can be determined by the Congo red assay; however, staphylococci can also produce protein-based biofilms that are PIA independent. Consequently, determining overall biofilm production requires the use of other methods such as crystal violet microtiter plate detection assays. Bacterial cells embedded in biofilms benefit from enhanced antimicrobial resistance (agr) system, influencing over 70 genes . After processing and export by AgrB, the AIP molecule is detected by the two-component receptor kinase AgrC/AgrA. AgrA activation leads to positive feedback of the agr system as well as an upregulation of proteases and toxins and a downregulation of surface proteins . MRSP lineages are clonal and associated with specific geographical distribution and antimicrobial resistance profiles, with genetic diversity achieved through the acquisition of mobile genetic elements (S. pseudintermedius (MSSP) isolates lack clonality and are poorly characterized despite comprising the majority of clinical isolates.The genetic lineage of an elements . Associaelements . MethiciS. pseudintermedius collected at the Texas Veterinary Medical Teaching Hospital (VMTH) at Texas A&M University between 2007 and 2016 in order to determine the associations between virulence characteristics, infection type, MLST, and agr group. Congo red assays (CRA) and crystal violet microtiter plate assays (CVA) were performed on the sequenced isolates and on an additional 550 canine clinical isolates collected during the same time period to characterize biofilm-forming capabilities.In this study, whole-genome sequencing (WGS) was performed on 160 canine clinical isolates of S. pseudintermedius isolates had 100% identity to 1 of the 4 known agrD alleles. One exception contained a silent mutation in the AIP region, and the other contained a missense mutation in the C-terminal region resulting in a lysine instead of glutamic acid. As neither of these mutations impacted the final AIP structure, they were categorized accordingly. Eleven (7%) isolates were classified in agr group I, 50 (31%) in agr group II, 44 (28%) in agr group III, and 55 (34%) in agr group IV.All but 2 of the sequenced 160 n = 710) from individual dogs (P = 0.0002) greater than that of isolates from healthy dogs .Biofilm assays were performed on clinical isolates  was 0.3317 (±0.1818). Overall biofilm production, measured by CVA, showed that a majority of isolates  produced weak or moderately weak biofilms. There was no significant difference in the distribution of overall biofilm production between slime-producing and non-slime-producing isolates. Overall levels of biofilm production differed significantly between healthy and diseased-sourced isolates (P = 0.0014), which was largely attributable to the presence of a high proportion of nonadherent isolates in the diseased category.The CVA optical density for the control (ODagr groups (agr II and III than with agr I and IV (P = 0.0415) (Biofilm results for the 160 WGS isolates are given in r groups . Slime p 0.0415) .agr group found in each disease group are summarized in agr groups differed significantly between healthy and diseased dogs (P = 0.025). Group II isolates were significantly more common in healthy dogs than in diseased dogs (P = 0.0058). No further significant associations were seen between agr groups and disease and the disease groups .The data corresponding to the number of isolates from each mecA. Methicillin resistance was identified for 45% (n = 5) of agr group I isolates, 18% (n = 9) of group II isolates, 34% (n = 15) of group III isolates, and 42% (n = 23) of group IV isolates (P = 0.0025) less likely to be MRSP. Isolates from healthy dogs were significantly (P = 0.0002) less likely to carry mecA than the diseased isolates. The mecA cassette was found in 8% of healthy isolates (n = 3), 48% of pyoderma isolates (n = 19), 30% of urinary isolates (n = 12), and 45% of surgical isolates (n = 18).The majority of WGS isolates were methicillin susceptible  as determined by the lack of isolates . The groaac(6')-aph(2''), ant-la, or aph(3′)-III], but there was no significant association between agr types and aminoglycoside resistance. There was a significant association between the agr groups and macrolide, lincosamide, and streptogramin (MLS) resistance gene carriage [erm(B) and inu(A)], with the proportion of MLS gene carriage significantly (P = 0.0171) lower in agr group II isolates. Similarly, the proportion of tetracycline resistance carriage [tet(K) and tet(M)] was significantly (P = 0.0057) lower in group II. For trimethoprim resistance, there was a significant association between agr types and resistance; the proportion of isolates carrying the dfrG resistance gene among agr group I or II isolates was significantly (P = 0.0005) lower than that seen with isolates of group III or IV. There was no association seen between agr group and beta-lactam resistance gene carriage, as most isolates (n = 139) carried blaZ. No association was seen between agr group and chloramphenicol resistance, as most isolates (n = 152) did not carry cat(pC221).Data representing the carriage of genes for resistance to selected antimicrobials are presented in aac'-aph(2''agr group and MDR as defined by resistance to 3 of the 5 classes of antibiotics other than beta-lactams. Group II isolates were significantly (P = 0.0045) less likely to be MDR. Only 16 isolates, consisting of a mix of agr types, were susceptible to all drug classes.There was a significant association between speta, siet, luk-S/F, and se-int toxin genes. Twenty isolates carried expA, and 17 carried expB, with 1 isolate carrying both genes. agr group IV isolates were significantly  more likely to carry sec-canine than groups I and II. Finally, one isolate carried the gene for the bacteriocin-like peptide BacSp222  analysis  represented in this study and in all submitted North American isolates to be CC45, CC64, CC68, CC71, CC84, CC150, and CC155. The most highly represented STs in our isolates were ST64, ST68, ST71, ST84, ST150, and ST155. Statistically significant associations were seen between ST64 and agr II , between ST68 and agr IV , between ST71 and agr III , and between ST 84 and agr I ; ST150 and ST155 had too few isolates (n = 3 each) for assessment of statistical significance, but all members were agr group IV.MLST determined 91 new allele combinations, 31 new alleles, and 113 new strain types submitted to the analysis  performeP = 0.0162). ST71 isolates were significantly more likely to be derived from surgical cases (P = 0.0111). STs also differed significantly by slime production (P = 0.0014); however, there was no evidence that individual STs were significantly associated with slime production. The distributions of overall biofilm production differed significantly (P = 0.0032) between ST71 and the other types by CVA, with a higher proportion of ST71 isolates being nonadherent.The proportion of isolates outside these main STs was significantly lower in diseased dogs than in healthy dogs (P < 0.001), and ST associated with methicillin resistance were significantly (P < 0.0001) associated with MDR; ST64, ST68, ST71, ST84, ST150, and ST155 were more likely to be MDR than other STs and significantly (P < 0.0001) more likely to carry mecA. These STs were also more likely to carry genes conferring resistance to aminoglycosides (P < 0.0001), beta-lactams (P = 0.0043), MLS (P < 0.0001), tetracycline (P = 0.0003), and trimethoprim (P < 0.0001).Overall, MRSP isolates were more likely to be MDR (expA carriage (P = 0.0142); ST155 isolates were significantly (P = 0.0017) more likely to be expA positive. No association was seen with expB carriage, but ST155 and ST150 were significantly (P = 0.0017) more likely to carry sec-canine.For toxin carriage, there was a significant association of ST with Staphylococcus clinical isolates (icaA and icaD genes for PIA (slime) production, which suggests that, similarly to observations in S. aureus, isolates may have the ica locus but may still fail to produce slime in vitro due to sensitive growth conditions  were biofilm producers, which agrees with the current literature on biofilm production in isolates , 24. Sliisolates . All butnditions –27. ThesS. pseudintermedius has been well examined. A 2016 review of 58 studies determined the following 5 major MRSP CCs worldwide: CC71, CC258, CC68, C45, and CC112  comprising all of the major STs. This suggests that MLST lacks the power to separate the groups, a problem recently observed in S. aureus , ST64 (n = 5), ST68 (n = 13), ST71 (n = 7), ST84 (n = 5), ST150 (n = 3), and ST155 (n = 3), are represented among our clinical isolates, which represents the first time that ST45 has been found to be a major ST in the United States. It should be noted that this finding is not representative of North America as a whole, as sample collection was limited to dogs in Texas.Worldwide, ST71 is the most predominant MRSP lineage, followed by ST45, ST258, ST261, ST112, ST265, ST68, ST169, and ST181 . A 2018 agrD alleles; indeed, in the previous 5-gene MLST scheme, agrD was among the genes used to determine ST  of the VMTH. The isolates were presumptively identified at initial collection as S. pseudintermedius based on the standard operating procedure of the laboratory, which included Gram stain, colony color, polymyxin B susceptibility, production of coagulase and catalase, and ability to grow on salt-mannitol agar prior to June 2016 and included identification to the level of the Staphylococcus intermedius group via matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) after June 2016. Species identification was performed for all isolates in the CML using PCR as previously described (n = 528) were residual patient diagnostic samples that had been collected from dogs with various disease conditions and that had been isolated from different culture sources, among which skin (n = 319) and urine (n = 81) were the most common. The isolates from dogs with healthy skin  were collected for a staphylococcal screening study that cultured samples from the nares and perineal skin of dermatologically healthy dogs being evaluated for elective orthopedic surgery. All sampling conformed to the ethical guidelines and standards of care for the hospital. The Institutional Animal Care and Use Committee and Clinical Research Review Committee approved the collection of isolates from the healthy dog group (AUP 2010-068).escribed . IsolateS. epidermidis strain 12228 and ATCC S. aureus strain 25923 were used as negative and positive controls, respectively, for biofilm production assays.For this study, all cultures were grown on Trypticase soy agar (TSA) with 5% sheep blood  and incubated at 37°C for 24 h. ATCC n = 160). The number of isolates was limited to 40 due to the availability of isolates from surgical site infections in the collection. Surgical infections were defined as cases where no clinical infections existed preoperatively and included infections of bone and implant hardware and incision line culture sites.For sequencing, 40 isolates were randomly selected from each of the following source groups: healthy dogs and dogs with pyoderma, urinary tract infection, and surgical infection  were adjusted for each plate by subtracting the average of the values determined for the blank control wells (TSB broth only). Cutoff values for biofilm production were established using a previously published 4-point scale (control), 1 represents weak adherence (ODcontrol < OD ≤ 2 × ODcontrol), 2 represents moderate adherence (2 × ODcontrol < OD ≤ 4 × ODcontrol), and 3 represents strong adherence (4 × ODcontrol < OD). Microtiter plate assays were performed in technical and biological triplicate.Overall biofilm production was assessed by the ability of the isolates to adhere to a 96-well microtiter plate as previously described , 41. Thent scale , where 0Isolates from source freezer stocks were grown on blood agar for 24 h at 37°C and subcultured twice to ensure the purity of the cultures. A single colony was inoculated into brain heart infusion broth  and grown for 8 h. A 1-ml aliquot was used for DNA extraction via the use of a MasterPure Gram-positive DNA purification kit, per their standard protocol. DNA was quantified using the Life Technologies Qubit high-sensitivity (HS) double-stranded DNA (dsDNA) assay, and all samples were normalized to 100 ng of DNA in a total volume of 14 μl. Sequencing libraries for 2 separate Illumina MiSeq sequencing runs were prepared by hand using a BiOO Scientific NEXTflex rapid DNA-Seq kit per their standard protocol. Prepared libraries were checked with the Qubit high-sensitivity dsDNA assay to determine concentrations and with an Agilent TapeStation D1000 HS system to determine the average fragment size for the prepared libraries. All samples were normalized to 4 nM and pooled per run. The 4 nM pool was diluted to 20 pM and sequenced on the Illumina MiSeq 300×300-cycle v3 sequencing kit. This resulted in approximately 500,000 paired-end reads per isolate and in approximately 50× coverage. All run data and FASTQ files were uploaded to BaseSpace (Illumina) for downstream analysis.de novo genome assembly (version 3.6.2) on the Texas A&M Institute for Genome Sciences and Society (TIGSS) computing cluster, with the following parameter: –careful. The resulting assemblies were annotated using the RAST tool kit (RASTtk) at the Pathosystems Resource Integration Center (PATRIC) (The Illumina MiSeq reads were assembled using SPAdes (PATRIC) .agr group, PATRIC’s BLASTn function was used on the assembled genomes using previously published sequences for the 4 agrD alleles  , and ResFinder 2.1 (In order to determine the 57402.1) . BLAST wnder 2.1  was usedStaphylococcus pseudintermedius MLST database   (Multilocus sequence typing was performed using the 7-gene MLST scheme utilized by the erreten) . The gen(BIGSdb) . Potenti(BIGSdb) , which u(BIGSdb) . CC clas(BIGSdb) .k × k, as indicated for the specific comparison; some tables were 2-by-2 layouts, whereas others exceeded dichotomous levels). Significance for analysis was set at P values of <0.05.Statistical significance was determined using the Chi-square test or, when the value in any cell exceeded the expected value by <5, Fisher’s exact test. Data were analyzed using contingency tables (https://patricbrc.org) and can be found in the PATRIC public workspaces portal under the name SLittle_StaphPseudAGR. The accession numbers are 283734.1312 to 283734.1471.The 160 WGS annotated genomes and contigs are available to the public on PATRIC (


