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The Archives of Bone and Joint Surgery Nov 2018The Plasminogen Activator Inhibitor-1 gene 4G/5G (PAI-1 4G/5G) polymorphism has been suggested to be associated with osteonecrosis of the femoral head (ONFH)... (Review)
Review
BACKGROUND
The Plasminogen Activator Inhibitor-1 gene 4G/5G (PAI-1 4G/5G) polymorphism has been suggested to be associated with osteonecrosis of the femoral head (ONFH) susceptibility; however, the results are conflicting and inconclusive. We have carried out a comprehensive meta-analysis to derive a more precise estimation of the association.
METHODS
A comprehensive search in PubMed, EMBASE, Google Scholar, and ISI Web of Knowledge databases was conducted to identify all eligible case-control publications investigating the association between PAI-1 4G/5G polymorphism and ONFH risk. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were used to assess the association.
RESULTS
A total of six studies with 456 cases and 1,019 controls were included in this review. Three studies were from Caucasian descendants and the three others were from East Asian descendants. Overall analysis suggests a significant association between PAI-1 4G/5G polymorphism and ONFH risk under the allele model (4G vs. 5G: OR =1.540, 95% CI =1.055-2.248, ) and the recessive model (4G4G vs. 4G5G+5G5G: OR=1.931, 95% CI: 1.162-3.207, ). When stratified by ethnicity, we have found a significant association between PAI-1 4G/5G polymorphism and ONFH risk among the Caucasian (4G5G vs. 5G5G: OR=1.806, 95% CI: 1.064-3.067, ) and East Asians (4G4G vs. 5G5G: OR=1.619, 95% CI: 1.025-2.556, and 4G4G vs. 4G5G+5G5G: OR=1.665, 95% CI: 1.207-2.297, ).
CONCLUSION
The present meta-analysis suggested that PAI-1 4G/5G (rs1799889) polymorphism is a potential risk factor for development of ONFH. However, large-scale and well-designed case-control studies in different ethnicities are required to validate these results.
PubMed: 30637301
DOI: No ID Found -
Frontiers in Neurology 2021Mechanical thrombectomy (MT) is now the standard-of-care treatment for acute ischemic stroke (AIS) of the anterior circulation and may be performed irrespective of...
Mechanical thrombectomy (MT) is now the standard-of-care treatment for acute ischemic stroke (AIS) of the anterior circulation and may be performed irrespective of intravenous tissue plasminogen activator (IV-tPA) eligibility prior to the procedure. This study aims to understand better if tPA leads to higher rates of reperfusion and improves functional outcomes in AIS patients after MT and to simultaneously evaluate the functionality and efficiency of a novel semi-automated systematic review platform. The Nested Knowledge AutoLit semi-automated systematic review platform was utilized to identify randomized control trials published between 2010 and 2021 reporting the use of mechanical thrombectomy and IV-tPA (MT+tPA) vs. MT alone for AIS treatment. The primary outcome was the rate of successful recanalization, defined as thrombolysis in cerebral infarction (TICI) scores ≥2b. Secondary outcomes included 90-day modified Rankin Scale (mRS) 0-2, 90-day mortality, distal embolization to new territory, and symptomatic intracranial hemorrhage (sICH). A separate random effects model was fit for each outcome measure. We subjectively found Nested Knowledge to be highly streamlined and effective at sourcing the correct literature. Four studies with 1,633 patients, 816 in the MT+tPA arm and 817 in the MT arm, were included in the meta-analysis. In each study, patient populations consisted of only tPA-eligible patients and all imaging and clinical outcomes were adjudicated by an independent and blinded core laboratory. Compared to MT alone, patients treated with MT+tPA had higher odds of eTICI ≥2b (OR = 1.34 [95% CI: 1.10; 1.63]). However, there were no statistically significant differences in the rates of 90-day mRS 0-2 (OR = 0.98 [95% CI: 0.77; 1.24]), 90-day mortality (OR = 0.94 [95% CI: 0.67; 1.32]), distal emboli (OR = 0.94 [95% CI: 0.25; 3.60]), or sICH (OR = 1.17 [95% CI: 0.80; 1.72]). Administering tPA prior to MT may improve the rates of recanalization compared to MT alone in tPA-eligible patients being treated for AIS, but a corresponding improvement in functional and safety outcomes was not present in this review. Further studies looking at the role of tPA before mechanical thrombectomy in different cohorts of patients could better clarify the role of tPA in the treatment protocol for AIS.
PubMed: 34975722
DOI: 10.3389/fneur.2021.759759 -
Journal of Diabetes and Metabolic... Dec 2020The 4G5G polymorphism of Plasminogen activator inhibitor-1 (PAI-1) gene is reported to be associated with diabetes nephropathy and retinopathy (DNR) risk. However, the... (Review)
Review
BACKGROUND
The 4G5G polymorphism of Plasminogen activator inhibitor-1 (PAI-1) gene is reported to be associated with diabetes nephropathy and retinopathy (DNR) risk. However, the findings are conflicting. Herein, we conducted a case-control and meta-analysis study to explore the association of PAI-1 4G5G polymorphism with risk of DNR.
METHODS
We retrieved PubMed, EMBASE, Web of Knowledge, and CNKI databases and screened eligible studies up to August 15, 2020. The strength of associations was assessed by odd ratio (OR) and the corresponding 95% confidence interval (95% CI).
RESULTS
A total of 27 case-control studies including 16 studies with 1,825 cases case and 1,731 controls on DN and eleven studies with 1,397 cases and 1,545 controls on DR were selected. Pooled data showed that the PAI-1 4G5G polymorphism was significantly associated with DN (allele model: OR = 0.674, 95% CI 0.524-0.865, p = 0.002; homozygote model: OR = 0.536, 95% CI 0.351-0.817, p = 0.004; heterozygote model: OR = 0.621, 95% CI 0.427-0.903, p = 0.013; dominant model: OR = 0.575, 95% CI 0.399-0.831, p = 0.003; and recessive model: OR = 0.711, 95% CI 0.515-0.981, p = 0.038) and DR (homozygote model: OR = 0.770, 95% CI 0.621-0.955, p = 0.0.017) risk. Stratified analyses by ethnicity indicated that PAI-1 4G5G polymorphism was associated with DN and DR risk in Asians and Caucasians, respectively.
CONCLUSIONS
The present meta-analysis revealed that the PAI-1 4G5G polymorphism was associated with increased risk of DN and DR risk. However, well-designed large-scale clinical studies are required to further validate our results.
PubMed: 33520873
DOI: 10.1007/s40200-020-00675-1 -
PloS One 2016Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides... (Meta-Analysis)
Meta-Analysis Review
Recombinant Tissue Plasminogen Activator Induces Neurological Side Effects Independent on Thrombolysis in Mechanical Animal Models of Focal Cerebral Infarction: A Systematic Review and Meta-Analysis.
BACKGROUND AND PURPOSE
Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke.
METHODS
Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger's test were obtained to detect publication bias.
RESULTS
We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate.
CONCLUSIONS
This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA.
Topics: Animals; Animals, Genetically Modified; Blood-Brain Barrier; Brain Edema; Cerebral Infarction; Data Interpretation, Statistical; Disease Models, Animal; Male; Rats; Recombinant Proteins; Sensitivity and Specificity; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 27387385
DOI: 10.1371/journal.pone.0158848 -
Thrombosis and Haemostasis Jul 2016Elevated plasma levels of the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 (PAI-1) may contribute to the pathogenesis of atherosclerotic... (Meta-Analysis)
Meta-Analysis Review
Elevated plasma levels of the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 (PAI-1) may contribute to the pathogenesis of atherosclerotic cardiovascular disease. Beyond their lipid-lowering effect, statins have been shown to modulate plasma PAI-1 levels but evidence from individual randomised controlled trials (RCTs) is controversial. Therefore, we aimed to assess the potential effects of statin therapy on plasma PAI-1 concentration through a meta-analysis of RCTs. We searched Medline and SCOPUS databases (up to October 3, 2014) to identify RCTs investigating the effect of statin therapy on plasma PAI-1 concentrations. We performed random-effects meta-analysis and assessed heterogeneity (I² test, subgroup and sensitivity analyses) and publication bias (funnel plot, Egger and "trim and fill" tests). Sixteen RCTs (comprising 19 treatment arms) were included and pooled analyses showed a significant effect of statins in reducing plasma PAI-1 concentrations (weighted mean difference WMD: -15.72 ng/ml, 95 % confidence interval [CI]: -25.01, -6.43,). In subgroup analysis, this effect remained significant in with lipophilic statins (atorvastatin and simvastatin) (WMD: -21.32 ng/ml, 95 % CI: -32.73, -9.91, I²=99 %) and particularly atorvastatin (WMD: -20.88 ng/mL, 95 % CI: -28.79, -12.97, I2=97 %). In the meta-regression analysis, the impact of statins on PAI-1 did not correlate with the administered dose, duration of treatment and changes in plasma LDL-cholesterol concentrations. Finally, evidence of publication bias was observed. In conclusion, taking into account the limit of heterogeneity between studies, the present meta-analysis suggests that statin therapy (mainly atorvastatin) significantly lowers plasma PAI-1 concentrations.
Topics: Atorvastatin; Coronary Artery Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Plasminogen Activator Inhibitor 1; Publication Bias; Randomized Controlled Trials as Topic; Regression Analysis; Risk Factors
PubMed: 27009446
DOI: 10.1160/TH15-10-0770 -
CNS Drugs Aug 2015Concerns about the harms of intravenous alteplase (recombinant tissue plasminogen activator) continue to deter physicians from treating patients with acute ischemic... (Meta-Analysis)
Meta-Analysis Review
Intravenous Recombinant Tissue Plasminogen Activator Does Not Impact Mortality in Acute Ischemic Stroke at Any Time Point up to 6 Months: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.
BACKGROUND AND OBJECTIVE
Concerns about the harms of intravenous alteplase (recombinant tissue plasminogen activator) continue to deter physicians from treating patients with acute ischemic stroke with the only drug proven to positively impact outcomes and reduce disability. Recent literature indicates an increase in mortality with alteplase within 7 days, an effect that does not persist from 3 months onwards. The objective of this meta-analysis was to pool mortality estimates from randomized controlled clinical trials (RCTs) at 7 days, 30 days, 90 days, and 6 months after stroke onset.
METHODS
PubMed, Embase, Scopus, CENTRAL, and clinicaltrials.gov were searched through to April 2014, using "hedges" for tissue plasminogen activator, acute ischemic stroke, and placebo. Two independent authors abstracted data and assessed study quality. Data were pooled using Dersimonian and Laird's random effects model.
RESULTS
Eleven RCTs (n = 6905) were included in the final analysis. Two authors independently performed study selection and data abstraction. There was no publication bias and total variance attributable to heterogeneity was not significant (I(2) < 50%) at any time point. There was no difference in mortality between alteplase and placebo groups at any time point. Trials that randomized patients beyond 3 h (excluded patients within the 3-h window) did not drive the mortality difference seen at any time point. Exclusion sensitivity analysis revealed that exclusion of the NINDS trial rendered the 7-day difference significant towards increased mortality with alteplase. Quality adjustment did not alter the results.
CONCLUSION
Intravenous alteplase did not impact mortality in patients with acute ischemic stroke at any of the measured time points up to 6 months (i.e., there was no increase in the risk of death with alteplase). Therefore, intravenous alteplase should be given to all eligible patients with acute ischemic stroke to improve long-term neurologic outcomes. The effects of alteplase on early survival are more complex than previously understood.
Topics: Administration, Intravenous; Brain Ischemia; Fibrinolytic Agents; Humans; Randomized Controlled Trials as Topic; Stroke; Time Factors; Tissue Plasminogen Activator; Treatment Outcome
PubMed: 26251162
DOI: 10.1007/s40263-015-0265-8 -
Annals of Agricultural and... Mar 2023In COVID-19, the rapid prediction of the severity of a patient's condition using modern biomarkers can accelerate the implementation of appropriate therapy, and thus... (Meta-Analysis)
Meta-Analysis
INTRODUCTION AND OBJECTIVE
In COVID-19, the rapid prediction of the severity of a patient's condition using modern biomarkers can accelerate the implementation of appropriate therapy, and thus improve the patient's prognosis.
MATERIAL AND METHODS
A meta-analysis was conducted of data available in the literature on the differences in baseline suPAR blood concentration between patients (1) who tested positive and negative for COVID-19, (2) who had severe and non-severe COVID-19, and (3) COVID-19 survivors and non-survivors.
RESULTS
SuPAR levels in SARS-CoV-2 negative and positive patients varied and amounted to 3.61±1.59 ng/ml vs. 6.45±3.13 ng/ml, respectively (MD = -3.18; 95%CI: -4.71 to -1.66; p<0.001). suPAR levels among non-severe and severe COVID-19 patients were 7.06±2.64 ng/ml and 5.06±3.16 ng/ml (MD = 0.18; 95%CI: -2.48 to 2.83; p=0.90), respectively. Pooled analysis showed that suPAR levels between severe versus critical COVID-19 patients to be 5.59±1.54 ng/ml and 6.49±1.43 ng/ml, respectively (MD = -1.00; 95%CI: -1.31 to -0.70; p<0.001). The suPAR levels between ICU survivors versus non-survivors amounted to 5.82±2.33 ng/ml and 8.43±4.66 ng/ml (MD = -3.59; 95%CI: -6.19 to -1.00; p=0.007). In the case of in-hospital mortality, the mean suPAR level among survivors to hospital discharge was 5.63±1.27 ng/ml, compared to 7.85±2.61 ng/ml for patients who did not survive (MD = -3.58; 95%CI: -5.42 to -1.74; p<0.001).
CONCLUSIONS
SuPAR levels are significantly elevated in severe COVID-19 illness and maybe useful in predicting mortality. Further studies are needed to determine cut-off points and clarify the association of suPAR levels with disease progression. This is of utmost importance given the ongoing pandemic and overburdened health care systems.
Topics: Humans; Receptors, Urokinase Plasminogen Activator; COVID-19; SARS-CoV-2; Disease Progression; Biomarkers
PubMed: 36999867
DOI: 10.26444/aaem/160084 -
Annals of Vascular Surgery Jul 2010To summarize the present evidence for an association between circulating tissue plasminogen activator (tPA) levels and abdominal aortic aneurysm (AAA) presence, we... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
To summarize the present evidence for an association between circulating tissue plasminogen activator (tPA) levels and abdominal aortic aneurysm (AAA) presence, we performed a systematic review and meta-analysis of case-control studies that compared plasma tPA levels between patients with AAA and subjects without AAA.
METHODS
MEDLINE was searched to identify all case-control studies that compared plasma tPA levels between patients with AAA and subjects without AAA. For each study, data regarding plasma tPA levels in both the AAA and control groups were used to generate standardized mean differences and 95% confidence intervals. Study-specific estimates were combined using inverse variance-weighted average of logarithmic standardized mean differences in both fixed- and random-effects models.
RESULTS
Our search identified five eligible case-control studies, including data on 234 patients with AAA and 459 subjects without AAA. Pooled analysis of the five studies demonstrated nonsignificantly higher plasma tPA levels in the AAA group than those in the control group in fixed-effect models (standardized mean differences = 0.07; 95% confidence interval = -0.09-0.24; p = 0.40). There was minimal study heterogeneity of results (p = 0.05) and no evidence of significant publication bias (p = 0.3272).
CONCLUSION
The results of our analysis suggest that plasma tPA levels may not be higher in patients with AAA than those in subjects without AAA. Higher plasma tPA levels may not be associated with AAA presence.
Topics: Aged; Aortic Aneurysm, Abdominal; Biomarkers; Case-Control Studies; Evidence-Based Medicine; Female; Humans; Male; Middle Aged; Risk Assessment; Risk Factors; Tissue Plasminogen Activator; Up-Regulation
PubMed: 20409678
DOI: 10.1016/j.avsg.2010.02.005 -
Frontiers in Immunology 2018Plasminogen activator inhibitor-1 (PAI-1), a crucial regulator of fibrinolysis, is increased in sepsis, but its values in predicting disease severity or mortality... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Plasminogen activator inhibitor-1 (PAI-1), a crucial regulator of fibrinolysis, is increased in sepsis, but its values in predicting disease severity or mortality outcomes have been controversial. Therefore, we conducted a systematic review and meta-analysis of its predictive values in sepsis.
METHODS
PubMed and Embase were searched until August 18, 2017 for studies that evaluated the relationships between PAI-1 levels and disease severity or mortality in sepsis.
RESULTS
A total of 112 and 251 entries were retrieved from the databases, of which 18 studies were included in the final meta-analysis. A total of 4,467 patients (36% male, mean age: 62 years, mean follow-up duration: 36 days) were analyzed. PAI-1 levels were significantly higher in non-survivors than survivors [odds ratios (OR): 3.93, 95% confidence interval (CI): 2.31-6.67, < 0.0001] and in patients with severe sepsis than in those less severe sepsis (OR: 3.26, 95% CI: 1.37-7.75, = 0.008).
CONCLUSION
PAI-1 is a significant predictor of disease severity and all-cause mortality in sepsis. Although the predictive values of PAI-1 reached statistical significance, the clinical utility of PAI-1 in predicting outcomes will require carefully designed prospective trials.
Topics: Biomarkers; Humans; Mortality; Odds Ratio; Plasminogen Activator Inhibitor 1; Prognosis; Sepsis; Severity of Illness Index
PubMed: 29967603
DOI: 10.3389/fimmu.2018.01218 -
World Neurosurgery Dec 2020Decompressive hemicraniectomy (DH) is widely recommended as a surgical treatment for intractable increased intracranial pressure after malignant cerebral infarction....
BACKGROUND
Decompressive hemicraniectomy (DH) is widely recommended as a surgical treatment for intractable increased intracranial pressure after malignant cerebral infarction. Many patients given recombinant tissue plasminogen activator (rtPA) develop cerebral edema after reperfusion or failed recanalization. However, the safety and efficacy of DH after rtPA administration remain largely unknown.
METHODS
A systematic review was performed using PubMed, Embase, Scopus, Cochrane, and HERDIN. Studies were eligible if they included patients who underwent DH after intravenous thrombolysis for acute ischemic stroke. Unweighted odds ratio (OR) for mortality (primary outcome) and good functional outcome defined as modified Rankin Scale score 0-3 or Glasgow Outcome Scale score 4-5 at 3-6 months (secondary outcome) were compared between the DH + rtPA group and DH alone group.
RESULTS
Four studies with a total of 98 patients undergoing DH + rtPA were compared with 110 patients undergoing DH alone without previous thrombolysis. Age, vascular risk factors, and cause of stroke were comparable between the 2 groups. Pooled analysis showed that mortality and functional outcomes were not statistically different between the DH + rtPA and DH alone groups (OR, 0.56, P = 0.07 and OR, 0.83, P = 0.30, respectively). Likewise, both minor and major hemorrhagic rates were similar between the 2 groups (37.76% vs. 27.27%; P = 0.053).
CONCLUSIONS
DH for malignant cerebral infarction after intravenous rtPA administration is a viable treatment option, with a comparable mortality and functional outcome to those who had DH without previous thrombolysis.
Topics: Brain Ischemia; Decompressive Craniectomy; Fibrinolytic Agents; Humans; Ischemic Stroke; Randomized Controlled Trials as Topic; Recombinant Proteins; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome
PubMed: 32822948
DOI: 10.1016/j.wneu.2020.08.088