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Reperfusion Therapies for Wake-Up Stroke

Systematic Review
Originally publishedhttps://doi.org/10.1161/STROKEAHA.114.005126Stroke. 2014;45:1869–1875

Introduction

Patients who present with stroke symptoms on awakening, often referred to as wake-up stroke (WUS), account for ≈25% of acute ischemic strokes.1 In this group, onset time is unknown and usually defined conservatively as time last seen well (LSW) before sleeping.2,3 Onset time is important because benefit from intravenous thrombolysis is time dependent until 4.5 hours after symptoms start.4 Patients with WUS are not treated routinely unless awake and symptom free within standard timescales. However, evidence suggests that clinical and imaging characteristics of patients with WUS do not differ significantly from those with stroke while awake (SWA) presenting within 0- to 3-hour thrombolysis time windows.1,5,6 Imaging findings for many patients with WUS are consistent with an onset immediately before waking.6 As patients with WUS may benefit from reperfusion treatment if promptly delivered, we systematically reviewed studies of patients with WUS treated with intravenous and intra-arterial reperfusion therapies to consider the strength of evidence and make future recommendations.

Methods

Search Strategy/Selection Criteria

An unlimited PubMed search (MEDLINE) was performed on April 16, 2013, using the terms: wake* OR awake* OR sleep* OR asleep OR unclear-onset OR unclear onset OR unwitness* OR witness* AND stroke. Further PubMed alerts were received until June 30, 2013. One author (D.B.) reviewed abstracts to identify potentially eligible studies. Because of the small number of publications anticipated, all study designs were included. Articles were included if they described additional analyses using data from previously identified cohorts.

Data Extraction

Two authors (D.B. and L.S.) independently extracted data. Discrepancies were resolved by discussion with C.P. as the final adjudicator.

The data extracted were

  1. inclusion criteria,

  2. type(s) of data comparison/numbers of patients,

  3. type(s) of intervention, drugs/doses,

  4. time to treatment (TTT) from wake-up and LSW,

  5. imaging findings,

  6. stroke severity (baseline National Institute of Health Stroke Scale [NIHSS]), and

  7. treatment outcomes: disability (modified Rankin Scale [mRS]), Barthel Index, mortality, asymptomatic brain hemorrhage, and symptomatic brain hemorrhage (SBH). Asymptomatic brain hemorrhage and SBH definitions varied (Table I in the online-only Data Supplement).

Synthesis of Results

Because of considerable heterogeneity of reported methods and data, meta-analysis was not feasible and no statistical examination was performed. An organized narrative summary is presented.

Results

The initial search yielded 881 articles, of which 36 were deemed potentially eligible. Eleven were retained for inclusion.718 Reasons for exclusion were nontreatment studies, failure to report WUS outcome by treatment group, and patients with WUS within broader unknown onset cohorts.

Study Characteristics

Characteristics of 12 articles reporting treatment outcomes for 10 WUS cohorts are shown in Table II in the online-only Data Supplement: 3 were case reports/series,79 7 were observational stroke registry/database analyses,1016 2 described the same randomized controlled trial (RCT) containing a cohort of patients with WUS17 with separately published secondary analysis.18 Including subgroup analysis based on additional criteria, there were 5 comparisons of treated versus untreated WUS and 7 of treated WUS versus treated SWA. Numbers of patients with WUS ranged from 2 in case reports to 68 in a registry study.

Types of Treatment and Time Windows

Five cohorts were treated with intravenous thrombolysis alone using doses that reflected international licensing variations. There was 1 RCT of an unlicensed alternative intravenous agent (abciximab).17,18 Patients in 3 cohorts individually received intra-arterial thrombolysis/thrombectomy±intravenous thrombolysis.7,9,16 Two cohorts contained a mixture of patients who had received intravenous thrombolysis or intra-arterial interventions or both according to timing of presentation, radiological criteria, and clinical judgment.12,13

Time criteria for generating study cohorts varied greatly: 1 was <3 hours of waking with symptoms,17,18 2 <6 hours,10,13 1 <12 hours,16 2 <12 hours of LSW rather than waking time,11,14,15 1 <24 hours of LSW,8 and 3 did not define time criteria.7,9,12 Studies were inconsistent when describing TTT. Four did not report time interval data.9,11,1416 Four specified a wake-up time7,12 and LSW data.7,10,12,17,18 Two reported first found abnormal time; it was unclear whether this was equivalent to wake-up time.8,13 Mean TTT from LSW was typically ≈10 to 12 hours (range, 4–18.8 hours), approximately twice the mean for patients with SWA.