The effect of antiviral therapy (AVT) on clinical outcomes in patients with hepatocellular carcinoma (HCC) who are seronegative for hepatitis B virus (HBV), defined as HBV DNA < 100 IU/ml prior to surgical resection, is unknown. The main purpose of this study was to evaluate the possible value of AVT in this cohort of patients.From January 2006 to January 2013, 161 HCC patients with positive serum tests for HBV surface antigen (HBsAg) but negative tests for HBV DNA who had undergone hepatectomy were included and analyzed. Propensity score matching (PSM) was used to balance the heterogeneity in baseline characteristics.n = 73, 45.34%) and the non-AVT group . HBV reactivation occurred in 20 patients in the non-AVT group (22.73%) but in only 2 patients in the AVT group . After PSM, the 1-, 2-, and 3-year recurrence-free survival (RFS) rates in the AVT group and the non-AVT group were 78.38%, 72.97%, and 62.16% and 81.08%, 72.97%, and 72.97%, respectively (p = 0.564); the 1-, 2-, and 3-year overall survival (OS) rates were 97.30%, 97.3%, and 91.89% and 94.59%, 94.59%, and 86.49% in the AVT group and non-AVT group, respectively (p = 0.447).All patients were divided into the following two groups: the AVT group  contains supplementary material, which is available to authorized users. With introduction and uptake of the vaccine, hepatitis B virus (HBV) infection rate has not been increasing at the same rate; however, the large population of infected individuals renders the situation less optimistic. Two billion people worldwide have been infected with HBV, the most common pathogen that causes human viral hepatitis, and 250 million are chronically infected , 2. HBV The present study evaluated the rate of post-hepatectomy HBV reactivation in HBV DNA-negative patients and explored the potential value of AVT for improving patient survival; the hypothesis was that AVT would be beneficial for HBV DNA-negative HCC patients (HBV DNA < 100 IU/ml).All patients in this study provided written informed consent before undergoing operation. All procedures in this study were performed in accordance with the principles of the Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-Sen University and the Helsinki Declaration and its amendments. The study was reported in accordance with the STROCCS criteria .We retrospectively collected and analyzed the data of HCC patients who underwent hepatectomy in our institution between January 2006 and January 2013. Patients who met the following inclusion criteria were enrolled in this study: (a) the patient’s hepatectomy was performed in our center, and HCC was pathologically confirmed after the operation; (b) the patient was positive for serum HBsAg before the surgery; (c) the patient’s serum HBV DNA level was < 100 IU/ml; (d) the patient’s liver function was Child-Pugh grade A or B; (e) if the patient received entecavir therapy, it was administered within 1 week before and after the hepatectomy; and (f) if the patient received entecavir (0.5 mg/d), they took it for at least 1 year after surgery.Patients were excluded if they met one or more of the following exclusion criteria: (a) the patient received treatment that might affect their prognosis before surgery such as transcatheter arterial chemoembolization (TACE) or radiation therapy; (b) the patient had other tumors in other organs, for example, renal cell carcinoma and cervical cancer, or certain severe diseases; (c) the patient had refractory ascites or hepatic encephalopathy; (d) the patient had a positive resection margin (R1 resection); or (e) they had previously received any antiviral treatment.In this study, we defined a negative result for HBV DNA as a serum level of HBV DNA < 100 IU/ml and defined macrovascular invasion as the presence of portal vein invasion (PVI) and/or hepatic vein invasion (HVI), which was detected by two different inspection methods, magnetic resonance imaging (MRI), or computed tomography (CT) accompanied by ultrasonographic testing. All imaging and ultrasonic reports were verified by at least two senior experts in related fields. We defined microscopic vascular invasion (MVI) as the invasion is visible only on microscopy and was assessed by several sections of non-tumoral hepatic parenchyma 1 cm away from the tumor according to previous studies , 19. HBVAll patients were followed up once a month in the first 3 months after hepatectomy and then every 3 months in subsequent months until 36 months after surgery or until death. Patients received routine blood tests, liver function tests, serum alpha-fetoprotein (AFP) assays, ultrasound and CT, or MRI at each reexamination. Recurrence-free survival (RFS) and overall survival (OS) were the outcomes of this study.Because grouping was based only on perioperative AVT rather than randomization, propensity score matching (PSM) was used to reduce the imbalance between the two groups. All possible clinicopathological covariates, such as tumor number, tumor size, and vascular invasion, which might have affected the target outcomes were included when conducting the PSM. Propensity scores were evaluated using a logistic regression model in this study. Patients were matched at a 1:1 ratio using the caliper matching method within 0.2 of the standard deviation from the propensity score logit, basing on previous literatures –24. And χ2 test or Fisher’s exact test, as appropriate. Univariate and multivariate analyses were performed using the Cox proportional hazards model. Survival curves were calculated and compared using the Kaplan-Meier method and log-rank test. All analyses were performed using SPSS version 22.0 , and the PSM analysis was conducted in R . A two-tailed P value of less than 0.05 was considered statistically significant.Intergroup categorical data were analyzed with the There were 728 such patients registered in our system. According to the inclusion and exclusion criteria, 161 HCC patients who tested positive for serum HBsAg but negative for HBV DNA before surgery were included. Among the selected 161 patients, 73 (45.34%) received AVT during the perioperative period and were included in the AVT group, while the remaining 88 (54.66%) were included in the non-AVT group  stage, tumor size, tumor capsule, vascular invasion, liver cirrhosis, anatomical hepatectomy, and HBV reactivation . Patients who experienced reactivation were considered for subsequent antiviral therapy.Before PSM, there were two patients (2.74%) presented with HBV reactivation in the AVT group, while 20 patients (22.73%) presented with HBV reactivation in the non-AVT group, and this difference was statistically significant (p > 0.05). However, albumin was significantly higher in the antiviral group than in the non-antiviral group at 1 month after hepatectomy, indicating better recovery of liver function to some extent .At 1 day, 3 days, 5 days, and 7 days after hepatectomy, liver function parameters such as alanine aminotransferase, total bilirubin, albumin, and prothrombin time all showed no significant difference between AVT and non-AVT groups  and HBV reactivation  were associated with