The characteristics of patients with possible Transient Ischemic Attack and Minor Stroke in the Hunter and Manning Valley regions, Australia (the INSIST Study)

This is the final version. Available on open access from the American Academy of Neurology via the DOI in this record. Background: Transient ischemic attack (TIA) and minor stroke (TIAMS) are risk factors for stroke recurrence. Some TIAMS may be preventable by appropriate primary prevention. We aimed to recruit “possible-TIAMS” patients in the INternational comparison of Systems of care and patient outcomes In minor Stroke and TIA (INSIST) study. Methods: A prospective inception cohort study performed across 16 Hunter–Manning region, Australia, general practices in the catchment of one secondary-care acute neurovascular clinic. Possible-TIAMS patients were recruited from August 2012 to August 2016. We describe the baseline demographics, risk factors and pre-event medications of participating patients. Results: There were 613 participants (mean age; 69 ± 12 years, 335 women), and 604 (99%) were Caucasian. Hypertension was the most common risk factor (69%) followed by hyperlipidemia (52%), diabetes mellitus (17%), atrial fibrillation (AF) (17%), prior TIA (13%) or stroke (10%). Eighty-nine (36%) of the 249 participants taking antiplatelet therapy had no known history of cardiovascular morbidity. Of 102 participants with known AF, 91 (89%) had a CHA2DS2-VASc score ≥ 2 but only 47 (46%) were taking anticoagulation therapy. Among 304 participants taking an antiplatelet or anticoagulant agent, 30 (10%) had stopped taking these in the month prior to the index event. Conclusion: This study provides the first contemporary data on TIAMS or TIAMS-mimics in Australia. Community and health provider education is required to address the under-use of anticoagulation therapy in patients with known AF, possibly inappropriate use of antiplatelet therapy and possibly inappropriate discontinuation of antiplatelet or anticoagulation therapy.National Health and Medical Research Counci

One-year risk of stroke after transient ischemic attack or minor stroke in Hunter New England, Australia (INSIST Study)

Background: One-year risk of stroke in transient ischemic attack and minor stroke (TIAMS) managed in secondary care settings has been reported as 5–8%. However, evidence for the outcomes of TIAMS in community care settings is limited. Methods: The INternational comparison of Systems of care and patient outcomes In minor Stroke and TIA (INSIST) study was a prospective inception cohort community-based study of patients of 16 general practices in the Hunter–Manning region (New South Wales, Australia). Possible-TIAMS patients were recruited from 2012 to 2016 and followed-up for 12 months post-index event. Adjudication as TIAMS or TIAMS-mimics was by an expert panel. We established 7-days, 90-days, and 1-year risk of stroke, TIA, myocardial infarction (MI), coronary or carotid revascularization procedure and death; and medications use at 24 h post-index event. Results: Of 613 participants (mean age; 70 ± 12 years), 298 (49%) were adjudicated as TIAMS. TIAMS-group participants had ischemic strokes at 7-days, 90-days, and 1-year, at Kaplan-Meier (KM) rates of 1% (95% confidence interval; 0.3, 3.1), 2.1% (0.9, 4.6), and 3.2% (1.7, 6.1), respectively, compared to 0.3, 0.3, and 0.6% of TIAMS-mimic-group participants. At one year, TIAMS-group-participants had twenty-five TIA events (KM rate: 8.8%), two MI events (0.6%), four coronary revascularizations (1.5%), eleven carotid revascularizations (3.9%), and three deaths (1.1%), compared to 1.6, 0.6, 1.0, 0.3, and 0.6% of TIAMS-mimic-group participants. Of 167 TIAMS-group participants who commenced or received enhanced therapies, 95 (57%) were treated within 24 h post-index event. For TIAMS-group participants who commenced or received enhanced therapies, time from symptom onset to treatment was median 9.5 h [IQR 1.8–89.9]. Conclusion: One-year risk of stroke in TIAMS participants was lower than reported in previous studies. Early implementation of antiplatelet/anticoagulant therapies may have contributed to the low stroke recurrence