Imaging Criteria

Additional imaging was often used to assist treatment decisions. One study used noncontrast computed tomography (CT) alone for all patients.17,18 Manawadu et al14 reported a sensitivity analysis of noncontrast CT–only patients, which did not change the balance of outcomes between treated and untreated WUS. In 2 cohorts, some14,15 or all16 patients with WUS were selected using CT perfusion techniques. Six cohorts included patients identified by MRI: 2 also used MR perfusion10,13 and 1 used MR angiography.8 One database study used all imaging techniques in different combinations for different patients.12 One case report used digital subtraction angiography.9

Stroke Severity

Differences in median baseline NIHSS among treated WUS, untreated WUS, and treated SWA reflected small populations and different study protocols. Reported median baseline NIHSS of treated WUS patients ranged from 10 to 14 points.

Treatment Outcomes

The outcomes of interest were not consistently reported.

Treated WUS Versus Untreated WUS

In the RCT of abciximab, the proportion of patients with 3-month mRS 0 to 1 was nonsignificantly lower in the treated compared with the placebo WUS group (9% versus 29%; P=0·1).17 There was a similar but less obvious imbalance for mRS 0 to 2, mortality and a primary efficacy measure, which controlled for stroke severity18 (for details, see footnotes of Table 1). Rates of SBH and asymptomatic brain hemorrhage were higher in the treatment group and although this did not reach statistical significance, it led to suspension of recruitment into the WUS cohort after an interim analysis (Table 1).

Table 1. Outcomes in Treated WUS Versus Untreated WUS

Eligible StudymRS: 0–1 and 0–2Asymptomatic Brain HemorrhageSymptomatic Brain HemorrhageMortalityOther Outcomes
Treated WUSUntreated WUSP ValueTreated WUSUntreated WUSP ValueTreated WUSUntreated WUSP ValueTreated WUSUntreated WUSP Value
IV reperfusion only
 Adams et al17*3 mo0–1: 2/22 (9%)3 mo0–1: 6/21 (29%)0.105 d or discharge2/22 (9%)5 d or discharge0/20 (0%)0.175 d or discharge3/22(14%)5 d or discharge1/20 (5%)0.353 mo6/22 (27%)3 mo3/21 (14%)0.29Primary efficacy at 3 mo achieved in 1/22 (5%) treated vs 3/21 (14%) untreated (P=0·27)
 Adams et al180–2: 7/22 (32%)0–2: 11/21 (52%)n/r3 mo2/22 (9%)3 mo0/20 (0%)0.173 mo4/22 (18%)3 mo1/20 (5%)0.19BI≥95 at 3 mo in 7/22 (32%) treated vs 10/21 (48%) untreated (P=0·29)
 Breuer et al103 mo0–1: 3/10 (30%)3 mo0–1: 11/35 (31%)0.9924–36 h1/10 (10%)24–36 h0/35(0%)0.2224–36 h0/10 (0%)24–36 h0/35 (0%)n/rn/rMedian NIHSS at 24 h: 7.5 (0–18) in treated vs 5 (0–21) in untreated (P=0·27)
0–2: 5/10 (50%)0–2: 21/35 (60%)0.72Median NIHSS at discharge: 6 (0–21) in treated vs 3 (0–15) in untreated (P=0·15)
 Manawadu et al14 (all patients)3 mo0–1: 11/68 (16%)3 mo0–1: 5/54 (9%)0.4924 h13/68 (19%)24 h2/54 (4%)n/rany ICH 0.00424 h2/68 (3%)24 h0/54 (0%)0.203 mo10/68 (15%)3 mo14/54 (26%)0.12Median NIHSS at 24 h: 6 in treated vs 5 in untreated WUS (P=0.82)
0–2: 25/68 (37%)0–2: 14/54 (26%)0.35Median change in NIHSS at 24 h: −4 in treated and −3 in untreated WUS (P=0.14)
Thrombolysis was associated with a 5.2-fold (1.3–20.3; P=0.02) increase in the odds of mRS 0–2 at 90 days when adjusted for age, sex, and baseline NIHSS
 Manawadu et al14 (NCCT patients only)3 mo0–1: 3/23 (13%)3 mo0–1: 1/35 (3%)0.3424 h4/23 (17%)24 h1/35 (3%)n/rany ICH 0.0624 h0 (0%)24 h0 (0%)3 mo2/23 (9%)3 mo10/35 (29%)0.07Median NIHSS at 24 h: 6 in treated vs 6.5 in untreated WUS (P=0.95)
0–2: 7/23 (30%)0–2: 7/35 (20%)0.36Median change in NIHSS at 24 h: −4 in treated and −3 in untreated WUS (P=0.47)
Thrombolysis was associated with odds ratio 6.5 (1.4–24.7; P=0.03) for mRS 0–2 at 3 mo after adjusting for baseline NIHSS
IV and IA reperfusion
 Barreto et al12Discharge0–1: 14%Discharge0–1: 6%0.06n/rTiming unclear2/46 (4%)Timing unclear0/34 (0%)0.52Timing unclear7/46 (15%)Timing unclear0/34 (0%)0.02No other outcomes reported
0–2: 28%0–2: 13%0.006

BI indicates Barthel Index; IA, intra-arterial; ICH, intracerebral hemorrhage; IV, intravenous; mRS, modified Rankin Scale; n/r, not reported; NCCT, noncontrast computed tomography; NIHSS, National Institute of Health Stroke Scale; and WUS, wake-up stroke.

*The initial randomized controlled trial was consulted as well as the secondary analysis of data, which contained a specific cohort of patients with WUS.

Primary efficacy: for favorable outcome among subjects with a baseline NIHSS score of 4 to 7, the mRS was 0; for subjects with a baseline NIHSS score of 8 to 14, the mRS score could be 1 or 2; and for those subjects with a baseline NIHSS score of 15 to 22, the mRS score could be 0 to 2.

Numbers not reported; P values for mRS outcomes refer to adjusted analyses (logistic regression), which controlled for baseline NIHSS.

Unadjusted outcome data for registry studies showed no difference in favorable (mRS, 0–1) or independent (mRS, 0–2) outcomes at 3 months between treated and untreated WUS. After regression analysis to adjust for baseline variables, which could affect outcome (severity, age, and sex), 2 studies reported a statistically significant advantage after treatment for mRS 0 to 2 at 3 months (odds ratio, 5.2 [1.3–20.3] after intravenous treatment; P=0.02)14 and discharge (28% versus 13% after intravenous and intra-arterial treatment; P=0.006).12 This apparent benefit was despite significant increases in total intracranial hemorrhage (13/68 versus 2/54; P=0.004)14 and mortality (7/46 versus 0/34; P=0.02).12 However, no study reported an increase in SBH. In a study where the decision to treat always involved MR perfusion imaging, no SBH was reported but 3-month mRS did not differ between treated and untreated WUS groups.10 A noncontrast CT–only sensitivity analysis for 1 cohort came close to a statistically significant mortality reduction (2/23 treated versus 10/35 untreated; P=0.07) although mRS was no different.14 Overall, there was no obvious distribution of outcomes according to imaging modality.

Treated WUS Versus Treated SWA

In the abciximab RCT the proportion of favorable and independent outcomes was lower in treated WUS than treated SWA but statistical comparison was not reported.18 SBH rates were significantly higher with treated WUS (4/22 versus 18/375; P=0.03; Table 2).

