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Critical Care (London, England) May 2020Heterogeneity of acute respiratory distress syndrome (ARDS) could be reduced by identification of biomarker-based phenotypes. The set of ARDS biomarkers to prospectively...
BACKGROUND
Heterogeneity of acute respiratory distress syndrome (ARDS) could be reduced by identification of biomarker-based phenotypes. The set of ARDS biomarkers to prospectively define these phenotypes remains to be established.
OBJECTIVE
To provide an overview of the biomarkers that were multivariately associated with ARDS development or mortality.
DATA SOURCES
We performed a systematic search in Embase, MEDLINE, Web of Science, Cochrane CENTRAL, and Google Scholar from inception until 6 March 2020.
STUDY SELECTION
Studies assessing biomarkers for ARDS development in critically ill patients at risk for ARDS and mortality due to ARDS adjusted in multivariate analyses were included.
DATA EXTRACTION AND SYNTHESIS
We included 35 studies for ARDS development (10,667 patients at risk for ARDS) and 53 for ARDS mortality (15,344 patients with ARDS). These studies were too heterogeneous to be used in a meta-analysis, as time until outcome and the variables used in the multivariate analyses varied widely between studies. After qualitative inspection, high plasma levels of angiopoeitin-2 and receptor for advanced glycation end products (RAGE) were associated with an increased risk of ARDS development. None of the biomarkers (plasma angiopoeitin-2, C-reactive protein, interleukin-8, RAGE, surfactant protein D, and Von Willebrand factor) was clearly associated with mortality.
CONCLUSIONS
Biomarker data reporting and variables used in multivariate analyses differed greatly between studies. Angiopoeitin-2 and RAGE in plasma were positively associated with increased risk of ARDS development. None of the biomarkers independently predicted mortality. Therefore, we suggested to structurally investigate a combination of biomarkers and clinical parameters in order to find more homogeneous ARDS phenotypes.
PROSPERO IDENTIFIER
PROSPERO, CRD42017078957.
Topics: Angiopoietin-2; Antigens, Neoplasm; Biomarkers; Humans; Mitogen-Activated Protein Kinases; Multivariate Analysis; Respiratory Distress Syndrome
PubMed: 32448370
DOI: 10.1186/s13054-020-02913-7 -
Therapeutic Advances in Respiratory... 2020Angiopoietin-2 (Ang-2), as one of the ligands of endothelial receptor Tie2, is known to be significant for vessel maturation and stabilization after birth. Previous... (Meta-Analysis)
Meta-Analysis
Circulating angiopoietin-2 and the risk of mortality in patients with acute respiratory distress syndrome: a systematic review and meta-analysis of 10 prospective cohort studies.
BACKGROUND
Angiopoietin-2 (Ang-2), as one of the ligands of endothelial receptor Tie2, is known to be significant for vessel maturation and stabilization after birth. Previous studies showed the relationship between Ang-2 level and the risk of mortality in patients with acute respiratory distress syndrome (ARDS). However, the link between circulating Ang-2 and the risk of mortality in patients with ARDS varied in different investigations.
RESULTS
We performed a systematic review and meta-analysis of all available cohort studies regarding the association between baseline circulating Ang-2 and mortality in patients with ARDS. Among the 10 eligible studies, pooled odds ratio (OR) showed that high Ang-2 level contributed to ARDS mortality [OR = 1.56, 95% confidence interval (CI): 1.30-1.89, = 76.2%]. Stratified analysis revealed that higher circulating Ang-2 was related to a 30% higher risk in the high-quality scores group (OR = 1.68, 95% CI: 1.33-2.68, = 62.4%). The of the bad compliance group decreased from 76.2% to 8.5%, which suggested that compliance is a significant source of heterogeneity. This association may be blunted by potential bias, although the results was not meaningfully changed by omitting only one study at a time. Further subgroup analysis and meta-regression support that compliance of patients also affects the results significantly, compared with the publication year, follow-up duration, the samples, or population characteristics.
CONCLUSION
Participants with higher baseline Ang-2 were at a higher risk for future risk of mortality in patients with ARDS. Higher circulating Ang-2 levels could independently predict the risk of mortality in patients with ARDS. However, further large scale prospective cohorts or even interventional studies are warranted to evaluate the diagnostic power of Ang-2 and its causative role on ARDS outcome.
Topics: Adolescent; Adult; Angiopoietin-2; Biomarkers; Child; Child, Preschool; Female; Humans; Infant; Male; Middle Aged; Predictive Value of Tests; Prognosis; Respiratory Distress Syndrome; Risk Assessment; Risk Factors; Up-Regulation; Young Adult
PubMed: 32043429
DOI: 10.1177/1753466620905274 -
Disease Markers 2019In this study, we evaluated the relationship between circulating betatrophin levels and obesity. Obesity is a common public health problem that is increasing globally.... (Meta-Analysis)
Meta-Analysis
In this study, we evaluated the relationship between circulating betatrophin levels and obesity. Obesity is a common public health problem that is increasing globally. Betatrophin, a newly identified protein, is predominantly expressed in white and brown fat tissues and in the liver. Growing evidence suggests that betatrophin plays a pivotal role in metabolism, including the synthesis and degradation of lipids in cells, and adipocyte differentiation. Previous studies have assessed the association between circulating betatrophin levels and obesity; however, this relationship remains unclear. Therefore, our study is aimed at examining the impact of betatrophin on obesity using a meta-analysis of the current evidence. We performed a meta-analysis to quantify the relationship between betatrophin levels and obesity. A literature search was conducted through the EMBASE, Web of Science, and MEDLINE databases. Retrieved studies were screened, without any language restrictions to identify relevant literature published up to December 2018. Observational studies, in which the association between circulating concentrations of betatrophin and obesity was evaluated, were considered suitable for the systematic review. Of the 65 manuscripts retrieved, 9 datasets from 6 studies, involving 681 participants, detected an association between circulating betatrophin and obesity. Circulating betatrophin levels of obese subjects were higher than those of nonobese subjects (random - effects weighted mean difference (WMD) = 0.250 g/mL, 95% CI: 0.048-0.451, = 94.8%, = 0.015), yet with significant between-study heterogeneity. This heterogeneity appeared to be modified by glycemic status but not by age, the ELISA kits used, sample source, or body mass index. The high circulating betatrophin concentration may directly increase the risk of obesity in adults. Betatrophin may serve as a therapeutic target for obesity in adults.
Topics: Angiopoietin-Like Protein 8; Angiopoietin-like Proteins; Humans; Obesity; Peptide Hormones
PubMed: 31772689
DOI: 10.1155/2019/5096860 -
Annals of Intensive Care Nov 2019Angiopoietin-1 (Ang-1) and 2 (Ang-2), high mobility group box 1 (HMGB1), soluble receptor for advanced glycation endproducts (sRAGE), soluble triggering receptor...
BACKGROUND
Angiopoietin-1 (Ang-1) and 2 (Ang-2), high mobility group box 1 (HMGB1), soluble receptor for advanced glycation endproducts (sRAGE), soluble triggering receptor expressed on myeloid cells 1 (sTREM1), and soluble urokinase-type plasminogen activator receptor (suPAR) have shown promising results for predicting all-cause mortality in critical care patients. The aim of our systematic review and meta-analysis was to assess the prognostic value of these biomarkers for mortality in adult patients with sepsis.
METHODS
A systematic literature search of the MEDLINE, PubMed, EMBASE, and Cochrane Library databases, for articles in English published from 01.01.1990 onwards, was conducted. The systematic review focused exclusively on observational studies of adult patients with sepsis, any randomized trials were excluded. For the meta-analysis, only studies which provide biomarker concentrations within 24 h of admission in sepsis survivors and nonsurvivors were included. Results are presented as pooled mean differences (MD) between nonsurvivors and survivors with 95% confidence interval for each of the six biomarkers. Studies not included in the quantitative analysis were narratively summarized. The risk of bias was assessed in all included studies using the Quality in Prognosis Studies (QUIPS) tool.
RESULTS
The systematic literature search retrieved 2285 articles. In total, we included 44 studies in the qualitative analysis, of which 28 were included in the meta-analysis. The pooled mean differences in biomarker concentration (nonsurvivors - survivors), measured at onset of sepsis, are listed as follows: (1) Ang-1: - 2.9 ng/ml (95% CI - 4.1 to - 1.7, p < 0.01); (2) Ang-2: 4.9 ng/ml (95% CI 2.6 to 7.1, p < 0.01); (3) HMGB1: 1.2 ng/ml (95% CI 0.0 to 2.4, p = 0.05); (4) sRAGE: 1003 pg/ml (95% CI 628 to 1377, p < 0.01); (5) sTREM-1: 87 pg/ml (95% CI 2 to 171, p = 0.04); (6) suPAR: 5.2 ng/ml (95% CI 4.5 to 6.0, p < 0.01).
CONCLUSIONS
Ang-1, Ang-2, and suPAR provide beneficial prognostic information about mortality in adult patients with sepsis. The further development of standardized assays and the assessment of their performance when included in panels with other biomarkers may be recommended. Trial registration This study was recorded on PROSPERO, prospective register of systematic reviews, under the registration ID: CRD42018081226.
PubMed: 31705327
DOI: 10.1186/s13613-019-0600-1 -
Journal of Vitreoretinal Diseases 2020Evidence suggests that inflammatory cytokines not only play a role in the pathogenesis of retinal vein occlusion (RVO) but also may be useful as biomarkers to predict... (Review)
Review
PURPOSE
Evidence suggests that inflammatory cytokines not only play a role in the pathogenesis of retinal vein occlusion (RVO) but also may be useful as biomarkers to predict disease severity and response to treatment. We aimed to quantitatively summarize data on inflammatory cytokines associated with RVO.
METHODS
A systematic search of peer-reviewed English-language articles was performed without year limitation up to August 19, 2019. Studies were included if they provided data on aqueous or vitreous cytokine concentrations in patients with RVO. Data were extracted from 116 studies that encompassed 3242 study eyes with RVO and 1402 control eyes. Effect sizes were generated as standardized mean differences (SMDs) of cytokine concentrations between patients with RVO vs controls.
RESULTS
Among the 4644 eyes in 116 studies, aqueous and vitreous concentrations (SMD, 95% CI, and value) of interleukin (IL)-6 (aqueous: 1.23, 0.65 to 1.81, .001 vitreous: 0.70, 0.49 to 0.90, .001), IL-8 (aqueous: 1.11, 0.73 to 1.49, .001; vitreous: 1.19, 0.73 to 1.65, .001), monocyte chemoattractant protein 1(aqueous: 1.22, 0.72 to 1.72, .001; vitreous 1.42, 0.92 to 1.91, .001), vascular endothelial growth factor (VEGF) (aqueous: 1.52, 1.09 to 1.94, .001; vitreous: 0.99, 0.78 to 1.21, .001) were significantly higher in patients with RVO than in healthy controls. Only aqueous concentrations of IL-10 (0.81, 0.45 to 1.18, .001), angiopoietin 4 (1.96, 0.92 to 3.00, .001), and platelet-derived growth factor (PDGF)-AA (0.82, 0.35 to 1.30, .001) were significantly higher in patients with RVO than in healthy controls. Only the vitreous concentration of soluble intercellular adhesion molecule-1 (sICAM-1) (1.23, 0.83 to 1.63, .001) was significantly higher in patients with RVO. No differences, failed sensitivity analyses, or insufficient data were found between patients with RVO and healthy controls for the concentrations of the remaining cytokines.
CONCLUSIONS
Several cytokines in addition to VEGF have the potential to be useful biomarkers and therapeutic targets in RVO.