One-year risk of stroke after transient ischemic attack or minor stroke in Hunter New England, Australia (INSIST study)

Background: One-year risk of stroke in transient ischemic attack and minor stroke (TIAMS) managed in secondary care settings has been reported as 5-8%. However, evidence for the outcomes of TIAMS in community care settings is limited. Methods: The INternational comparison of Systems of care and patient outcomes In minor Stroke and TIA (INSIST) study was a prospective inception cohort community-based study of patients of 16 general practices in the Hunter–Manning region (New South Wales, Australia). Possible-TIAMS patients were recruited from 2012 to 2016 and followed-up for 12 months post-index event. Adjudication as TIAMS or TIAMS-mimics was by an expert panel. We established 7-day, 90-day, and one-year risk of stroke, TIA, myocardial infarction (MI), coronary or carotid revascularization procedure and death; and medications use at 24 hours post-event. Results: Of 613 participants (mean age; 70 ± 12 years), 298 (49%) were adjudicated as TIAMS. TIAMS-group participants had ischemic strokes at 7-days, 90-days, and one-year, at Kaplan-Meier (KM) rates of 1% (95% confidence interval; 0.3, 3.1), 2.1% (0.9, 4.6), and 3.2% (1.7, 6.1), respectively, compared to 0.3%, 0.3% and 0.6% of TIAMS-mimic-group participants. At one year, TIAMS-group-participants had twenty-five TIA events (KM rate: 8.8%), two MI events (0.6%), four coronary revascularization (1.5%), eleven carotid revascularization (3.9%) and three death (1.1%), compared to 1.6%, 0.6%, 1.0%, 0.3% and 0.6% of TIAMS-mimic-group participants. Of 167 TIAMS-group participants who commenced or received enhanced therapies, 95 (57%) were treated within 24 hours post-index event. For TIAMS-group participants who commenced or received enhanced therapies, time from symptom onset to treatment was median 9.5 hours [IQR 1.8-89.9]). Conclusion: One-year risk of stroke in TIAMS participants was lower than reported in previous studies. Early implementation of antiplatelet/anticoagulant therapies may have contributed to the low stroke recurrence

Aberrant crossed corticospinal facilitation in muscles distant from a spinal cord injury.

Crossed facilitatory interactions in the corticospinal pathway are impaired in humans with chronic incomplete spinal cord injury (SCI). The extent to which crossed facilitation is affected in muscles above and below the injury remains unknown. To address this question we tested 51 patients with neurological injuries between C2-T12 and 17 age-matched healthy controls. Using transcranial magnetic stimulation we elicited motor evoked potentials (MEPs) in the resting first dorsal interosseous, biceps brachii, and tibialis anterior muscles when the contralateral side remained at rest or performed 70% of maximal voluntary contraction (MVC) into index finger abduction, elbow flexion, and ankle dorsiflexion, respectively. By testing MEPs in muscles with motoneurons located at different spinal cord segments we were able to relate the neurological level of injury to be above, at, or below the location of the motoneurons of the muscle tested. We demonstrate that in patients the size of MEPs was increased to a similar extent as in controls in muscles above the injury during 70% of MVC compared to rest. MEPs remained unchanged in muscles at and within 5 segments below the injury during 70% of MVC compared to rest. However, in muscles beyond 5 segments below the injury the size of MEPs increased similar to controls and was aberrantly high, 2-fold above controls, in muscles distant (>15 segments) from the injury. These aberrantly large MEPs were accompanied by larger F-wave amplitudes compared to controls. Thus, our findings support the view that corticospinal degeneration does not spread rostral to the lesion, and highlights the potential of caudal regions distant from an injury to facilitate residual corticospinal output after SCI

Status Update and Interim Results from the Asymptomatic Carotid Surgery Trial-2 (ACST-2)

Objectives: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. Methods: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. Results: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. Conclusions: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. Clinical trial: ISRCTN21144362. © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease