50 Shades of 'Groundhog Day'.

Introduction: The 2017 European Society for Vascular Surgery (ESVS) guidelines on carotid and vertebral artery disease concluded that the evidence did not support a role for carotid endarterectomy (CEA) or carotid artery stenting (CAS) in patients with asymptomatic carotid stenosis (ACS) in preventing cognitive impairment or dementia. What new data have emerged since 2017, and have they influenced the 2023 ESVS guidelines? Report: In a systematic review, 33/35 studies (94%) reported a "significant association" between ACS and cognitive impairment; 20 studies had 1-3 tests with significant cognitive impairment; 10 reported 4-6 tests with cognitive impairment; and three studies reported ≥7 tests with significant cognitive impairment. Baseline data from 1 000 patients with ACS in the second Carotid Revascularisation Endarterectomy versus Stenting Trial (CREST-2) reported that the overall Z score for cognition in patients with ACS was significantly lower than expected, especially for word list recall and word list learning. Another systematic review reported that (in the long term) 69% of patients with ACS undergoing CEA/CAS had no change in cognitive function. However, in another 25%, cognitive scores/domains were mostly unchanged, but 1-2 individual tests were significantly improved. In addition, 1 601 UK and Swedish patients with ACS were randomised in the first Asymptomatic Carotid Surgery Trial (ACST-1) to CEA or best medical therapy (BMT). There was no difference in 10 year rates of dementia (CEA 6.7% vs. 6.6% with BMT) or at 20 years (14.3% [CEA] vs. 15.5% [BMT]), suggesting that CEA did not prevent dementia vs. BMT (hazard ratio 0.98, 95% confidence interval 0.75-1.28; p = .89). Discussion: ACS is associated with significant cognitive impairment, but whether this supports a direct aetiological role, or a marker for something else, remains unknown. There is no evidence that CEA/CAS prevents late dementia. The 2023 ESVS guidelines have not changed its recommendation compared with the 2017 version.

Platelet Biomarkers in Patients with Atherosclerotic Extracranial Carotid Artery Stenosis: A Systematic Review.

OBJECTIVE: The aim was to enhance understanding of the role of platelet biomarkers in the pathogenesis of vascular events and risk stratifying patients with asymptomatic or symptomatic atherosclerotic carotid stenosis. DATA SOURCES: Systematic review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. REVIEW METHODS: A systematic review collated data from 1975 to 2020 on ex vivo platelet activation and platelet function/reactivity in patients with atherosclerotic carotid stenosis. RESULTS: Forty-three studies met the inclusion criteria; the majority included patients on antiplatelet therapy. Five studies showed increased platelet biomarkers in patients with ≥ 30% asymptomatic carotid stenosis (ACS) vs. controls, with one neutral study. Preliminary data from one study suggested that quantification of "coated platelets" in combination with stenosis severity may aid risk stratification in patients with ≥ 50% - 99% ACS. Platelets were excessively activated in patients with ≥ 30% symptomatic carotid stenosis (SCS) vs. controls (≥ 11 positive studies and one neutral study). Antiplatelet-High on Treatment Platelet Reactivity (HTPR), previously called "antiplatelet resistance", was observed in 23% - 57% of patients on aspirin, with clopidogrel-HTPR in 25% - 100% of patients with ≥ 50% - 99% ACS. Aspirin-HTPR was noted in 9.5% - 64% and clopidogrel-HTPR in 0 - 83% of patients with ≥ 50% SCS. However, the data do not currently support the use of ex vivo platelet function/reactivity testing to tailor antiplatelet therapy outside of a research setting. Platelets are excessively activated (n = 5), with increased platelet counts (n = 3) in recently symptomatic vs. asymptomatic patients, including those without micro-emboli on transcranial Doppler (TCD) monitoring (n = 2). Most available studies (n = 7) showed that platelets become more reactive or activated following carotid endarterectomy or stenting, either as an acute phase response to intervention or peri-procedural treatment. CONCLUSION: Platelets are excessively activated in patients with carotid stenosis vs. controls, in recently symptomatic vs. asymptomatic patients, and may become activated/hyper-reactive following carotid interventions despite commonly prescribed antiplatelet regimens. Further prospective multicentre studies are required to determine whether models combining clinical, neurovascular imaging, and platelet biomarker data can facilitate optimised antiplatelet therapy in individual patients with carotid stenosis.

Rugby league ball carrier injuries: The relative importance of tackle characteristics during the European Super League.

Rugby league carries a high injury incidence with 61% of injuries occurring at tackles. The ball carrier has a higher injury incidence than the defender, therefore understanding mechanisms occurring during injurious tackles are important. Given the dynamic, open nature of tackling, characteristics influencing tackle outcome likely encompass complex networks of dependencies. This study aims to identify important classifying characteristics of the tackle related to ball carrier injurious and non-injurious events in rugby league and identify the characteristics capability to correctly classify those events. Forty-one ball carrier injuries were identified and 205 matched non-injurious tackles were identified as controls. Each case and control were analysed retrospectively through video analysis. Random forest models were built to (1) filter tackle characteristics possessing relative importance for classifying tackles resulting in injurious/non-injurious outcomes and (2) determine sensitivity and specificity of tackle characteristics to classify injurious and non-injurious events. Six characteristics were identified to possess relative importance to classify injurious tackles. This included 'tackler twisted ball carrier's legs when legs were planted on ground', 'the tackler and ball carrier collide heads', 'the tackler used body weight to tackle ball carrier', 'the tackler has obvious control of the ball carrier' 'the tackler was approaching tackle sub-maximally' and 'tackler's arms were below shoulder level, elbows were flexed'. The study identified tackle characteristics that can be modified in attempt to reduce injury. Additional injury data are needed to establish relationship networks of characteristics and analyse specific injuries. Sensitivity and specificity results of the random forest were 0.995 and 0.525.

Editor's Choice - Timing of Carotid Intervention in Symptomatic Carotid Artery Stenosis: A Systematic Review and Meta-Analysis.

OBJECTIVE: This review aimed to analyse the timing of carotid endarterectomy (CEA) and carotid artery stenting (CAS) after the index event as well as 30 day outcomes at varying time periods within 14 days of symptom onset. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-analysis statement, comprising an online search of the Medline and Cochrane databases. Methodical quality assessment of the included studies was performed. Endpoints included procedural stroke and/or death stratified by delay from the index event and surgical technique (CEA/CAS). RESULTS: Seventy-one studies with 232 952 symptomatic patients were included. Overall, 34 retrospective analyses of prospective databases, nine prospective, three RCT, three case control, and 22 retrospective studies were included. Compared with CEA, CAS was associated with higher 30 day stroke (OR 0.70; 95% CI 0.58 - 0.85) and mortality rates (OR 0.41; 95% CI 0.31 - 0.53) when performed ≤ 2 days of symptom onset. Patients undergoing CEA/CAS were analysed in different time frames (≤ 2 vs. 3 - 14 and ≤ 7 vs. 8 - 14 days). Expedited CEA (vs. 3 - 14 days) presented a sampled 30 day stroke rate of 1.4%; 95% CI 0.9 - 1.8 vs. 1.8%; 95% CI 1.8 - 2.0, with no statistically significant difference. Expedited CAS (vs. 3 - 14 days) was associated with no difference in stroke rate but statistically significantly higher mortality rate (OR 2.76; 95% CI 1.39 - 5.50). CONCLUSION: At present, CEA is safer than transfemoral CAS within 2/7 days of symptom onset. Also, considering absolute rates, expedited CEA complies with the accepted thresholds in international guidelines. The ideal timing for performing CAS (when indicated against CEA) is not yet defined. Additional granular data and standard reporting of timing of intervention will facilitate future monitoring.

Editor's Choice - Effect of Carotid Interventions on Cognitive Function in Patients With Asymptomatic Carotid Stenosis: A Systematic Review.

