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Background and aims: Clinical predictive models for stroke recovery could offer the opportunity of targeted early intervention and more specific information for patients and carers. In this study, we developed and validated a patientspecific prognostic model for monitoring recovery after stroke and assessed its clinical utility. Methods: Four hundred and ninety-five patients from the population-based South London Stroke Register were included in a substudy between 2002 and 2004. Activities of daily living were assessed using Barthel Index) at one, two, three, four, six, eight, 12, 26, and 52 weeks after stroke. Penalized linear mixed models were developed to predict patients' functional recovery trajectories. An external validation cohort included 1049 newly registered stroke patients between 2005 and 2011. Prediction errors on discrimination and calibration were assessed. The potential clinical utility was evaluated using prognostic accuracy measurements and decision curve analysis. Results: Predictive recovery curves showed good accuracy, with root mean squared deviation of 3 Barthel Index points and a R² of 83% up to one year after stroke in the external cohort. The negative predictive values of the risk of poor recovery (Barthel Index <8) at three and 12 months were also excellent, 96% (95% CI [93.6-97.4]) and 93% [90.8-95.3], respectively, with a potential clinical utility measured by likelihood ratios (LR+:17 [10.8-26.8] at three months and LR+:11 [6.5-17.2] at 12 months). Decision curve analysis showed an increased clinical benefit, particularly at threshold probabilities of above 5% for predictive risk of poor outcomes. Conclusions: A recovery curves tool seems to accurately predict progression of functional recovery in poststroke patients. [ABSTRACT FROM AUTHOR]

In a multicenter observational study, Benjamin Bray and colleagues evaluate whether weekend rounds by stroke specialist physicians, or the ratio of registered nurses to beds on weekends, is associated with patient mortality after stroke. Please see later in the article for the Editors' Summary [ABSTRACT FROM AUTHOR]

Background Survival after stroke has dramatically increased in the last two decades as the treatment of stroke has improved. However, time-trend analyses of health-related quality of life in stroke patients covering this time period are still not well investigated. Aims The study aims to examine temporal trends in mental and physical health-related quality of life of stroke survivors between the period of 1995 and 2011. Methods First in a lifetime strokes were registered in the South London Stroke Register between 1995 and 2011. Using the Short Form-12 Health Survey, trends in self-reported health-related quality of life at one-year after stroke were assessed over a 17-year period using linear regression, adjusting for socio-demographics, risk factors, and case-mix variables. Analyses stratifying by age, gender, race-ethnicity, and functional impairment were also performed. Results The overall trends of mental and physical health-related quality of life scores at one-year after stroke remained relatively unchanged over the period 1995-2011. However, mental health-related quality of life scores significantly improved between the period of 1995-2007 [β = 0·94 (95% CI; 0·15 to 1·74), P = 0·02], after which scores deteriorated [β = −2·02 (−3·82 to −0·22), P = 0·03]. Physical health-related quality of life scores remained stable until 2007, after which scores declined [β = −1·63 (−3·25 to −0·01), P = 0·05]. Conclusions Despite declining health-related quality of life trends within the general population, stroke survivors' overall health-related quality of life remained unchanged, possibly due to lower expectations of health among stroke survivors. However, in recent years there has been a significant unexplained decline in both physical and mental health-related quality of life, suggesting that despite stroke policy aims to improve health-related quality of life, more needs to be done to target this decline. [ABSTRACT FROM AUTHOR]

Background: There is inconsistent evidence that patients with stroke admitted to hospital out of regular working hours (such as weekends) experience worse outcomes. We aimed to identify if inequalities in the quality of care and mortality exist in contemporary stroke care in England. Methods: SINAP is a prospective database of acute stroke patients, documenting details of processes of care over the first 72 hours. We compared quality of care indicators and mortality at 72 hours, 7 days and 30 days, for patients who arrived within normal hours (Monday–Friday 8am to 6pm) and for those who arrived out of hours, using multivariable logistic and Cox proportional hazard models. Quality of care was defined according to time from arrival at hospital to interventions (e.g., brain scan), and whether the patient received therapeutic interventions (such as thrombolysis). Results: 45,726 stroke patients were admitted to 130 hospitals in England between 1 April 2010 and 31 January 2012. Patients admitted out of hours (n = 23779) had more features indicative of worse prognosis (haemorrhagic stroke, reduced consciousness, pre stroke dependency). Out of hours admission was significantly associated with longer delays in receiving a CT scan or being admitted to a stroke unit, and reduced odds of receiving thrombolysis. After adjusting for casemix, there was no consistent evidence of higher mortality for patients admitted out of hours, but patients admitted at the weekends had a higher risk of 30 day mortality (OR 1.14, 95% CI 1.06–1.21) Conclusion: Inequalities in the provision of stroke care for people admitted out of regular hours persist in contemporary stroke in England. The association with mortality is small and largely attributable to higher illness severity in patients admitted out of hours. [ABSTRACT FROM AUTHOR]

Background Deep vein thrombosis (DVT) is an important complication of stroke. Guidelines recommend that DVT prophylaxis should be guided by an assessment of the individual patient’s risk. The authors aimed to develop and test models to predict DVT risk. Methods The Clots in Legs Or sTockings after Stroke (CLOTS) Trial 1 randomised 2518 immobile patients with acute stroke to thigh-length graduated compression stockings (GCS) or no GCS and CLOTS Trial 2 randomised 3114 to thigh-length or below-knee GCS. The authors collected potential predictive variables at baseline and detected DVTs with compression duplex ultrasound scans at about 7e10 days and 25e30 days. The authors developed models with logistic regression to predict DVT in 1242 Trial 2 patients who had two scans and tested the models in the 1422 Trial 1 patients with two scans by estimating the area under the receiver operating characteristic curve (AUC). Results 168 (11.8%) patients in Trial 1 and 122 (9.8%) in Trial 2 had proximal DVTs. A model based on the Trial 2 cohort contained four of the 12 baseline variables: dependent before stroke (OR¼3.62, 95% CI 2.15 to 6.08), unable to lift arms off bed (OR 1.89, 95% CI 1.23 to 2.90), history of DVT/pulmonary embolism (OR 3.69, 95% CI 1.98 to 6.88) and diabetes (OR 0.55, 95% CI 0.30 to 0.99). The AUC in the development cohort was 0.65 but only 0.57, 95% CI (0.53 to 0.61) in the Trial 1 cohort, indicating poor discrimination. Conclusions Unfortunately, models based on clinical factors alone discriminate poorly between immobile patients with stroke at high and low risk, and would not facilitate individual tailoring of DVT prophylaxis strategies. [ABSTRACT FROM AUTHOR]

BACKGROUND: Stroke risk is higher in black ethnic groups compared with white. Although risk factors for stroke are known to differ between these populations, few population studies have reported on the risk of aetiological stroke subtypes in black ethnic populations. METHODS: Ethnic group differences in incidence of first ever ischaemic stroke by aetiological subtype were investigated with the South London Stroke Register (SLSR). The SLSR is a population based stroke register covering a multi-ethnic inner city population of 271 871 inhabitants comprising 63% white, 28% black and 9% other ethnic group. A modified pathophysiological Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification of stroke was used to estimate patterns of aetiological subtype and stroke was subtyped into large artery atherosclerosis (LAA), cardioembolism (CE), small vessel occlusion (SVO), other aetiology (OTH), undetermined (UND) and multiple possible or concurrent aetiologies (CONC). RESULTS: Between September 1999 and August 2006, 1181 patients with first ever ischaemic stroke were included in the study. Mean age was 71.4 years, 51% were female and 71% were white patients, 20% were black patients, 6% were other and 3% were of unknown ethnic group. The distribution of the aetiological subtypes was as follows: LAA, 109 (9.3%); CE, 325 (27.8%); SVO, 316 (27.0%); OTH, 40 (3.4%); UND, 283 (24.2%) and CONC, 96 (8.2%). The annual age adjusted incidence rate per 100 000 was for total ischaemic stroke 101.2 (95% CI 82.4 to 122.9) in men and 75.1 (95% CI 59.1 to 94.1) in women; for LAA 10.4 (95% CI 5.1 to 18.9) in men and 6.8 (95% CI 2.7 to 14.2) in women; for CE 23.0 (95% CI 14.6 to 34.5) in men and 21.5 (95% CI 13.4 to 32.8) in women; and for SVO 30.3 (95% CI 20.5 to 43.2) in men and 20.3 (95% CI 12.5 to 31.3) in women. The overall incidence rate ratio (IRR) for black patients was 1.25 (1.07 to 1.46), for black Caribbean (BC) patients 1.31 (1.09 to 1.58), for black African (BA) patients 1.22 (0.93 to 1.61) and for other ethnic groups 1.24 (0.96 to 1.61). IRRs for black ethnic groups as well as for BA and BC were significantly higher for SVO in both sexes, for OTH in black patients for females and in BA for males and females compared with the white ethnic group; IRRs for other ethnic groups compared with white patients were higher for SVO in females and for UND in males. INTERPRETATION: Independent important differences in risk of stroke between different ethnic populations strengthen the evidence base for studying genetic susceptibility and environmental influences in ethnic groups separately. [ABSTRACT FROM AUTHOR]

Some patients with anosognosia for hemiplegia, i.e. apparent unawareness of hemiplegia, have been clinically observed to show ‘tacit’ or ‘implicit’ awareness of their deficits. Here we have experimentally examined whether implicit and explicit responses to the same deficit-related material can dissociate. Fourteen stroke patients with right hemisphere lesions and contralesional paralysis were tested for implicit and explicit responses to brief sentences with deficit-related themes. These responses were elicited using: (i) a verbal inhibition test in which patients had to inhibit completing each sentence with an automatic response (implicit task) and (ii) a rating procedure in which patients rated the self-relevance of the same sentences (explicit task). A group of anosognosic hemiplegic patients was significantly slower than a control group of aware hemiplegic patients in performing the inhibition task with deficit-related sentences than with other emotionally negative themes (relative to neutral themes). This occurred despite their explicit denial of the self-relevance of the former sentences. Individual patient analysis showed that six of the seven anosognosic patients significantly differed from the control group in this dissociation. Using lesion mapping procedures, we found that the lesions of the anosognosic patients differed from those of the ‘aware’ controls mainly by involving the anterior parts of the insula, inferior motor areas, basal ganglia structures, limbic structures and deep white matter. In contrast, the anosognosic patient without implicit awareness had more cortical lesions, mostly in frontal areas, including lateral premotor regions, and also in the parietal and occipital lobes. These results provide strong experimental support for a specific dissociation between implicit and explicit awareness of deficits. More generally, the combination of our behavioural and neural findings suggests that an explicit, affectively personalized sensorimotor awareness requires the re-representation of sensorimotor information in the insular cortex, with possible involvement of limbic areas and basal ganglia circuits. The delusional features of anosognosia for hemiplegia can be explained as a failure of this re-representation. [ABSTRACT FROM AUTHOR]

Background: Randomised controlled trials have shown a beneficial effect of antihypertensive treatment on stroke recurrence. The effect of antihypertensive treatment on survival and recurrence in an unselected sample of the general population, using the General Practice Research Database, was analysed. Methods: Cox regression estimating the effect of antihypertensive treatment on survival and stroke recurrence >1 year among 44,244 first-ever strokes in the UK from 1997 to 2006 was adjusted by propensity score analysis considering gender, age, general practice, stroke year, drug prescriptions and diagnostic codes from other diseases. Results: The EU standardised stroke incidence was 118 per 100,000 (95% CI = 117–120). The 90-day case fatality was 19%. By 90 days after stroke 20,147 (58%) were diagnosed as having hypertension, of whom 75% had received antihypertensive treatment after stroke. After 5 years 68% of the hypertensive stroke patients receiving antihypertensive treatment were alive, while this proportion for patients not prescribed antihypertensive treatment was 59%. This could not be explained by potential confounders with an adjusted relative risk of 0.62 (95% CI = 0.58–0.66; p < 0.001) for antihypertensive treatment and premature death. The adjusted relative risk of antihypertensive treatment on stroke recurrence after 1 year, which was observed in 35% until 5 years after stroke, was 0.92 (95% CI = 0.84–1.01; p = 0.092). Conclusions: A high proportion of hypertensive stroke patients did not receive antihypertensive treatment. The protective effect of antihypertensive treatment on survival was higher in this general population than reported in randomised controlled trials, while an effect of antihypertensive treatment on late stroke recurrence was borderline, but not significant. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: urinary incontinence (UI) after stroke is associated with significant morbidity and mortality. The UK National Sentinel Audits of Stroke have collected data on UI which has not previously been reported. Methods: data on standards relating to both organisations and process of care were extracted from the audits to look for trends in service provision, continence care planning and discharge destination of incontinent versus continent stroke survivors. In addition, 2004 data was analysed statistically to look for a link between stroke units meeting certain standards and the likelihood of patients having continence plans. Results: UI rates have changed little over the four audit cycles. The influence of UI on discharge destination has also altered little. Stroke unit care is more strongly associated with management planning for UI in stroke. [ABSTRACT FROM AUTHOR]

Summarizes the effects of a British national stroke program aiming to improve stroke care, focusing on audit and guidelines, and reports some of the recent audit results and changes to the recommendations made in guidelines in Great Britain. Lack of a randomized, controlled trial evidence to show that maintaining normal levels of hydration, oxygenation, blood glucose, and temperature in fhe early hours after stroke is effective in improving outcomes; Inclusion of sections on the management of fransient ischemic attack and the medical management of subarachnoid hemorrhage.

Study objectives: to measure the quality of secondary prevention of stroke provided to patients in England, Wales and Northern Ireland. Design: retrospective case note analysis. Setting: 235 hospitals (95% of all such hospitals), providing care for acute stroke patients in England, Wales and Northern Ireland and primary health care for follow-up data. Patients: 8,200 patients admitted with stroke between 1st April and 30th June 2001. Data on up to 40 consecutive cases submitted by each hospital. Audit tool: Royal College of Physicians Intercollegiate Stroke Working Party Stroke Audit. Results: 24% of patients with previous cerebrovascular disease were not on anti-thrombotic medication at the time of admission. Nine percent of appropriate patients were not taking anti-thrombotic medication at discharge. Patients left with moderate to very severe disability (Barthel scores 14 or less) compared with those independent with mild disability (Barthel score 15-20) were more likely not to have anti-thrombotic treatment (18% versus 8%). Fifty-four percent of patients with known hyperlipidaemia and 21% of those with previous ischaemic heart disease were on lipid lowering therapy on admission. Sixty-four percent of patients had lipids measured during their hospital stay and of those with high total cholesterol or LDL the rate of non-treatment was 36%. Older patients (75+ years) were less likely to be treated (54%) than those <65 years (71%). Seventy-nine percent of known patients with hypertension were on treatment at admission, with 78% being treated by discharge from hospital. At 6 months after stroke a systolic blood pressure of 140mmHg or less, and a diastolic of 85 mmHg or less, was achieved in 41% of known pre-stroke hypertensives on treatment, 31% of previously untreated hypertensives hut on treatment at follow-up and 40% of patients not previously labelled as hypertensive. Conclusions: major deficiencies in... [ABSTRACT FROM AUTHOR]

Presents a study that described the organization and staffing of specialist hospital-based stroke services in Great Britain by the British Association of Stroke Physicians. Methods; Results; Discussion.

Objectives: To describe the natural history of cognitive impairment following stroke over three years; determine factors associated with recovery of post-stroke cognitive impairment and examine the effect of this recovery on stroke outcomes. Design: Observational study. Setting: Population-based register of first-ever strokes. Measures: Mini-Mental State Examination (MMSE) for cognition (cognitive impairment: MMSE<24), Barthel and Frenchay activity indices for disability. Methods: To describe its natural history, cognition was assessed at three months, 1, 2 and 3 years after stroke in 163 subjects registered in 1995. Recovery of cognitive impairment was examined using a larger cohort registered between 1995 and 1998 (n = 476) and 193 subjects cognitively impaired at three months were reassessed a year post stroke; 34 who had recovered cognitively (MMSE 24-30) were compared with 102 with persistent cognitive impairment in terms of demography, risk factors, initial impairments and stroke subtype. Results: At three months, 1, 2 and 3 years post stroke, the prevalence rates of cognitive impairment were 39%, 35%, 30% and 32% respectively. Multivariable analyses showed that recovery was associated with smoking (OR 3.7; 95% CI 1.2-11.8), compromised by visuospatial neglect (OR 0.27; 95% CI 0.08-0.89), and had a near-significant association with right hemispheric lesion (OR 2.87; 95% CI 0.94-8.78). Cognitive recovery was associated with less institutionalization (p = 0.032) and being less disabled, on Barthel (p = 0.001) and Frenchay Activity Indices (p = 0.028). Conclusions: Cognitive impairment remains highly prevalent up to three years after first stroke. Recovery from cognitive impairment is associated with smoking and possibly right hemisphere strokes, but compromised by visuospatial neglect. These associations require further clarification. [ABSTRACT FROM AUTHOR]

Discusses the identification of pulmonary embolism (PE) and pneumonia in acute stroke. Frequency of the two complications after acute stroke; Patients at risk for the complications; Co-existence of PE and pneumonia.