Table 2. Outcomes in Treated WUS Versus Treated SWA

Eligible StudymRS: 0–1 and 0–2Asymptomatic Brain HemorrhageSymptomatic Brain HemorrhageMortalityOther Outcomes
Treated WUSTreated SWAP ValueTreated WUSTreated SWAP ValueTreated WUSTreated SWAP ValueTreated WUSTreated SWAP Value
IV reperfusion only
 Adams et al18*3 mo0–1: 2/22 (9%)3 mo0–1: 153/381 (40%)n/r5 d or discharge2/22 (9%)5 d or discharge40/375 (10%)1.05 d or discharge3/22 (14%)5 d or discharge15/375 (4%)0.073 mo6/22 (27%)3 mo35/221 (16%)n/rPrimary efficacy at 3 mo achieved in 1/22 (5%) treated WUS vs 112/381 (29%) treated SWA (P value n/r)
0–2: 7/22 (32%)0–2: 214/381 (56%)n/r3 mo 2/22 (9%)3 mo 25/217 (11%)n/r3 mo4/22 (18%)3 mo18/375 (5%)0.03BI≥95 at 3 mo: 7/22 (32%) treated vs 217/381 (57%) untreated (P=0·29)
 Bai et al113 mo0–1 or decrease in NIHSS>8 points: 37/48 (77%)3 mo0–1 or decrease in NIHSS>8 points: 105/138 (76%)0.53Timing unclear6/48 (13%)Timing unclear16/138 (12%)0.52Timing unclear1/48 (2%)Timing unclear2/138 (2%)0.593 mo1/48 (2%)3 mo1/138 (1%)0.45Mean NIHSS at 24 h: 7.8 WUS vs 6.9 AIS within 12 h (P=0.79)
Mean NIHSS at 7 days: 5.6 WUS vs 5.1 AIS within 12 h (P=0.72)
BI≥95 at 3 mo: 73% WUS vs 71% AIS within 12 h (P=0.48)
Vascular recanalization in 67% WUS vs 71% AIS within 12 h (P=0.58)
Vascular stenosis: 15/48 (31%) WUS vs 48/138 (35%) AIS within 12 h (P=0.39)
 Manawadu et al15 (all patients)3 mo0–1: 11/68 (16%)3 mo0–1: 77/326 (24%)0.1824 h13/68 (19%)24 h55/326 (17%)n/rany ICH 0.4224 h2/68 (2.9%)24 h11/326 (3.4%)1.03 mo10/68 (15%)3 mo82/326 (26%)0.06Median NIHSS at 24 h: 6 in WUS vs 9 in RG (P=0.26)
0–2: 25/68 (37%)0–2: 124/328 (38%)0.89Median change in NIHSS at 24 h: −4 in both groups (P=0.53)
No differences in mRS 0–1 or 0–2 at 90 days, sICH and mortality after adjusting for independent predictors
 Manawadu et al15 (ECASS III criteria patients only)3 mo0–1: 7/33 (21%)3 mo0–1: 62/197 (32%)0.2324 h8/33 (24%)24 h35/197 (18%)0.3824 h0/33 (0%)24 h6/197 (3%)0.313 mo1/33 (3%)3 mo34/197 (18%)0.03Median NIHSS at 24 h: 5 in WUS vs 9 in RG (P=0.02)
0–2: 19/33 (58%)0–2: 101/197 (51%)0.50Median change in NIHSS at 24 h: −6 in WUS and −4 in RG (P=0.09)
IA reperfusion only
 Natarajan et al163 mo0–1n/r3 mo0–1n/rn/rTiming unclear3/21 (14%)Timing unclear<8 h AC9/153 (7%)n/r3 mo5/21 (24%)3 mo<8 h AC34/135 (25%)n/rTIMI 2/3 recanalization in 81% WUS, 69% <8 h AC, 70% ≥8 h AC
0–2: AC9/21 (43%)0–2: <8 h AC54/135 (40%)n/r≥8 h AC5/33 (15%)≥8h AC11/33 (33%)Multivariate regression found that sICH rate was higher in ≥8 h AC (OR, 3.8) and in WUS (OR, 4.9). No differences between WUS and <8 h AC
≥8 h AC6/33 (18%)
IV and IA reperfusion
 Barreto et al12Discharge0–1: 14%Discharge0–1: 32%0.14n/rTiming unclear2/46 (4%)Timing unclear5/174 (3%)0.64Timing unclear7/46 (15%)Timing unclear17/174 (10%)0.29No other outcomes reported
0–2: 28%0–2: 48%0.64
 Kang et al13 (WUS vs SWA supplementary analysis)3 mo0–1: 18/63 (29%)3 mo0–1: 6/20 (30%)n/rn/r48 h2/63 (3%)48 h1/20 (5%)n/rn/rNo other outcomes reported
0–2: 29/63 (46%)0–2: 8/20 (40%)n/r

AC indicates anterior circulation; AIS, acute ischemic stroke; BI, Barthel Index; IA, intra-arterial; ICH, intracerebral hemorrhage; IV, intravenous; ECASS, European Cooperative Acute Stroke Study; mRS, modified Rankin Scale; n/r, not reported; NIHSS, National Institute of Health Stroke Scale; OR, odds ratio; RG, reference group; sICH, symptomatic intracerebral hemorrhage; SWA, stroke while awake; and WUS, wake-up stroke.

*The initial randomized controlled trial was consulted as well as the secondary analysis of data, which contained a specific cohort of patients with WUS.

Primary efficacy: for favorable outcome among subjects with a baseline NIHSS score of 4 to 7, the mRS was 0; for subjects with a baseline NIHSS score of 8 to 14, the mRS score could be 1 or 2; and for those subjects with a baseline NIHSS score of 15 to 22, the mRS score could be 0 to 2.

Base number not reported; P values for mRS outcomes refer to adjusted analyses (logistic regression), which controlled for baseline NIHSS.

Among registry studies there was no significant difference reported in mRS outcomes, suggesting a similar treatment effect. In a cohort of mixed intravenous and intra-arterial treatment of patients with WUS, Barreto et al12 reported nonstatistically significant improved rates of favorable and independent outcomes at discharge after adjustment for baseline NIHSS (mRS, 0–1: odds ratio, 0·48 [0.18–1.27]; P=0·14 and mRS, 0–2: odds ratio, 0·64 [0.3–1.38]; P=0·62). With comparison to a treated SWA reference group, Manawadu et al15 found no difference for dependency including sensitivity analysis of patients meeting European Cooperative Acute Stroke Study (ECASS) III criteria, but there was a reduction in mortality (1/33 WUS versus 34/197; P=0.03) among these patients with WUS. Bai et al11 presented a combined outcome of mRS 0 to 1 or NIHSS decrease >8 points, but the proportions in each group were equivalent. No significant difference in SBH was shown between treated WUS and treated SWA patients.

Case Reports/Series

One case series measured disability (mRS) and reported that 1 of 4 patients with WUS had a favorable outcome (mRS, 0–2).8 The other 2 case reports described improved clinical characteristics for each of their 2 patients.7,9 Asymptomatic brain hemorrhage occurred in 4 of 8 patients and SBH in 1 of 8; all received treatment based on MRI findings or digital subtraction angiography. No deaths were reported (Table 3).

Table 3. Outcomes in Wake-Up Stroke–Specific Case Reports

Eligible StudymRSAsymptomatic Brain HemorrhageSymptomatic Brain HemorrhageMortalityOther Outcomes
IV reperfusion only
 Aoki et al83 moPt 1: 0Pt 2: 5Pt 3: 5Pt 4: 524 h3/47 d3/40/40/4Partial recanalization at 1 h in 1/4 cases. Complete recanalization at 24 h in 1 and partial in 2. Complete recanalization at 7 d in 2, partial in 1
Clinical recovery at 7 d: dramatic recovery in 1 case, good in 1, no change in 1, and worsening in 1
NIHSS at 1 h: range 8–19; 24 h: range 0–26; 7 d: range 0–28
IA reperfusion only
 Iosif et al72 moPt 1: 11/21/20/2Pt 1: discharge 9 d with no motor deficit but mild language deficit
Pt 2: n/rPt 2: NIHSS=4 at 2 h; 2 at 24 h; discharge 16 days symptom free
 Kuruvilla et al9n/r0/20/20/2Pt 1: discharge at 2 dPt 2: discharge at 5 dBoth pts: no neurological deficit 18 mo

IA indicates intra-arterial; IV, intravenous; mRS, modified Rankin Scale; n/r, not reported; and NIHSS, National Institute of Health Stroke Scale.

Discussion

In this systematic review, we have examined studies reporting outcomes of patients with WUS treated with intravenous and intra-arterial reperfusion therapies. The published literature was limited, data reporting were inconsistent and studies were generally small. However, the reported median baseline NIHSS for treated WUS patients was similar to the score of 11 from pooled clinical trials of intravenous thrombolysis19 and the score of 12 described by the Safe Implementation of Treatments for Stroke register.20

Meta-analysis was not possible because only 1 study was randomized and there was marked variation in settings, criteria, treatments, and outcome measures. It is important to recognize that data from 1 cohort featured more than once.14 No randomized data were found, which described outcomes related to a treatment currently used in clinical practice. Although the abciximab RCT reported an unfavorable trend against treatment of patients with WUS,17,18 this examined reperfusion using a glycoprotein IIb/IIIa antagonist in a small subgroup of patients presenting within 5 hours of stroke symptoms. Therefore, it would not be appropriate to reach a conclusion about reperfusion WUS treatment from this single study. However, the apparent advantage seen after baseline adjustment for 2 WUS studies12,14 must also be interpreted cautiously as the cohorts were small, nonrandomized, and unblinded during protocols, which relied on local clinical judgment for patient selection.

