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Clinical Gastroenterology and... Apr 2022Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring....
BACKGROUND AND AIMS
Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures.
METHODS
We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal).
RESULTS
Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties.
CONCLUSIONS
There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.
Topics: Biomarkers; Cartilage Oligomeric Matrix Protein; Constriction, Pathologic; Crohn Disease; Humans; Intestinal Obstruction; MicroRNAs; Serine Endopeptidases
PubMed: 34089850
DOI: 10.1016/j.cgh.2021.05.054 -
The Cochrane Database of Systematic... Oct 2019Pleural infection, including parapneumonic effusions and thoracic empyema, may complicate lower respiratory tract infections. Standard treatment of these collections in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pleural infection, including parapneumonic effusions and thoracic empyema, may complicate lower respiratory tract infections. Standard treatment of these collections in adults involves antibiotic therapy, effective drainage of infected fluid and surgical intervention if conservative management fails. Intrapleural fibrinolytic agents such as streptokinase and alteplase have been hypothesised to improve fluid drainage in complicated parapneumonic effusions and empyema and therefore improve treatment outcomes and prevent the need for thoracic surgical intervention. Intrapleural fibrinolytic agents have been used in combination with DNase, but this is beyond the scope of this review.
OBJECTIVES
To assess the benefits and harms of adding intrapleural fibrinolytic therapy to standard conservative therapy (intercostal catheter drainage and antibiotic therapy) in the treatment of complicated parapneumonic effusions and empyema.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, ClinicalTrials.gov and the World Health Organization (WHO) trials portal. We contacted trial authors for further information and requested details regarding the possibility of unpublished trials. The most recent search was conducted on 28 August 2019.
SELECTION CRITERIA
Parallel-group randomised controlled trials (RCTs) in adult patients with post-pneumonic empyema or complicated parapneumonic effusions (excluding tuberculous effusions) who had not had prior surgical intervention or trauma comparing an intrapleural fibrinolytic agent (streptokinase, alteplase or urokinase) versus placebo or a comparison of two fibrinolytic agents.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data. We contacted study authors for further information. We used odds ratios (OR) for dichotomous data and reported 95% confidence intervals (CIs). We used Cochrane's standard methodological procedures of meta-analysis. We applied the GRADE approach to summarise results and to assess the overall certainty of evidence.
MAIN RESULTS
We included in this review a total of 12 RCTs. Ten studies assessed fibrinolytic agents versus placebo (993 participants); one study compared streptokinase with urokinase (50 participants); and one compared alteplase versus urokinase (99 participants). The primary outcomes were death, requirement for surgical intervention, overall treatment failure and serious adverse effects. All studies were in the inpatient setting. Outcomes were measured at varying time points from hospital discharge to three months. Seven trials were at low or unclear risk of bias and two at high risk of bias due to inadequate randomisation and inappropriate study design respectively. We found no evidence of difference in overall mortality with fibrinolytic versus placebo (OR 1.16, 95% CI 0.71 to 1.91; 8 studies, 867 participants; I² = 0%; moderate certainty of evidence). We found evidence of a reduction in surgical intervention with fibrinolysis in the same studies (OR 0.37, 95% CI 0.21 to 0.68; 8 studies, 897 participants; I² = 51%; low certainty of evidence); and overall treatment failure (OR 0.16, 95% CI 0.05 to 0.58; 7 studies, 769 participants; I² = 88%; very low certainty of evidence, with evidence of significant heterogeneity). We found no clear evidence of an increase in adverse effects with intrapleural fibrinolysis, although this cannot be excluded (OR 1.28, 95% CI 0.36 to 4.57; low certainty of evidence). In a sensitivity analysis, the reduction in referrals for surgery and overall treatment failure with fibrinolysis disappeared when the analysis was confined to studies at low or unclear risk of bias. In a moderate-risk population (baseline 14% risk of death, 20% risk of surgery, 27% risk of treatment failure), intra-pleural fibrinolysis leads to 19 more deaths (36 fewer to 59 more), 115 fewer surgical interventions (150 fewer to 55 fewer) and 214 fewer overall treatment failures (252 fewer to 93 fewer) per 1000 people. A single study of streptokinase versus urokinase found no clear difference between the treatments for requirement for surgery (OR 1.00, 95% CI 0.13 to 7.72; 50 participants; low-certainty evidence). A single study of alteplase versus urokinase showed no clear difference in requirement for surgery (OR alteplase versus urokinase 0.46, 95% CI 0.04 to 5.24) but an increased rate of adverse effects, primarily bleeding, with alteplase (OR 5.61, 95% CI 1.16 to 27.11; 99 participants; low-certainty evidence). This translated into 154 (6 to 499 more) serious adverse events with alteplase compared with urokinase per 1000 people treated.
AUTHORS' CONCLUSIONS
In patients with complicated infective pleural effusion or empyema, intrapleural fibrinolytic therapy was associated with a reduction in the requirement for surgical intervention and overall treatment failure but with no evidence of change in mortality. Discordance between the negative largest trial of this therapy and other studies is of concern, however, as is an absence of significant effect when analysing low risk of bias trials only. The reasons for this difference are uncertain but may include publication bias. Intrapleural fibrinolytics may increase the rate of serious adverse events, but the evidence is insufficient to confirm or exclude this possibility.
Topics: Anti-Bacterial Agents; Drainage; Empyema, Pleural; Fibrinolytic Agents; Humans; Pleural Effusion; Randomized Controlled Trials as Topic; Streptokinase; Thrombolytic Therapy; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator
PubMed: 31684683
DOI: 10.1002/14651858.CD002312.pub4 -
Medicina (Kaunas, Lithuania) May 2021: The aim of this systematic review is to summarize the current data about the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its entry... (Meta-Analysis)
Meta-Analysis Review
: The aim of this systematic review is to summarize the current data about the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its entry factors in oral tissues and cells. : This systematic review was carried out based on the Preferred Reporting Items for a Systematic Review and Meta-Analysis (PRISMA). Three databases were analyzed (Pubmed, Web of science and Scopus) by three independent researchers. From the 18 identified studies, 10 of them met the inclusion criteria. The presence of SARS-CoV-2 or its entry factors (angiotensin-converting enzyme II (ACE2), transmembrane serine proteases (TMPRSS), and furin) was analyzed in these 10 studies during the pandemic. ACE2 expression was analyzed in 9 of the 10 studies. ACE2 is expressed mainly in the tongue, oral mucosa, salivary glands and epithelial cells. The expression of the TMPRSS2 gene or protein was analyzed in 6 studies. These studies reported that the expression of TMPRSS2 was mainly in the salivary glands, tongue, sulcular epithelium and oral mucosa; as well as in cells of the salivary glands (ductal, acinar and myoepithelial cells) and the tongue (the spinous-based cell layer, horny layer and the epithelial surface). Other TMPRSS were also reported. The expression of TMPRSS3, TMPRSS4, TMPRSS5, TMPRSS7 and TMPRSS11D was reported mainly in salivary glands and in epithelial-type cells. Furan expression was analyzed in three studies. The expression of furin was detected mainly in epithelial cells of the tongue. A variety of methods were used to carry out the detection of SARS-CoV-2 or its input molecules. : These results show that SARS-CoV-2 can infect a wide variety of oral tissues and cells, and that together with the theories dedicated to explaining the oral symptoms present in SARS-CoV-2 positive patients, it provides us with a good scientific basis for understanding the virus infection in the oral cavity and its consequences.
Topics: COVID-19; Furin; Humans; Membrane Proteins; Mouth Mucosa; Neoplasm Proteins; Pandemics; SARS-CoV-2; Serine Endopeptidases
PubMed: 34070998
DOI: 10.3390/medicina57060523 -
Lasers in Medical Science Jun 2023We conducted a meta-analysis to evaluate the efficacy and safety of photo selective vaporisation of the prostate (PVP) with the GreenLight Laser versus transurethral... (Meta-Analysis)
Meta-Analysis Review
A systematic review and meta-analysis of efficacy and safety comparing greenlight laser vaporization with transurethral resection of the prostate for benign prostatic hyperplasia with prostate volume less than 80 ml.
We conducted a meta-analysis to evaluate the efficacy and safety of photo selective vaporisation of the prostate (PVP) with the GreenLight Laser versus transurethral resection of the prostate (TURP) for the treatment of small-volume benign prostatic hyperplasia (BPH). As of July 2022, relevant literature in online databases such as Cochrane Library, PubMed, and Embase was searched, including studies published on or before that date, and there were 9 studies in total, including 5 RCTs and 4 non-RCTs. In total 1525 patients were included to compare the efficacy of PVP and TURP in treating BPH. The Cochrane Collaboration criteria were used to evaluate the risk of bias. The software was used for random effect meta-analysis with RevMan 5.3. Data extraction included: clinical baseline characteristics, perioperative parameters, complication rates, International Prostate Symptom Score (IPSS), prostate specific antigen (PSA), post-void residual urine (PVR), maximum flow rate (Qmax), and quality of life (QoL). The pooled analysis showed that PVP was associated with reduced blood loss, blood transfusion, clot retention, catheterization time, definitive catheter removal, and hospital stay, but was associated with longer operative time and more severe dysuria (all p < 0.05). The results of this meta-analysis show that PVP as a technique for the treatment of benign prostatic hyperplasia with a volume of less than 80 cc has similar efficacy to standard TURP in IPSS, PSA, PVR, Qmax and QoL, and is an effective alternative. It outperformed TURP in terms of blood transfusion, catheterization time and hospital stay, while TURP is superior to PVP in terms of operation time.
Topics: Male; Humans; Prostate; Prostatic Hyperplasia; Transurethral Resection of Prostate; Quality of Life; Prostate-Specific Antigen; Treatment Outcome; Laser Therapy; Urinary Retention
PubMed: 37289405
DOI: 10.1007/s10103-023-03794-2 -
European Journal of Medical Research Feb 2022To determine the effect of polymorphisms and mutations in angiotensin-converting enzyme 2 (ACE2) and Type 2 transmembrane serine proteases (TMPRSS2) genes on...
OBJECTIVE
To determine the effect of polymorphisms and mutations in angiotensin-converting enzyme 2 (ACE2) and Type 2 transmembrane serine proteases (TMPRSS2) genes on susceptibility to corona virus disease 2019 (COVID-19) and patient prognosis.
INTRODUCTION
From December 2019 to the current time, an outbreak of epidemic of COVID-19, characterized by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has occurred around the world. It is now clear that SARS-CoV-2 binds to human ACE2 receptors, with expression of these receptors correlated with the rate of SARS-CoV-2 infection and mortality. Polymorphisms in individual patient factors, such as ACE2 and TMPRSS2 genes have been linked with an increase in negative outcomes, although evidence to affirm remains debatable.
METHODS
Here, we performed a systematic review, based on guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, with the aim of assessing whether polymorphisms in ACE2 and TMPRSS2 genes affect the COVID-19 condition. We extensively searched PubMed, MEDLINE, Embase, the Cochrane Library, and Web of Science databases, for relevant articles and reports published in English between December 2019 and December 2021.
RESULTS
A total of 495 full-text articles were downloaded, of which 185 were excluded after preliminary examination as they were duplicates. Finally, 310 articles were evaluated, by reading their titles and abstracts, and 208 of them eliminated based on our selection criteria. Finally, 33 articles met our inclusion criteria and were included in the final assessment. Genetic data from 33,923 patients with COVID-19 drawn from the general population and deriving from over 160 regions and 50 countries, as well as approximately 560,000 samples from global-public genetic databases, were included in our analysis. Ultimately, we identified 10 SNPs and 21 mutations in the ACE2 gene, along with 13 SNPs and 12 variants in the TMPRSS2 gene, which may be associated with COVID-19.
CONCLUSIONS
ACE2 and TMPRSS2 play vital roles in the onset, development, and prognosis of SARS-CoV-2 infection, and have both been strongly associated with vulnerability, intensity, and the clinical result of COVID-19. Overall, these genetic factors may have potential for future development of personalized drugs and vaccines against COVID-19.
TRIAL REGISTRATION
CRD42021239400 in PROSPERO 2021.
Topics: Angiotensin-Converting Enzyme 2; COVID-19; Genetic Predisposition to Disease; Humans; Mutation; Polymorphism, Single Nucleotide; SARS-CoV-2; Serine Endopeptidases
PubMed: 35193695
DOI: 10.1186/s40001-022-00647-6 -
Complementary Therapies in Medicine Mar 2022Prostate cancer is a major malignancy, affecting men, worldwide. The protective effect of dietary or supplemental lycopene on prostate cancer has been reported in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Prostate cancer is a major malignancy, affecting men, worldwide. The protective effect of dietary or supplemental lycopene on prostate cancer has been reported in several studies; however, the findings are equivocal.
OBJECTIVE
The aim of this study was to evaluate the effects of supplemental lycopene on PSA level, by conducting a systematic review and meta-analysis of randomized controlled trials.
METHODS
We searched online databases, including PubMed, Scopus, and Web of Science, up to 9 Jun 2020, to obtain relevant publications. The publication search was not limited by language or date.
RESULTS
A total of 1036 records were identified in the systematic search; from these, 9 were included in the systematic review and 6 in meta-analysis. The pooled analysis of the 6 studies showed no significant differences in PSA levels in subjects treated with lycopene or tomato extract containing lycopene (WMD= -0.12 ng/ml; 95% CI: -0.62, 0.38 ng/ml; P = 0.64) compared to the control.
CONCLUSION
Overall, tomato extracts or lycopene treatment yielded no significant effect on PSA level compared to the control. However, more consistent clinical trials, with larger sample sizes, are required to better discern the actual effect of tomato extract or lycopene on PSA level.
Topics: Carotenoids; Humans; Lycopene; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 35031434
DOI: 10.1016/j.ctim.2022.102801 -
Immunity, Inflammation and Disease Aug 2023Lactoferrin is a versatile protein with important modulatory functions in inflammation and immune response. This glycoprotein can bind and sequester iron and LPS,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Lactoferrin is a versatile protein with important modulatory functions in inflammation and immune response. This glycoprotein can bind and sequester iron and LPS, thereby intervening in certain signaling pathways and biological processes. In the present meta-analysis, we aimed to pool experimental data regarding the immunomodulatory effects of lactoferrin and its derived peptides on the NF-κB signaling pathway.
MATERIALS
We searched PubMed, Google Scholar, and Web of Science databases and obtained all related articles published before April 2022. Finally, 25 eligible studies were selected, and their reports were analyzed.
METHODS
We used Review Manager Version 5.2 to compute the standardized mean difference (SMD) and its 95% confidence interval. In addition, the source of heterogeneity was explored using meta-regression and sensitivity analysis. The symmetry of the funnel plot and Egger's test were also used to evaluate publication bias utilizing Comprehensive Meta-Analysis Version 2.
RESULTS
Comparing the group of cells and animals exposed to lipopolysaccharide alone with the group that received pretreatment with lactoferrin and its derivatives, we observed significant reductions in TNF-α, IL-1 beta, and IL-6 levels by 8.73 pg/mL, 2.21 pg/mL, and 3.24 pg/mL, respectively, in the second group. Additionally, IKK-β, p-IκB, and NF-κB (p65) levels were significantly lower by 7.37-fold, 15.02-fold, and 3.88-fold, respectively, in various cells and tissues.
CONCLUSION
Based on the results of this meta-analysis, lactoferrin and its derived peptides can be considered potent prophylactic and therapeutic candidates against inflammation-associated diseases by targeting the NF-kB pathway.
Topics: Animals; NF-kappa B; Lactoferrin; Signal Transduction; Peptides; Inflammation; Lipopolysaccharides; Immunity
PubMed: 37647433
DOI: 10.1002/iid3.972 -
Pediatric Nephrology (Berlin, Germany) Jul 2022Observing biomarkers that affect alternative pathway dysregulation components may be effective in obtaining a new and more rapid diagnostic portrayal of atypical... (Review)
Review
BACKGROUND AND OBJECTIVES
Observing biomarkers that affect alternative pathway dysregulation components may be effective in obtaining a new and more rapid diagnostic portrayal of atypical hemolytic uremic syndrome. We have conducted a systematic review on the aHUS biomarkers: C3, C5a, C5b-9, factor B, complement factor B, H, and I, CH50, AH50, D-dimer, as well as anti-CFH antibodies.
METHODS
An exhaustive literature search was conducted for aHUS patient population plasma/serum, collected/reported at the onset of diagnosis. A total of 60 studies were included with the data on 837 aHUS subjects, with at least one biomarker reported.
RESULTS
The biomarkers C3 [mean (SD): 72.1 (35.0), median: 70.5 vs. reference range: 75-175 mg/dl, n = 752]; CH50 [28.3 (32.1), 24.3 vs. 30-75 U/ml, n = 63]; AH50 [27.6% (30.2%), 10% vs. ≥ 46%, n = 23]; and CFB [13.1 (6.6), 12.4, vs. 15.2-42.3 mg/dl, n = 19] were lower among aHUS subjects as compared with the reference range. The biomarkers including C4 [mean (SD): 20.4 (9.5), median: 20.5 vs. reference range: 14-40 mg/dl, n = 343]; C4d [7.2 (6.5), 4.8 vs. ≤ 9.8 μg/ml, n = 108]; CFH [40.2 (132.3), 24.5 vs. 23.6-43.1 mg/dl, n = 123 subjects]; and CFI [8.05 (5.01), 6.55 mg/dl vs. 4.4-18.1 mg/dl, n = 38] were all observed to be within the reference range among aHUS subjects. The biomarkers C5a [mean (SD): 54.9 (32.9), median: 48.8 vs. reference range: 10.6-26.3 mg/dl, n = 117]; C5b-9 [466.0 (401.4), 317 (186-569.7) vs. ≤ 250 ng/ml, n = 174]; Bb [2.6 (2.1), 1.9 vs. ≤ 1.6 μg/ml, n = 77] and D-dimer [246 (65.05), 246 vs. < 2.2 ng/ml, 2, n = 2 subjects] were higher among patients with aHUS compared with the reference range.