OBJECTIVE: To determine the effect of carotid endarterectomy (CEA) and carotid artery stenting (CAS) on early (baseline vs. maximum three months) and late (baseline vs. at least five months) cognitive function in patients with exclusively asymptomatic carotid stenoses (ACS). METHOD: Searches were conducted in PubMed/Medline, Embase, Scopus, and the Cochrane library. This systematic review includes 31 non-randomised studies. RESULTS: Early post-operative period: In 24 CEA/CAS/CEA+CAS cohorts (n = 2 059), two cohorts (representing 91/2 059, 4.4% of the overall study population) reported significant improvement in cognitive function, while one (28/2 059, 1%) reported significant decline. Three cohorts (250/2 059, 12.5% reported "mixed findings" where some cognitive scores significantly improved, and a similar proportion declined. The majority (nine cohorts; 1 086/2 059, 53%) reported no change. Seven cohorts (250/2 059, 12.1%) were mostly unchanged but one to two individual test scores improved, while two cohorts (347/2 059, 16.8%) were mostly unchanged with one to two individual test scores worse. Late post-operative period: In 21 cohorts (n = 1 554), one (28/1 554, 1.8%) reported significantly worse cognitive function, one reported significant improvement (24/1 554, 1.5%), while a third (19/1 554, 1.2%) reported "mixed findings". The majority were unchanged (six cohorts; 1 073/1 554, 69%) or mostly unchanged, but with one to two cognitive tests showing significant improvement (11 cohorts; 386/1 554, 24.8%). Overall, there was a similar distribution of findings in small, medium, and large studies, in studies with controls vs. no controls, in studies comparing CEA vs. CAS, and in studies with shorter/longer late follow up. CONCLUSION: Notwithstanding accepted limitations regarding heterogeneity within non-randomised studies, CEA/CAS rarely improved overall late cognitive function in ACS patients (< 2%) and the risk of significant cognitive decline was equally low (< 2%). In the long term, the majority were either unchanged (69%) or mostly unchanged with one to two test scores improved (24.8%). Until new research identifies vulnerable ACS subgroups (e.g., impaired cerebral vascular reserve) or provides evidence that silent embolisation from ACS causes cognitive impairment, evidence supporting intervention in ACS patients to prevent/reverse cognitive decline is lacking.

Carotid Endarterectomy Following Intravenous Thrombolysis in the UK.

OBJECTIVE: The aim of this study was to evaluate the effect of pre-operative intravenous thrombolytic therapy (ivTT) on short term outcomes after carotid endarterectomy (CEA) among patients who presented with ischaemic stroke. METHODS: A retrospective study using a large population based dataset from the National Vascular Registry in the United Kingdom (UK-NVR). The cohort included adult patients who underwent CEA for ischaemic stroke between 1 January 2014 and 31 December 2019. NVR records provided information on patient demographics, Rankin score, medication, time from onset of symptoms to surgery and whether the patient received ivTT prior to surgery. Logistic regression was used to evaluate the relationship between ivTT and rates of any stroke at 30 days after CEA and in hospital complication rates for neck haematoma. Secondary outcomes included in hospital cardiac and respiratory complications, and cranial nerve injury. RESULTS: Between 2014 and 2019, 9 030 patients presented with a stroke and underwent CEA, of whom 1 055 (11.7%) had received pre-operative ivTT. Those receiving ivTT were younger (mean 70.6 vs. 72.0 years, p < .001). The median (IQR) time from symptom to CEA was 10 days (6 - 17) for ivTT patients and 11 days (7 - 20) for CEA patients not receiving ivTT. Post-operative rates of 30 day stroke were similar between the no ivTT (2.1%) and ivTT (1.8%) cohorts (p = .48). In hospital neck haematomas were statistically significantly more common in CEA patients receiving ivTT (3.7%) vs. no ivTT (2.3%) (p = .006). There was no statistically significant association between 30 day stroke and neck haematoma complications when stratified for delays from symptom onset to CEA, but the overall cohort contained few adverse events for analysis during the very early time period. CONCLUSION: The use of ivTT before CEA in stroke patients was not associated with an increased risk of 30 day stroke, but there was an increase in the risk of neck haematoma.

Editor's Choice - Asymptomatic Carotid Stenosis and Cognitive Impairment: A Systematic Review.