The effect of treatment on disability was inconsistent and depended on whether the reference group was untreated WUS or treated SWA. Excluding results derived from the abciximab trial17,18 or those adjusted for baseline characteristics,12,14 there was no difference in mRS when treated and untreated WUS were compared, but there was also no difference when treated WUS was compared with treated SWA. This probably reflects the small sample sizes limiting detection of any treatment effect and the impact of patient selection by clinical criteria across all groups. A clinical influence is apparent in the variation in absolute numbers of patients with favorable or independent mRS outcomes in studies, ranging from 13% to 30% for mRS 0 to 1 and 30% to 58% for mRS 0 to 2 after any treated WUS and from 3% to 31% for mRS 0 to 1 and 20% to 60% for mRS 0 to 2 in untreated WUS. After treatment of SWA the dependency outcome ranged from 24% to 32% for mRS 0 to 1 and 18% to 51% for mRS 0 to 2. By comparison, 35% of patients allocated recombinant tissue-type plasminogen activator in 10 clinical trials of intravenous thrombolysis had an mRS 0 to 1 and 46% had mRS 0 to 2 versus control results of 29% and 42%, respectively.21 It would not be surprising if WUS outcomes were inferior to these because of a likely shift of TTT distribution toward longer intervals.

Overall, there was no clear effect on mortality, including both an increase12 and a reduction15 after WUS treatment. However, as intravenous thrombolysis has not shown a beneficial effect on short-term mortality in clinical trials,21 it would be surprising if reperfusion treatment reduced WUS mortality.

Comparison of hemorrhage rates was limited by the differing event definitions and reporting time points. Asymptomatic hemorrhage rates ranged from 9% to 19% for treated WUS cohorts. Only the abciximab trial found an excess of symptomatic bleeding during comparison of treated WUS and treated SWA.17,18 However, an estimation of harm from WUS reperfusion treatment is not possible without trials including sufficient numbers of patients, a standard definition of symptomatic hemorrhage, and blinded assessment. When it was clear which imaging modality and treatment had been used, symptomatic hemorrhage rates after intravenous recombinant tissue-type plasminogen activator were 1 of 58 (1.7%) for MRI approaches10,11 and 2 of 68 (2.9%) for CT approaches.14 In this context, it was unclear whether CT perfusion, MRI, and MR perfusion imaging were of additional value, particularly as 1 well-defined noncontrast CT–only subgroup included no symptomatic hemorrhages.14 This suggests that CT selection may be an appropriate imaging modality for future trials of reperfusion therapy in WUS, although current trials are focusing on the possible advantage of MRI estimation of salvageable penumbra.2224

In addition to variations in patient selection and TTT, the lack of modality-specific data reported by studies with mixed treatment approaches has prevented any conclusion on intravenous and intra-arterial therapy for WUS. As intravenous thrombolysis can be administered more rapidly than intra-arterial therapies, and the latter are being assessed by clinical trials for effectiveness after known recent onset, we recommend intravenous treatment to be the priority for WUS research. Study design should be modified if intra-arterial treatments are proven to have a longer therapeutic time window and greater effectiveness than recombinant tissue-type plasminogen activator or other intravenous agents in development.

Conclusions

There are limited data on the risks and benefits of reperfusion therapies for WUS. Although the only randomized data do not support the safety or benefit of a glycoprotein IIb/IIIa antagonist (abciximab), there is currently insufficient evidence to make recommendations on the use of other treatments or the imaging approach for patient selection. Results from RCTs are required.

Footnotes

The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.005126/-/DC1.

Correspondence to Gary A. Ford, MB BChir, FRCP, John Eccles House, Oxford Science Park, Oxford, OX4 4GA, United Kingdom. E-mail

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