RFS. Similarly, based on multivariate analysis, tumor size, anatomical hepatectomy, operative time, and HBV reactivation were related to overall survival ; the 1-, 2-, and 3-year OS rates were 97.26%, 94.52%, and 93.15% and 90.91%, 86.36%, and 84.09% in the AVT group and non-AVT group, respectively . After PSM, the 1-, 2-, and 3-year RFS rates in the AVT group and the non-AVT group were 78.38%, 72.97%, and 62.16% and 81.08%, 72.97%, and 72.97%, respectively ; however, the 1-, 2-, and 3-year OS rates were 97.30%, 97.3%, and 91.89% and 94.59%, 94.59%, and 86.49%, respectively, and there was no significant difference between the two groups .Before propensity matching analysis, the 1-, 2-, and 3-year RFS rates were 80.82%, 69.86%, and 58.90% and 69.32%, 60.23%, and 55.68% in the AVT group and control group, respectively .Our results showed that antiviral therapy can substantially reduce the postoperative HBV reactivation rate, which was consistent with the results of previous studies –41. In tOur results indicate that perioperative antiviral therapy does not improve liver function in 1 week after hepatectomy, but can better promote albumin recovery than non-antiviral therapy at 1 month, which is consistent with previous studies , 48. The3 IU/ml). Perhaps, with such an extremely low viral load, HBV was in a very stable state and seldom caused inflammation of the liver or an immune response; thus, AVT was not be able to exert any influence on tumor recurrence and patient survival. Of course, this conjecture requires more supporting research.In this study, we concluded that antiviral therapy may not improve RFS. On the other hand, although there was no significant difference in OS rates between the two groups, we still observed that OS in the antiviral group was higher than that in the non-antiviral group; we hypothesized that the lack of a significant difference may be the result of the small sample size, and studies with larger samples sizes are needed in the future. The conclusion of OS rates was different from that of a previous study , and theThis study had some limitations. First, it was a single-center study. Second, the research period was large, and the importance of AVT for HCC patients has gradually changed over the years, leading to the large initial baseline heterogeneity of patients administered AVT. Third, given that this study was a retrospective study, the duration of AVT was inconsistent. In addition, the sample size may have been a limiting factor for the separation of the KM curves when analyzing OS, and the role played by the tumor-immune microenvironment during this process is still unknown. At the same time, patients’ data about HBeAg, anti-HBe, and HBV phase was absent restricted by the detection means.In conclusion, AVT can reduce the HBV reactivation rate but has no effect on survival for HCC patients who are negative for HBV DNA (HBV DNA < 100 IU/ml). This conclusion will be useful for selecting treatment methods for this type of patient. However, studies with larger sample size are needed to further verify this conclusion and explore the possible mechanism underlying this result.Additional file 1:Eligible patients included in the AVT and non-AVT group. (XLSX 68 kb)


Sudden cardiac arrest (SCA) is one of the most common critical illnesses encountered in clinical practice. Shenfu injection (SFI) has received extensive attention as an alternative therapy that can effectively maintain the autonomic circulation function after cardiopulmonary resuscitation. However, the mechanism of SFI is not yet fully understood. In addition, there has been no systematic review or meta-analysis of SFI in the treatment of patients with return of spontaneous circulation after SCA. Herein, we describe the protocol of a proposed study based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines that aims to systematically evaluate the efficacy and safety of SFI in patients with return of spontaneous circulation after SCA.Two researchers will search 9 electronic databases  to identify all studies that meet the inclusion criteria and were published before July 2018. After information extraction and methodological quality evaluation, we will use Stata 13.0 software  to synthesize the data. The primary outcomes will be the survival rate and Glasgow Coma Scale.The data synthesis results will objectively illustrate the efficacy and safety of SFI in patients with return of spontaneous circulation after SCA.The findings will provide a reference for the use of SFI in the treatment of patients with return of spontaneous circulation after SCA.PROSPERO (registration number: CRD42018104230). The survival rate of SCA remains low, despite the development of Cardio Pulmonary Resuscitation (CPR), defibrillation, and other advanced resuscitation techniques over the past 50 years.–8 Therefore, increasing the survival rate of such patients has become a popular research topic. In particular, there is a need for research into alternative and complementary treatments, especially in the field of traditional Chinese medicine.Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) refer to the sudden termination of the mechanical activity of the heart with hemodynamic failure; these conditions are usually caused by persistent ventricular tachycardia or ventricular fibrillation (VF). If the autonomic cycle resumes as a result of an intervention  or automatic heart rate conversion, the event is called SCA (or SCD attempt); if the patient dies, the event is called SCD. The exact incidence of SCA in the United States is currently unclear, but is estimated to range from 180,000 to 450,000 annually.,10 In addition, higenamine strengthens myocardial contractility, relaxes the aorta, inhibits platelet aggregation, and has antithrombotic properties.–13Shenfu injection (SFI) is a patented traditional Chinese medicine that consists mainly of ginseng and aconite extracts. The active ingredient of ginseng is ginsenoside, while the main component of aconite is higenamine. Modern pharmacological studies have shown that ginsenoside has potential positive effects on heart disease through various properties, including anti-oxidation, reduction of platelet adhesion, regulation of vasomotor activity, improvement of lipid mass spectrometry, effects on various ion channels, and inhibition of the production and release of pro-inflammatory cytokines.,15 Furthermore, SFI can significantly reduce cerebral ischemia-reperfusion injury after resuscitation by regulating neuronal mitochondrial function.–18 Animal experiments have confirmed that SFI improves microvascular blood flow and coronary perfusion pressure during VF and CPR, reduces the required number of shocks and duration of CPR, and reduces energy exhaustion during VF.,20 However, no meta-analysis has investigated the efficacy and safety of SFI in the treatment of SCA. Therefore, the proposed study was designed to evaluate the efficacy and safety of SFI combined with conventional therapy in patients with spontaneous circulation recovery after SCA, and thus provides a reference for the use of SFI in clinical practice.Recent meta-analyses have shown that SFI combined with conventional therapy is more effective than conventional therapy alone in improving the heart function of patients with heart failure, regulating the blood pressure of patients with septic shock, and ultimately reducing mortality.22.12.1.1The proposed study will include all randomized controlled trials evaluating the use of SFI in the treatment of patients with return of spontaneous circulation after SCA.2.1.2All participants must have been diagnosed with SCA and recovered spontaneously after CPR. There will be no restrictions on the primary disease, disease duration, age, sex, or ethnicity.2.1.3 The experimental group must have received SFI in addition to the treatment received by the control group.The control group must have been treated using modern guidelines for routine treatment after CPR.2.1.42.1.4.1Primary outcomes will be the survival rate and Glasgow Coma Scale.2.1.4.2Secondary outcomes will be the mechanical ventilation time, mean arterial pressure, blood oxygen saturation, and adverse events.2.2#1 “cardiac arrest”[MeSH Terms] OR “cardiac arrest”[Title/Abstract] OR “sudden cardiac arrest”[Title/Abstract] OR “sudden cardiac”[Title/Abstract] OR “heart arrest”[Title/Abstract] OR “heart sudden arrest”[Title/Abstract] OR “cardio arrest”[Title/Abstract] OR “heart sudden pause”[Title/Abstract] OR “heart stop sudden”[Title/Abstract]#2 “cardiopulmonary resuscitation”[MeSH Terms] OR “cardiopulmonary resuscitation” [Title/Abstract] OR “cardio pulmonary resuscitation”[MeSH Terms] OR “cardio pulmonary resuscitation”[Title/Abstract] OR “cardio pulmo resuscitation”[Title/Abstract] OR “the cardiopulmonary resuscitation”[Title/Abstract] OR “cardio-pulmonary resuscitation” [Title/Abstract] OR “cpr”[Title/Abstract] OR “CPR”[Title/Abstract]#3 “return of spontaneous circulation”[MeSH Terms] OR “return of spontaneous circulation” [Title/Abstract] OR “spontaneous circulation restoration”[MeSH Terms] OR “spontaneous circulation restoration”[Title/Abstract] OR “restoration of spontaneous circulation”[Title/Abstract] OR “spontaneous circulation recovery”[Title/Abstract]#4 “Shenfu injection”[MeSH Terms] OR “Shenfu injection”[Title/Abstract] OR “Shen-Fu injection”[Title/Abstract] OR “Sf injection”[Title/Abstract] OR “ginseng-monkshood extract”[Title/Abstract]#5 (#1 OR #2 OR #3) AND #4Nine databases will be searched to identify relevant randomized, controlled trials published before July 2018. Retrieval strategies will not be restricted by publication type, region, or language. The 9 databases will be: PubMed, Medline, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese VIP Information, Wanfang Database, and Chinese Biomedical Database. The search strategy used in the PubMed database will be formulated as follows:2.2.1The reference lists of the retrieved literature will be further searched to identify any relevant grey literature. In addition, our members will read relevant medical journals and magazines to identify literature not included in the searched electronic databases.2.32.3.1Two researchers will work together to complete the literature search. The same 2 researchers will screen the retrieved literature by reading the titles and abstracts. The full text of relevant literature will then be read, and the studies will be selected in accordance with the inclusion criteria.2.3.2Two researchers will extract the necessary information based on the “Information Extraction Form” that has been prepared in advance, including the basic condition of the patient, treatment plan, observation indicators, and adverse reactions. In cases of disagreement, the 2 researchers will crosscheck and discuss the discrepancy, or seek advice from a third party.2.3.3 We will try to obtain any missing information from the original authors when possible. Ultimately, the studies will be classified as having a low, unclear, or high risk of bias in accordance with the quality classification criteria. The methodological quality of each study will be independently assessed by 2 authors, and any disputes will be resolved through consultation with a senior author.To assess the methodological quality of the included studies, our team will use the Cochrane risk of bias tool to examine 6 aspects: randomization of sequence generation, concealment of allocation methods, integrity of outcome data, selectivity of outcome reporting, and other sources of bias.2.3.4Continuous variables will be weighted by the mean differences, while dichotomous variables will be compared using the odds ratios. The confidence intervals (CI) for all reported results will be set at 95%.2.3.5If data are missing from the literature, we will attempt to contact the corresponding author by phone or e-mail. If the contact fails, we will perform a limited analysis based on the existing data.2.3.6I2 or P values. Values of I2 ≥50% or P < .1 indicate the presence of significant heterogeneity, and so a random effect model will be selected. Conversely, the fixed effect model will be selected when there is a small degree of heterogeneity.Heterogeneity testing is required for the synthesis analysis of the same outcome assessed in multiple studies. The heterogeneity is assessed using the 2.3.7The presence of publication bias can be analyzed by funnel plots. If the points on both sides of the funnel plot are scattered and asymmetrical, there is a publication bias, and the reliability is low. In contrast, if there is basically symmetrical distribution of the points on both sides of the funnel plot, there is no publication bias, and the result is reliable.2.3.8Z test results indicate that P is <.05, and the 95% CI do not contain 1 (for dichotomous variables) or the 95% CI do not contain 0 (for continuous variables). When the difference is not statistically significant, sensitivity analysis and subgroup analysis will be performed to identify the source(s) of heterogeneity.The appropriate treatment effect will be chosen based on different variables. In accordance with the heterogeneity test results, the appropriate model (random or fixed) will then be selected to merge the outcome indicators. Differences are considered statistically significant if the 2.3.9When heterogeneity is detected, the source of the heterogeneity will be determined by performing further subgroup analyses based on patient sex, age, disease type, drug dose, and course of treatment.2.3.10If the primary outcome analyses involve a large number of included studies and a large degree of heterogeneity, the included studies will be investigated individually to increase the stability of the final results.2.3.11All data included in this study are derived from published literature and do not include patient personal data, so no ethical approval is required. The final meta-analysis results will be published in a peer-reviewed journal.3 At present, CPR is the main treatment of SCA. However, the success rate of CPR is low, and the patient often cannot effectively maintain the autonomic cycle. Therefore, it is imperative to seek more effective and safe treatments for SCA.SCA is relatively common in clinical practice, and can occur due to a variety of disease processes. Furthermore, SCA accounts for the highest mortality rate in emergency patients. The mechanism by which SFI improves the cardiovascular circulation is not completely clear. Therefore, we plan to conduct a systematic review and meta-analysis of existing clinical studies to objectively evaluate the efficacy and safety of SFI in the treatment of patients with self-circulatory recovery after SCA. However, the proposed study has certain limitations; there is no guarantee that consistent criteria will have been used to assess all outcomes in included studies, and individual differences in populations of different ethnicities may affect the final study results.The recent wide application of traditional Chinese medicine has revealed that many traditional Chinese medicines can strengthen the body and promote recovery. Among them, SFI plays a huge role in the treatment of critically ill patients and those with severe diseases. Clinical studies have shown that SFI combined with conventional treatment can effectively maintain the spontaneous circulation of patients after successful CPR, with minimal adverse effects.www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.The authors thank Dr. Kelly Zammit, BVSc, from Liwen Bianji, Edanz Group China (This manuscript is completed by Jiarong Ye and Zehao Zhu. Study retrieval and data curation are handled by Jiarong Ye and Qianrong Liang. In terms of methodology, we mainly consult Xiaotu Xi and Xia Yan. Zehao Zhu is responsible for software operations. Research costs are fully funded by Zhongde Zhang.Data curation: Jiarong Ye, Qianrong LiangFunding acquisition: Zhongde ZhangMethodology: Xiaotu Xi, Xia YanSoftware: Zehao ZhuWriting – original draft: Jiarong Ye, Zehao ZhuJiarong Ye orcid: 0000-0002-7512-5639Zehao Zhu orcid: 0000-0003-0293-8986Qianrong Liang orcid: 0000-0003-0801-4557Xia Yan orcid: 0000-0001-6144-9336Xiaotu Xi orcid: 0000-0002-0711-4137Zhongde Zhang orcid: 0000-0002-7909-8877


Linear IgA bullous dermatosis (LABD) is a rare autoimmune subepithelial vesiculobullous disease due to IgA autoantibodies directed against different antigens of the basement membrane zone (BMZ) of the skin and/or mucosae. It affects mainly preschool-aged children and adults, with only few studies on large series. The aim of this study was to assess possible differences between adults and children regarding clinical presentation, immunopathologic features, management and course of the disease.A retrospective review of 38 LABD patients, followed-up from November 2006 to September 2018, was performed.p = 0.008), particularly perioral (p = 0.001), involvement, as well as “string of pearls” arrangement (p = 0.03), were more prevalent in children. Mucosal involvement was seen in 9 (23.7%) patients and was more frequent in children than adults . Linear IgA deposits along the BMZ were observed in 30 patients (78.9%), while linear/granular IgA deposits in 8 patients (21.1%). Dapsone was the most commonly used drug (78.9%) and complete remission was achieved in most cases (81.6%).Of 38 patients, 27 were adults and 11 children. Mean age at diagnosis was 5.4 years and 60.6 years in the pediatric and adult group, respectively. Considering both groups, limbs were the most commonly involved site (73.7%), followed by trunk (55.3%), head (36.8%) and buttocks (13.2%). Interestingly, head  contains supplementary material, which is available to authorized users. Linear immunoglobulin A (IgA) bullous dermatosis  is a rare autoimmune subepithelial vesiculobullous disease caused by IgA autoantibodies directed against different antigens of the basement membrane zone (BMZ) of the skin and/or mucosae , 2. On dLiterature is lacking retrospective studies on LABD from Italy, as only a few case reports have been published –29. TherWe retrospectively examined medical records of LABD patients admitted to our outpatient service from November 2006 to September 2018. The diagnosis of LABD was rendered based on both clinical examination and immunopathological criteria . Inclusip ≤ 0.05.Categorical variables are reported as number (percentage), and continuous variables as mean (range). Data analysis was performed with Fisher’s exact test, as appropriate, using GraphPad Prism version 6.0 . Statistical significance was defined as n = 35; 92.1%) skin lesions. The “string of pearls” arrangement , as shown in Table n = 28: 73.7%), trunk , head  and buttocks . Head involvement was more common in children than adults  and, when considering only the perioral area, the statistical significance increased . Mucous membrane involvement was observed in 9 (23.7%) patients and the most frequent mucosal localisation was oral cavity (15.8%), followed by genital (7.8%)  and, interestingly, all patients with genital involvement (n = 3) were children. Pre-biopsy diagnostic hypothesis was correct in 7 cases (18.4%), while bullous pemphigoid (BP)  and bullous impetigo  represented the most frequent misdiagnoses. All but two cases were idiopathic; the two probably drug-induced cases were triggered by amoxicillin/clavulanic acid (NS = 6) and clarithromycin (NS = 5), with a latency time from the intake of 1 and 3 weeks, respectively. Losartan (NS = 2), oxcarbazepine (NS = 3) and chlorambucil (NS = 2) were regarded as possible culprit drugs in three other cases.Detailed clinical and laboratory data of the 38 collected patients are shown in Additional file ent Fig.  was desc8%) Fig. , conjuncp = 0.47). Neutrophil microabscesses at the tip of the dermal papillae were seen in three cases (7.9%).Histological examination on skin or mucous biopsies as well as DIF examination were routinely performed in all patients. On histopathological assessment, all cases revealed subepidermal blisters associated with dermal infiltrate of neutrophils. In 22 cases (57.9%), eosinophils were observed in association with neutrophils in the upper dermis, without statistically significant differences between adults and children (p = 0.21).On DIF, linear IgA deposits along the BMZ were observed in 30 patients (78.9%), while linear/granular IgA deposits were detected in 8 patients 21.1%). As shown in Table .1%. As sn = 4; 10.5%). Cyclosporine eye drops were administered in two patients with ocular involvement. One adult patient with a drug-induced form and one pediatric patient received neither systemic nor topical treatments owing to a self-limiting course, with a follow-up time of 16 months in both cases. The mean follow-up time was 30.7 months. CR was achieved in most cases , while PR in three patients. Only two cases were refractory to multiple drugs, showing NR , with no statistically significant differences between adults and children. All patients with relapsed disease were not taking any medication for their LABD at the moment of the relapse. The mean time from drug withdrawal to relapse was 10 months. All patients who experienced a relapse re-achieved a CR after treatment reintroduction. As shown in Table All patients except two self-resolving cases received systemic therapy, combined with topical treatment in some cases. Dapsone, administered to 30 patients (78.9%), with a mean starting dosage of 0.5 mg/kg per day, was the most common treatment option. Median duration of dapsone treatment was 26.2 months. We observed dapsone-induced methemoglobinemia only in a patient, who was switched to oral methylprednisolone and consequently