OBJECTIVES: To identify factors that were associated with cognitive impairment 3 months after stroke, and to examine the associations of cognitive impairment with stroke outcomes up to 4 years after stroke. DESIGN: Observational study. SETTING: Population-based stroke register. PARTICIPANTS: Six hundred forty-five subjects with first-ever stroke, identified from the register. MEASUREMENTS: Subjects were assessed for cognition using the Mini-Mental State Examination (MMSE) 3 months after stroke. Cognitively impaired subjects (MMSE <24, n = 248 (38%)) were compared with cognitively intact subjects (MMSE 24–30, n = 397) in terms of demographic details, stroke risk factors, laterality of stroke, and initial poststroke impairments. Outcome data collected at 1, 3, and 4 years poststroke included disability assessed by the Barthel Index (BI) and the Frenchay Activity Index, case fatality, and institutionalization. RESULTS: Two hundred forty-eight (38%) of 645 subjects were cognitively impaired 3 months after stroke. Using multivariate analyses, cognitive impairment was associated with age of 75 and older (odds ratio (OR) = 2.5, 95% confidence interval (CI) = 1.5–4.2), ethnicity (Caribbean/African (OR = 1.9, 95% CI = 1.2–3.2) and Asian (OR = 3.4, 95% CI = 1.1–10.2), lower socioeconomic class (OR = 2.1, 95% CI = 1.3–3.3), left hemispheric lesion (OR = 1.6, 95% CI = 1.01–2.4), visual field defect (OR = 2.0, 95% CI = 1.2–3.2), and urinary incontinence (OR = 4.8, 95% CI = 3.1–7.3). Using multivariate analyses, cognitive impairment was associated with death or disability (BI <15) at 4 years after stroke (OR = 2.2, 95% CI = 1.1–4.5). In univariate analyses, it was also associated with higher institutionalization 4 years after stroke (P = .001). CONCLUSIONS: Cognitive impairment is common 3 months after stroke and is independently associated with older age, ethnicity, lower social class, left hemispheric stroke,... [ABSTRACT FROM AUTHOR]

The article discusses the guidelines of the U.S. National Institute for Health and Clinical Excellence (NICE) for the diagnosis and treatment of stroke and transient ischaemic attack (TIA). It is recommended that the risk of subsequent stroke in patients who have had a suspected TIA be assessed using a validated scoring system. Patients considered as being at high risk of stroke are those with crescendo TIA. Immediate brain imaging is recommended in patients with acute stroke.

The article presents an overview of guidelines that have been created by Great Britain's National Institute for Health and Clinical Excellence for the diagnosis and initial management of acute stroke and transient ischaemic attack. A discussion of the importance of rapid symptom recognition and diagnosis in patients suspected of having had a stroke or attack, and of diagnostic tests which can be performed to accurately diagnose stroke or ischaemic attack, is presented. The role thrombolysis, aspirin, nutrition and hydration play in the treatment of stroke is discussed.

Objectives: To identify ethnic differences in survival after stroke and examine the factors that influence survival. Design: Population based stroke register with follow-up. Settings: South London stroke register. Participants: 2321 patients with first stroke registered between January 1995 and December 2002. Main outcome measures: Sociodemographic factors, risk factors for stroke and their management, severity of stroke, and acute service provision factors. Survival analysis with Kaplan-Meier curves, log rank test, and Cox's proportional hazard model with stratification. Results: In univariable analyses of survival, outcome was better for black people than white people (median 33.7 v 20.0 months). After stratification by socioeconomic status, type of stroke, and Glasgow coma score, and adjustment for other potential confounders, being black was generally associated with better survival, taking into account the interaction between ethnicity and age, and ethnicity and prior Barthel score. Of the risk factors for stroke considered, current smoking, untreated atrial fibrillation, untreated diabetes, and treated diabetes were associated with reduced survival. Conclusion: In general, black patients in a south London population with first ever stroke are more likely to survive than white patients, the exceptions being in those aged < 65 and those with a prior Barthel score < 15. Some pre-stroke risk factors that have the potential to be modified, including the appropriate treatment of existing health problems, have a strong impact on survival.