CONCLUSION
If a comprehensive complement profile were built using our data, aHUS would be identified by low levels of C3, CH50, AH50, and CFB along with increased levels of C5a, C5b-9, Bb, anti-CFH autoantibodies, and D-dimer. A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Atypical Hemolytic Uremic Syndrome; Autoantibodies; Biomarkers; Complement Factor B; Complement Factor H; Complement Membrane Attack Complex; Humans
PubMed: 35118546
DOI: 10.1007/s00467-022-05451-2 -
European Journal of Gastroenterology &... Nov 2023Restorative proctocolectomy (RPC) is the most common surgical procedure to restore gastrointestinal continuity after surgical resection of the colon and rectum.... (Meta-Analysis)
Meta-Analysis
Restorative proctocolectomy (RPC) is the most common surgical procedure to restore gastrointestinal continuity after surgical resection of the colon and rectum. Pouchitis is a common complication with several different modalities that can be used to aid diagnosis. This systematic review and meta-analysis aimed at exploring the sensitivity and specificity these diagnostic modalities. The medical literature was searched using MEDLINE, EMBASE and EMBASE classic and PubMed from 1978 to June 2022. We calculated descriptive statistics using sensitivity, specificity, and false-positive rate of the primary studies and also their positive and negative likelihood ratios, and their diagnostic odds ratios. The screen found 5477 records with 13 studies being included. Faecal lactoferrin was found to have the highest pooled sensitivity and specificity of 98% and 88% respectively with imaging modalities coming in second and faecal calprotectin third with pooled sensitivities and specificities of 87% and 79% and 74% and 81% respectively. Faecal biomarkers particularly lactoferrin and imaging modalities may have an important role to play in diagnosing pouchitis. Importantly due to delays in availability of pouchoscopy, our data supports early ordering of these tests to help delineate from other causes. Further studies are required with larger cohort sizes to further validate these tests.
Topics: Humans; Pouchitis; Lactoferrin; Proctocolectomy, Restorative; Sensitivity and Specificity; Feces
PubMed: 37695613
DOI: 10.1097/MEG.0000000000002638 -
Clinical Neurology and Neurosurgery Oct 2023Alteplase is the standard medical therapy for acute ischemic stroke (AIS) patients who present within 4.5 h of symptom onset. Tenecteplase is a modified alteplase... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Alteplase is the standard medical therapy for acute ischemic stroke (AIS) patients who present within 4.5 h of symptom onset. Tenecteplase is a modified alteplase variant with pharmacological and practical advantages over alteplase. Many trials have investigated the efficacy and safety of tenecteplase against alteplase. This systematic review and meta-analysis aimed to compare the efficacy and safety of tenecteplase to alteplase across randomized controlled trials.
METHOD
Medline, Embase, and Cochrane CENTRAL were used to search the related articles until February 20, 2023. Randomized controlled trials (RCTs) that compared the effectiveness and safety of tenecteplase against alteplase for AIS patients were included. Screening, risk of bias assessment, and data extraction were performed following PRISMA guidelines. Data were pooled using a random-effect model.
RESULTS
Ten RCTs were included, with a total of 5123 patients. There was no significant difference between the two interventions in modified rankin scale 0-1 (mRS 0-1) (RR= 1.04, 95% CI [0.99-1.10], P = 0.11, I =0%) and early neurological improvement (RR= 1.06, 95% CI [0.97-1.15], P = 0.21, I =35). There was no difference in the rates of symptomatic intracranial hemorrhage (RR= 1.18, 95% CI [0.84-1.65], P = 0.35, I = 0%). Tenecteplase was associated with significantly higher complete recanalization rate compared to alteplase (RR= 1.17, 95% CI [1.00-1.36], P = 0.05, I =0%). For large vessel occlusion (LVO) patients assigned to tenecteplase, there was a significant improvement in mRS 0-1 (RR= 1.28, 95% CI [1.07-1.52], P = 0.006, I =0%).
CONCLUSION
Based on our meta-analysis, tenecteplase has similar efficacy and safety to alteplase, with a more promising effect in patients with LVO.
Topics: Humans; Tissue Plasminogen Activator; Tenecteplase; Fibrinolytic Agents; Stroke; Brain Ischemia; Randomized Controlled Trials as Topic; Ischemic Stroke; Treatment Outcome
PubMed: 37713743
DOI: 10.1016/j.clineuro.2023.107961