showed a CR. Systemic corticosteroids  were given in concomitance with, preceding or following dapsone in 22 cases (57.9%), while in 5 cases 13.2%) they represented a stand-alone therapy. In a case resistant to corticosteroid monotherapy, a combination of methotrexate and oral methylprednisolone induced a CR. Other treatment options for steroid-refractory cases are reported in Additional file 3.2% theyWe present the largest case-series of Italian patients with LABD and compare our findings with data reported in the literature . This is in line with literature data reporting the head and face more commonly involved in children than adults [p = 0.03), similarly to the findings of Jabłońska et al. [Regarding clinical manifestations, of note, in our study head, particularly perioral, involvements were significantly more common in the pediatric than adult group  cases . AlthougThe increasingly described association of LABD with inflammatory bowel diseases –37 was cApproximately 15% of the adult patients had a history of cancer. Although malignancies, especially of lymphoreticular origin, have been described in association with LABD,  in all oLinear IgA deposition along the BMZ with neither Ig class other than IgA nor complement resulted the most frequent pattern on DIF in our case series. In our study, patients with linear IgG deposits in addition to linear IgA deposits were considered as a subgroup of LABD. Indeed, Ohata et al.  suggesteIIF on human skin has been reported to be positive for IgA in just over 80% of children and approximately 40% of adults , 14, 40.Most frequent and successful treatment was dapsone, given both as a stand-alone therapy and combined with systemic steroids. In our comparison of the adult and children group, we failed to identify any differences in terms of response to treatment. As compared to the study of Gottlieb et al.,  higher CThe main limitation of the present study was its retrospective nature, which, however, depended on the rarity of the disease. Furthermore, a direct comparison between the two groups might have been biased by the fact that adults were more numerous than children in the study population. An additional limitation was represented by the fact that immunoblotting and enzyme-linked immunoassay for BP180, BP230 and/or collagen VII were not performed. Therefore, it cannot be stated with certainty whether cases of sublamina densa-type LABD and IgA-epidermolysis bullosa acquisita, whose common autoantigen is collagen VII, –44 have In summary, the results of this retrospective study conducted on a cohort of 38 Italian LABD patients diagnosed and followed-up in a single center confirmed the biphasic age at onset of the disease and showed a higher prevalence of head, particularly perioral, and mucosal involvements as well as a more frequent “string of pearls” arrangement in children than adults. Thus, these clinical parameters may be a diagnostic tool for LABD in children.Additional file 1:Table S1. Demographic data, clinical features, diagnostic findings, treatments and outcomes of 38 linear IgA bullous dermatosis patients. (DOCX 37 kb)Additional file 2:Table S2. Summary of the main studies on linear IgA bullous dermatosis including study design, patients’ number, clinical features and laboratory findings. (DOCX 25 kb)


Photosynthesis is able to convert solar energy into chemical energy in the form of biomass, but the efficiency of photosynthetic solar energy conversion is low. Chlorophyll fluorescence measurements are rapid, non-destructive, and can provide a wealth of information about the efficiencies of the photosynthetic light reaction processes. Efforts aimed at assessing genetic variation and/or mapping of genetic loci associated with chlorophyll fluorescence phenotypes have been rather limited.Evaluation of SoySNP50K iSelect SNP Beadchip data from the 189 genotypes phenotyped in this analysis identified 32,453 SNPs with a minor allele frequency (MAF) ≥ 5%. A total of 288 (non-unique) SNPs were significantly associated with one or more of the 21 chlorophyll fluorescence phenotypes. Of these, 155 were unique SNPs and 100 SNPs were only associated with a single fluorescence phenotype, while 28, 11, 2, and 14 SNPs, were associated with two, three, four and five or more fluorescence phenotypes, respectively. The 288 non-unique SNPs represent 155 unique SNPs that mark 53 loci. The 155 unique SNPs included 27 that were associated with three or more phenotypes, and thus were called multi-phenotype SNPs. These 27 multi-phenotype SNPs marked 13 multi-phenotype loci (MPL) identified by individual SNPs associated with multiple chlorophyll fluorescence phenotypes or by more than one SNP located within 0.5 MB of other multi-phenotype SNPs.A search in the genomic regions highlighted by these 13 MPL identified genes with annotations indicating involvement in photosynthetic light dependent reactions. These, as well as loci associated with only one or two chlorophyll fluorescence traits, should be useful to develop a better understanding of the genetic basis of photosynthetic light dependent reactions as a whole as well as of specific components of the electron transport chain in soybean. Accordingly, additional genetic and physiological analyses are necessary to determine the relevance and effectiveness of the identified loci for crop improvement efforts.The online version of this article (10.1186/s12870-018-1517-9) contains supplementary material, which is available to authorized users. At mid-day (when PAR is around 2000 μmol m− 2 s − 1) the efficiency can fall to or below 10%  obtained from STRUCTURE runs against mal Fig. , Table 3mal Fig. .Fig. 3PoEvaluation of SoySNP50K iSelect SNP Beadchip data from the 189 genotypes phenotyped in this study identified 32,453 SNPs with a minor allele frequency (MAF) ≥ 5%. The number of genotypes with MAF was relatively stable in the MAF range of 0.15 to 0.50 Fig. . The nump value > 3.10) association were considered putative marker-phenotype associations (MPAs).The 32,453 SNPs with MAF ≥ 5% were used for marker-phenotype association analyses with the BLUP mean across all four environments. A compressed mixed linear model (CMLM) accounting for population structure (Q-matrix) and genetic relatedness (K-matrix) was applied to help avoid false positives. The markers that showed a significant (−log10 I) with the lowest number of SNPs (3 SNPs)  Table . Signifis) Table .Table 4SThe 288 non-unique SNPs represent a total of 155 unique SNPs contributing to 53 loci, 14 of which were identified based on single SNPs and the remaining 39 by at least two and up to 22 SNPs. Of the 53 loci, 15 were associated with a single fluorescence phenotype, 19 with two fluorescence phenotypes, and another 19 with three or more phenotypes  and 0.989 (ABS/RC) reported by Hao et al. [V/FM) and 0.91 (ABS/RC) observed by Yin et al. [ABS observed in this study, 1.12, was narrower than the ranges observed in both previous studies  genotypes that had been selected for differing grain yield under drought stress [V) and 0.14 (FV/FM), the ranges documented in the present study also exceed those of four potato genotypes (ranges of 451 for FV and 0.11 for FV/FM) that differed in response to