OBJECTIVE: The aim was to evaluate the relationship between asymptomatic carotid stenosis (ACS) of any severity and cognitive impairment and to determine whether there is evidence supporting an aetiological role for ACS in the pathophysiology of cognitive impairment. DATA SOURCES: PubMed/Medline, Embase, Scopus, and the Cochrane library. REVIEW METHODS: This was a systematic review (35 cross sectional or longitudinal studies) RESULTS: Study heterogeneity confounded data interpretation, largely because of no standardisation regarding cognitive testing. In the 30 cross sectional and six longitudinal studies (one included both), 33/35 (94%) reported an association between any degree of ACS and one or more tests of impaired cognitive function (20 reported one to three tests with poorer cognition; 11 reported four to six tests with poorer cognition, while three studies reported seven or more tests with poorer cognition). There was no evidence that ACS caused cognitive impairment via silent cortical infarction, or via involvement in the pathophysiology of lacunar infarction or white matter hyperintensities. However, nine of 10 studies evaluating cerebral vascular reserve (CVR) reported that ACS patients with impaired CVR were significantly more likely to have cognitive impairment and that impaired CVR was associated with worsening cognition over time. Patients with severe ACS but normal CVR had cognitive scores similar to controls. CONCLUSION: Notwithstanding significant heterogeneity within the constituent studies, which compromised overall interpretation, 94% of studies reported an association between ACS and one or more tests of cognitive impairment. However, "significant association" does not automatically imply an aetiological relationship. At present, there is no clear evidence that ACS causes cognitive impairment via silent cortical infarction (but very few studies have addressed this question) and no evidence of ACS involvement in the pathophysiology of white matter hyperintensities or lacunar infarction. There is, however, better evidence that patients with severe ACS and impaired CVR are more likely to have cognitive impairment and to suffer further cognitive decline with time.

A Systematic Review of Procedural Outcomes in Patients With Proximal Common Carotid or Innominate Artery Disease With or Without Tandem Ipsilateral Internal Carotid Artery Disease.

OBJECTIVE: To establish 30 day and mid term outcomes in patients treated for significant stenoses affecting the proximal common carotid artery (CCA) or innominate artery (IA) with/without tandem disease of the ipsilateral internal carotid artery (ICA). METHODS: Systematic review of early and mid term outcomes in 1 969 patients from 77 studies (1960-2017) who underwent: (i) hybrid open retrograde angioplasty/stenting of the IA/proximal CCA plus carotid endarterectomy (CEA) in patients with tandem disease of the ipsilateral proximal ICA (n = 700); (ii) isolated open surgery to the IA or proximal CCA (no CEA) (n = 686); or (iii) an isolated endovascular approach to IA or proximal CCA stenoses (no CEA) (n = 583). RESULTS: In the hybrid group with tandem disease (66% involving proximal CCA), the 30 day death/stroke was 3.3%, with a late ipsilateral stroke rate of 3.3% at a median six years follow up. Late re-stenosis was 10.5% for proximal CCA/IA and 4.1% for the ICA. In the isolated open surgery group (78% involving the IA), the 30 day death/stroke was 7%, with a late ipsilateral stroke rate of 1% at a median 12 years follow up. Late re-stenosis within aortic bypasses was 2.6%. In the isolated endovascular group (52% IA, 47% proximal CCA), the majority of procedures were done percutaneously (84%), with a 30 day death/stroke rate of 1.5%. Late ipsilateral stroke was 1% at a median four years follow up, with a re-stenosis rate of 9%. CONCLUSION: Procedural risks were higher following isolated open surgical interventions involving the proximal CCA/IA, compared with proximal lesions treated by isolated angioplasty/stenting, or in tandem with CEA. This higher morbidity/mortality may, however, reflect a greater proportion of innominate (vs. proximal CCA) lesions in open surgical series, changes in patient selection, time dependent evolution of medical interventions, and publication bias. The available data were limited and related to very different patient groups and management strategies spanning 57 years. Caution is raised, particularly for open surgery IA and CCA surgery, and for any procedures in asymptomatic patients. In symptomatic patients, the data cautiously support an "endovascular first" strategy for isolated proximal CCA/IA lesions and a hybrid approach for tandem proximal CCA/IA and ICA stenoses.

Editor's Choice - Overview of Primary and Secondary Analyses From 20 Randomised Controlled Trials Comparing Carotid Artery Stenting With Carotid Endarterectomy.

OBJECTIVES: The aim of this review was to carry out primary and secondary analyses of 20 randomised controlled trials (RCTs) comparing carotid endarterectomy (CEA) with carotid artery stenting (CAS). METHODS: A systematic review and meta-analysis of data from 20 RCTs (126 publications) was carried out. RESULTS: Compared with CEA, the 30 day death/stroke rate was significantly higher after CAS in seven RCTs involving 3467 asymptomatic patients (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.02-2.64) and in 10 RCTs involving 5797 symptomatic patients (OR 1.71, 95% CI 1.38-2.11). Excluding procedural risks, late ipsilateral stroke was about 4% at 9 years for both CEA and CAS, i.e., CAS was durable. Reducing procedural death/stroke after CAS may be achieved through better case selection, e.g., performing CEA in (i) symptomatic patients aged > 70 years; (ii) interventions within 14 days of symptom onset; and (iii) situations where stroke risk after CAS is predicted to be higher (segmental/remote plaques, plaque length > 13 mm, heavy burden of white matter lesions [WMLs], where two or more stents might be needed). New WMLs were significantly more common after CAS (52% vs. 17%) and were associated with higher rates of late stroke/transient ischaemic attack (23% vs. 9%), but there was no evidence that new WMLs predisposed towards late cognitive impairment. Restenoses were more common after CAS (10%) but did not increase late ipsilateral stroke. Restenoses (70%-99%) after CEA were associated with a small but significant increase in late ipsilateral stroke (OR 3.87, 95% CI 1.96-7.67; p < .001). CONCLUSIONS: CAS confers higher rates of 30 day death/stroke than CEA. After 30 days, ipsilateral stroke is virtually identical for CEA and CAS. Key issues to be resolved include the following: (i) Will newer stent technologies and improved cerebral protection allow CAS to be performed < 14 days after symptom onset with risks similar to CEA? (ii) What is the optimal volume of CAS procedures to maintain competency? (iii) How to deliver better risk factor control and best medical treatment? (iv) Is there a role for CEA/CAS in preventing/reversing cognitive impairment?

11ß-HSD1 plays a critical role in trabecular bone loss associated with systemic glucocorticoid therapy.

BACKGROUND: Despite their efficacy in the treatment of chronic inflammation, the prolonged application of therapeutic glucocorticoids (GCs) is limited by significant systemic side effects including glucocorticoid-induced osteoporosis (GIOP). 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a bi-directional enzyme that primarily activates GCs in vivo, regulating tissue-specific exposure to active GC. We aimed to determine the contribution of 11ß-HSD1 to GIOP. METHODS: Wild type (WT) and 11ß-HSD1 knockout (KO) mice were treated with corticosterone (100 µg/ml, 0.66% ethanol) or vehicle (0.66% ethanol) in drinking water over 4 weeks (six animals per group). Bone parameters were assessed by micro-CT, sub-micron absorption tomography and serum markers of bone metabolism. Osteoblast and osteoclast gene expression was assessed by quantitative RT-PCR. RESULTS: Wild type mice receiving corticosterone developed marked trabecular bone loss with reduced bone volume to tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N). Histomorphometric analysis revealed a dramatic reduction in osteoblast numbers. This was matched by a significant reduction in the serum marker of osteoblast bone formation P1NP and gene expression of the osteoblast markers Alp and Bglap. In contrast, 11ß-HSD1 KO mice receiving corticosterone demonstrated almost complete protection from trabecular bone loss, with partial protection from the decrease in osteoblast numbers and markers of bone formation relative to WT counterparts receiving corticosterone. CONCLUSIONS: This study demonstrates that 11ß-HSD1 plays a critical role in GIOP, mediating GC suppression of anabolic bone formation and reduced bone volume secondary to a decrease in osteoblast numbers. This raises the intriguing possibility that therapeutic inhibitors of 11ß-HSD1 may be effective in preventing GIOP in patients receiving therapeutic steroids.