PubMed: 37009560
DOI: 10.1177/2474126419880391 -
Journal of Cerebral Blood Flow and... Dec 2019Clinical studies report that low circulating angiopoietin-1 concentration at presentation predicts worse outcomes after ischaemic stroke. Upregulating angiopoietin-1 may... (Meta-Analysis)
Meta-Analysis
Clinical studies report that low circulating angiopoietin-1 concentration at presentation predicts worse outcomes after ischaemic stroke. Upregulating angiopoietin-1 may therefore have therapeutic benefit for ischaemic stroke. This systematic review assessed whether upregulating angiopoietin-1 improved outcomes in rodent models of ischaemic stroke. Random-effects models quantified the effect of angiopoietin-1 upregulation on stroke severity in terms of the size of cerebral infarction and the extent of blood-brain barrier permeability. Eleven studies utilising rat and mouse models of ischaemic stroke fulfilled the inclusion criteria. Meta-analyses demonstrated that angiopoietin-1 upregulation significantly reduced cerebral infarction size (standardised mean difference: -3.02; 95% confidence intervals: -4.41, -1.63; < 0.001; = 171 animals) and improved blood-brain barrier integrity (standardized mean difference: -2.02; 95% confidence intervals: -3.27, -0.77; = 0.002; = 129 animals). Subgroup analyses demonstrated that angiopoietin-1 upregulation improved outcomes in models of transient, not permanent cerebral ischaemia. Six studies assessed the effect of angiopoietin-1 upregulation on neurological function; however, inter-study heterogeneity prevented meta-analysis. In conclusion, published rodent data suggest that angiopoietin-1 upregulation improves outcome following temporary cerebral ischaemia by reducing cerebral infarction size and improving blood-brain barrier integrity. Additional research is required to examine the effect of angiopoietin-1 upregulation on neurological function during stroke recovery and investigate the benefit and risks in patients.
Topics: Angiopoietin-1; Animals; Blood-Brain Barrier; Cerebral Infarction; Disease Models, Animal; Humans; Mice; Rats; Stroke; Up-Regulation
PubMed: 31581897
DOI: 10.1177/0271678X19876876 -
World Journal of Orthopedics Apr 2019Over 400000 Americans annually undergo spinal fusion surgeries, yet up to 40% of these procedures result in pseudoarthrosis even with iliac crest autograft, the current...
BACKGROUND
Over 400000 Americans annually undergo spinal fusion surgeries, yet up to 40% of these procedures result in pseudoarthrosis even with iliac crest autograft, the current "gold standard" treatment. Tissue engineering has the potential to solve this problem the creation of bone grafts involving bone-promoting growth factors (., bone morphogenetic protein 2). A broad assessment of experimental growth factors is important to inform future work and clinical potential in this area. To date, however, no study has systematically reviewed the investigational growth factors utilized in preclinical animal models of spinal fusion.
AIM
To review all published studies assessing investigational growth factors for spinal fusion in animal models and identify promising agents for translation.
METHODS
We conducted a systematic review of the literature using PubMed, Embase, Cochrane Library, and Web of Science databases with searches run on May 29, 2018. The search query was designed to include all non-human, preclinical animal models of spinal fusion reported in the literature without a timespan limit. Extracted data for each model included surgical approach, level of fusion, animal species and breed, animal age and sex, and any other relevant characteristics. The dosages/sizes of all implant materials, spinal fusion rates, and follow-up time points were recorded. The data were analyzed and the results reported in tables and text. PRISMA guidelines were followed for this systematic review.