The article discusses research which focused on the challenges faced by the hyper acute stroke unit services in Great Britain. It mentions that the transformation of services causes the risk of losing expertise and valuable experience from decommissioned acute units. It says that London, England is considered one of the cities in the world that has undergone the most influential transformation of such health care facilities.

The authors reflect on the concept of telemedicine for stroke called telestroke. According to the authors, the concept of telestroke aims to overcome inequalities for care of stroke patients between hospitals and stroke specialists. The authors also mention that a telestroke team must have information technologists to ensure the reliability of computer-based technology.

Reports on the treatment of stroke in Great Britain. Negative survival rate of stroke patients in London compared with two central European populations; Criticism of stroke care in Great Britain, including a lack of physician specialty in stroke; Opinion that strokes should be treated as a medical emergency.

The article discusses research on improvements in the provision of effective acute stroke care between 1995 and 2009, based on the data recorded by the South London Stroke Register in England. Trends in the receipt of acute care interventions have been examined. Hospital admission rates, brain imaging, and thrombolysis data gathered over the study period are reported. Significant inequalities in the provision of care have been observed.

Summary: This paper reviews the current evidence for the association between socioeconomic status and stroke incidence, survival, mortality, and other outcomes. The evidence is strongest for mortality and incidence of stroke, with high rates of stroke in low socioeconomic groups being a consistent finding. Low socioeconomic groups also have lower survival and greater stroke severity than high socioeconomic groups, although there is less evidence for this association. The mechanisms through which socioeconomic status affects stroke risk and outcomes are unclear but some studies report that differences in risk-factor prevalence could account for some of the variation. We discuss the implications of these findings and make recommendations for future research. Studies using prospective population-based methods with improved control for confounding factors are needed to confirm or refute these associations. Understanding the causal associations between socioeconomic status and stroke will allow interventions to be appropriately targeted and assessed. [Copyright &y& Elsevier]

Abstract: Background: Information on determinants and prognosis of ischemic stroke subtypes is scarce. We aimed at evaluating risk factors, pathogenesis, treatment and outcome of different ischemic stroke subtypes. Methods: In a European Concerted Action involving seven countries, ischemic stroke subtypes defined according to the Oxfordshire Community Stroke Project (OCSP) were evaluated for demographics, baseline risk factors, resource use, 3-month survival, disability (Barthel Index) and handicap (Rankin Scale). Results: During the 12-month study period, cerebral infarction was diagnosed in 2740 patients with first-in-a-lifetime stroke (mean age 70.5±12.4 years, 53.4% males). OCSP classification was achieved in 2472 (90.2%). Of these, 26.7% were total anterior circulation infarctions (TACI), 29.9% partial anterior circulation infarctions (PACI), 16.7% posterior circulation infarctions (POCI) and 26.7% lacunar infarctions (LACI). In multivariate analysis, atrial fibrillation was predictive of TACI (odds ratio [OR], 1.61; 95% CI, 1.28–2.03), hypertension (OR, 1.38; 95% CI, 1.16–1.65) and myocardial infarction (OR, 1.42; 95% CI, 1.08–1.86) predictive of PACI, hypertension (OR, 1.25; 95% CI, 1.04–1.50) predictive of LACI. A negative association was observed between TACI and hypertension (OR, 0.51; 95% CI, 0.42–0.61). Discharge home was 50% less probable in TACI and PACI than in LACI patients. As compared to LACI, TACI significantly increased the risk of 3-month death (OR, 5.73; 95% CI, 3.91–8.41), disability (OR, 3.27; 95% CI, 2.30–4.66) and handicap (OR, 2.71; 95% CI, 1.91–3.85). Conclusions: Ischemic stroke subtypes have different risk factors profile, with consequences on pathogenesis and prognosis. Information on determinants of the clinical syndromes may impact on prevention and acute-phase interventions. [Copyright &y& Elsevier]