nitrogen levels [Knowledge regarding natural genotypic variation in chlorophyll fluorescence phenotypes in soybean is very limited. In the present study, 21 chlorophyll fluorescence phenotypes were assessed in a diverse panel of 189 soybean genotypes grown in four different environments. Significant genotype and environment effects were observed for all 21 phenotypes and significant genotype by environment interactions for all but TRo et al.  and 0.08n et al. . The rano et al. ; 5.05 byo et al. . In a QTo et al.  found a t stress . With 55n levels .0/RC) and 36.8% (F0). Hao et al. [In general, broad sense heritability values for chlorophyll fluorescence phenotypes vary considerably –63. In to et al. , reporteo et al.  assayed Genome-wide association analysis identified 288 SNPs that were associated with at least one of 21 chlorophyll fluorescence phenotypes. Marker-trait associations were absent on chromosomes 14 and 20 but were found on all other chromosomes. The 288 total SNPs identified across all four environments comprised 153 unique SNPs, which marked 53 loci. Fourteen of the 53 loci were identified based on single SNPs and 39 by at least two and up to 22 SNPs. Of the 53 loci, 19, 9, and 25 were associated with a single, two, and three or more phenotypes, respectively , TRf ET0/RC –82 for i centers . Little r et al.  indicateM/F0 and FV/F0, are among the more commonly reported traits and were associated with four consecutive SNPs in MPL-13. The phenotype Fv/F0, maximum primary yield of photochemistry of photosystem II, was less affected by drought in drought tolerant barley genotypes [Pisum sativum L.) than FV/FM [0, with tolerance to drought and cold stress, the MPL-13 on chromosome 19 may represent a useful marker to improve photosynthetic efficiency in soybean under abiotic stress conditions.Since the phenotypes examined in this study are all describing aspects related to the photosynthetic electron transport chain, the identification of a considerable number of MPL was not surprising. To date, for many of the individual chlorophyll fluorescence phenotypes assessed in this study, the impact of different values on biomass accumulation or grain yield and even photosynthetic rates are not well understood. As such, the 19 loci identified to be associated with individual chlorophyll fluorescence phenotypes should be useful for future efforts aimed at establishing the importance of specific traits relative to plant performance. In addition to loci that could be targeted for in depth studies and to improve individual fluorescence phenotypes or different categories of fluorescence phenotypes in advanced germplasm, MPL represent promising targets to impact several aspects of the light-dependent reactions. Among them, MPL-13, which was associated with the largest number of fluorescence phenotypes (9), is of particular interest. Two of the nine fluorescence phenotypes, Fenotypes  and morean FV/FM . Given tV/FM, φEo and φPo and a locus previously identified by Hao et al. (2012) was located approximately 1.5 Mb from MPL-3 and was associated with ABS/RC and ET0/TR0. Additionally, Hao et al. [0/ABS, ET0/TR0 and PIABS, and was within approximately 1.4 Mb of MPL-11 which was associated with ET0/RC, Ψ0 and VJ. Although the phenotypes that Hao et al. [V/FM on chromosome seven, it was more than 12 Mb from MPL-4 which was not associated with FV/FM.Previously Hao et al.  and Yin o et al.  reportedo et al.  found too et al. , provideo et al.  was loca0 under well-watered conditions [− 2 [Arabidopsis thaliana mutant of AT5G18660, pale-green and chlorophyll b reduced 2, was identified based on a lack of grana and was found to accumulate divinyl chlorophylls [Regions of the genome marked by MPL may contain groups of genes that are important for different chlorophyll fluorescence phenotypes, or alternatively, these regions may encompass single genes that have a significant impact on photosynthetic light dependent reactions, and thus, influence the values of multiple chlorophyll fluorescence phenotypes. Examination of gene annotations in the vicinity of the 13 MPL identified in this study revealed 30 candidate genes Table . Of the nditions . The panons [− 2 . Given tons [− 2  and the ons [− 2  et a, itons [− 2 . Plants rophylls . The accV/FM as well as altered chlorophyll fluorescence induction. The PsbP knock down mutants also had altered growth characteristics when not grown on sucrose containing media and was most pronounced with mutants that displayed less PsbP levels. Thus, the loci identified here may be used to identify variations in the PsbP gene that may be useful to improve photosynthetic efficiency. Additionally the PS2 core protein T candidate, PsbT, has previously been shown to be involved with the assembly and efficiency of PS2 [The second largest group of candidate genes located near MPLs were proteins of the PSII complex Table . Severaly of PS2 . Mutantsy of PS2 .V/FM, net photosynthesis, Rubisco activase gene expression and Rubisco activity. [Some candidate genes were not directly associated with the light dependent reactions. These candidate genes such as Glyma.12G061600 and Glyma.11G108800 were involved with reactions that utilize the products of the light dependent reactions. The most studied enzyme associated with the light independent reactions is Ribulose-bisphosphate carboxylase (Rubisco) and has been the target of a plethora of investigations on improving photosynthesis –94. The ctivity. . The chactivity.  showed tChlorophyll fluorescence measurements on 189 MG IV soybean genotypes grown in four different field environments demonstrated high diversity across 21 chlorophyll fluorescence phenotypes. Genome-wide association analysis based on these genotypes and chlorophyll fluorescence phenotypes lead to the identification of 153 unique SNPs. Based on these SNPs, 13 loci associated with at least three phenotypes (multi phenotype loci) were identified. Despite the low heritabilities of Energy flux traits the Primary and Relative fluorescence phenotypes have in some cases much higher values. A search in the genomic regions highlighted by these 13 MPL identified genes with annotations indicating involvement in photosynthetic light dependent reactions. These, as well as loci associated with only one or two chlorophyll fluorescence traits, should be useful to develop a better understanding of the genetic basis of photosynthetic light dependent reactions as a whole as well as of specific components of the electron transport chain in soybean. Since many chlorophyll fluorescence traits are responsive to changes in environmental conditions, careful characterization of the loci identified here may lead to avenues for improved stress tolerance. Accordingly, additional genetic and physiological analyses are necessary to determine the relevance and effectiveness of the identified loci for crop improvement efforts.Additional file 1:Table S1. List of all significant SNP markers for 21 chlorophyll flourescence phenotypes evalauted in the study. (XLSX 43 kb)Additional file 2:Table S2. List of putative loci significantly associated with same SNP identified for at least three phenotypes or more for 19 of 21 fluorescence phenotypes. (XLSX 32 kb)