RESULTS
Twenty-six articles were included in this study, comprising 14 experimental growth factors: AB204 ( = 1); angiopoietin 1 ( = 1); calcitonin ( = 3); erythropoietin ( = 1); basic fibroblast growth factor ( = 1); growth differentiation factor 5 ( = 4), combined insulin-like growth factor 1 + transforming growth factor beta ( = 4); insulin ( = 1); NELL-1 ( = 5); noggin ( = 1); P-15 ( = 1); peptide B2A ( = 2); and secreted phosphoprotein 24 ( = 1). The fusion rates of the current gold standard treatment (autologous iliac crest bone graft, ICBG) and the leading clinically used growth factor (BMP-2) ranged widely in the included studies, from 0-100% for ICBG and from 13%-100% for BMP-2. Among the identified growth factors, calcitonin, GDF-5, NELL-1, and P-15 resulted in fusion rates of 100% in some cases. In addition, six growth factors - AB204, angiopoietin 1, GDF-5, insulin, NELL-1, and peptide B2A - resulted in significantly enhanced fusion rates compared to ICBG, BMP-2, or other internal control in some studies. Large heterogeneity in animal species, fusion method, and experimental groups and time points was observed across the included studies, limiting the direct comparison of the growth factors identified herein.
CONCLUSION
Several promising investigational growth factors for spinal fusion have been identified herein; directly comparing the fusion efficacy and safety of these agents may inform clinical translation.
PubMed: 31041160
DOI: 10.5312/wjo.v10.i4.176 -
Medicine Sep 2017Angiogenesis is an essential process in the development and progression of malignant tumors including lung cancer, in which angiopoietin-2 (Ang-2) plays an important... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Angiogenesis is an essential process in the development and progression of malignant tumors including lung cancer, in which angiopoietin-2 (Ang-2) plays an important role. The objective of this study was to assess the prognostic value of serum Ang-2 levels in patients with lung cancer.
METHODS
A comprehensive systematic electronic search was performed in the Pubmed, Embase, Web of Science, china national knowledge infrastructure, and VIP databases update to October, 2016 (qikan.cqvip.com). Literatures examining the relevance of serum Ang-2 levels to progression and prognosis of lung cancer were eligible for our study. Standardized mean differences (SMD) with 95% confidence interval (95% CI) and a P value were applied to compare continuous variables, and hazard ratio (HR) with 95% CI as well as P value were applied for prognostic role.
RESULTS
Twenty studies with 1911 patients met the eligibility criteria. Among them, 7 studies with 575 patients with lung cancer assessed the association between expression of serum Ang-2 and prognosis. According to our results, higher levels of serum Ang-2 were associated with the later stage of tumor. Serum Ang-2 levels were significantly lower in stage I than in stage II (SMD: -0.51; 95% CI: -0.75 to -0.27; P < .001), in stage II than in stage III (SMD: -0.52; 95% CI: -0.80 to -0.24; P < .001), in stage III than in stage IV (SMD: -0.58; 95% CI: -0.93 to -0.23; P = .001). In addition, serum Ang-2 levels were higher in patients with lymph node metastasis (SMD: 1.06; 95% CI, 0.57-1.56; P < .001). Meanwhile, patients with lung cancer with higher levels of serum Ang-2 were associated with a significant poorer prognosis when compared to those with lower serum Ang-2 levels (HR: 1.64; 95% CI: 1.20-2.25; P = .002), and this role was further detected when stratified by ethnicity and histological type.
CONCLUSIONS
This systematic review and meta-analysis suggested that serum Ang-2 levels might be a potential predictor for staging, and were associated with prognosis of lung cancer.
Topics: Angiopoietin-2; Biomarkers, Tumor; Disease Progression; Humans; Lung Neoplasms; Prognosis
PubMed: 28906403
DOI: 10.1097/MD.0000000000008063 -
PloS One 2017The association between circulating betatrophin levels and gestational diabetes mellitus (GDM) is controversial. The aim of our study was to systematically review... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The association between circulating betatrophin levels and gestational diabetes mellitus (GDM) is controversial. The aim of our study was to systematically review available literature linking betatrophin to GDM for a comprehensive understanding of the relationship between circulating betatrophin levels and GDM in human.
METHODS
PubMed, The Cochrane Library, Medline and CNKI were searched for studies published up to August 2016. Manual searches of references of the relevant original studies were conducted. Pooled estimates were measured using the fixed or random effect model. Overall effect was reported in a standard mean difference (SMD). All data were analyzed with Review Manager 5.3 and Stata 12.0.
RESULTS
Of 25 references reviewed, 8 studies met our inclusion criteria and contributed to meta-analysis. All the studies were used to evaluate the relationship between betatrophin levels in blood and GDM. Betatrophin levels were significantly elevated in women with GDM compared with those without GDM (SMD = 1.05; 95% CI: 0.41-1.68, P = 0.001). This evidence was more consistent among women with betatrophin blood draw during the third trimester (SMD = 1.3, 95% CI: 1-1.61, P < 0.001) and for women BMI ≥ 28 kg/m2 (SMD = 1.53, 95% CI: 1.30-1.75, P < 0.001).
CONCLUSIONS
The evidences from this meta-analysis indicated that the levels of circulating betatrophin were significantly elevated among women with GDM compared with women with normal glucose tolerance, especially with BMI ≥ 28 kg/m2 and in the third trimester.
Topics: Angiopoietin-Like Protein 8; Angiopoietin-like Proteins; Body Mass Index; Databases, Factual; Diabetes, Gestational; Female; Humans; Peptide Hormones; Pregnancy; Pregnancy Trimester, Third; Risk Factors
PubMed: 28081192
DOI: 10.1371/journal.pone.0169941 -
Malaria Journal Dec 2016Levels of both angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) correlate with malaria disease severity and are proposed as biomarkers and possible therapeutic targets.... (Review)
Review
BACKGROUND
Levels of both angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) correlate with malaria disease severity and are proposed as biomarkers and possible therapeutic targets. To establish their role in malaria, a systematic review was performed of the literature on Ang-1 and Ang-2 with regard to their potential as biomarkers in malaria and discuss their possible place in adjuvant treatment regimens.
METHODS
Ten electronic databases were systematically searched to identify studies investigating Ang-1 and Ang-2 in human and murine malaria in both clinical and experimental settings. Information about the predictive value of Ang-1 and Ang-2 for disease severity and their regulatory changes in interventional studies were extracted.
RESULTS
Some 579 studies were screened; 26 were included for analysis. In all five studies that determined Ang-1 levels and in all 11 studies that determined Ang-2 in different disease severity states in falciparum malaria, a decline in Ang-1 and an increase of Ang-2 levels was associated with increasing disease severity. All nine studies that determined angiopoietin levels in Plasmodium falciparum patients to study their ability as biomarkers could distinguish between multiple disease severity states; the more the disease severity states differed, the better they could be distinguished. Five studies differentiating malaria survivors from non-survivors with Ang-2 as marker found an AUROC in a range of 0.71-0.83, which performed as well or better than lactate. Prophylactic administration of FTY720, rosiglitazone or inhalation of nitric oxide (NO) during malaria disease in mice resulted in an increase in Ang-1, a decrease in Ang-2 and an increased survival. For rosiglitazone, a decrease in Ang-2/Ang-1 ratio was observed after post-infection treatment in mice and humans with malaria, but for inhalation of NO, an effect on Ang-1 and survival was only observed in mice.
CONCLUSION
Both Ang-1 and Ang-2 levels correlate with and can distinguish between malaria disease severity states within the group of malaria-infected patients. However, distinct comparisons of disease severity states were made in distinct studies and not all distinctions made had clinical relevance. Changes in levels of Ang-1 and Ang-2 might also reflect treatment effectiveness and are promising therapeutic targets as part of multi-targeted therapy.
Topics: Angiopoietin-1; Angiopoietin-2; Animals; Biomarkers; Disease Models, Animal; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Malaria, Falciparum; Mice; Predictive Value of Tests; ROC Curve; Survival Analysis; Treatment Outcome
PubMed: 27905921
DOI: 10.1186/s12936-016-1624-8