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Researchers, institutions, funders, and publishers are considering how to improve research culture and quality, but no single part of the research ecosystem can effect change on its own. The UK Reproducibility Network (UKRN) was established to facilitate the necessary coordination. Its experience can inform the establishment of like-minded networks around the world to drive positive change.

Transparency in reporting benefits scientific communication on many levels. While specific needs and expectations vary across fields, the effective interpretation and use of research findings relies on the availability of core information about research materials, study design, data, and experimental and analytical methods. For preclinical research, transparency in reporting is a key focus in response to concerns of replication failure. The inconsistent reporting of key elements of experimental and analytical design, alongside ambiguous description of reagents and lack of access to underlying data and code, has been shown to impair replication (1) and raise doubt about the robustness of results (2, 3). In response to early concerns about replication of published results, funders, publishers, and other stakeholders have called for improvements in reporting transparency (4⇓⇓–7). Several initiatives ensued, including journal policies and joint efforts by journals, funders, and other stakeholders (8⇓–10). One of these initiatives, the Transparency and Openness Promotion (TOP) guidelines (11), outlines a policy framework at the journal level that over 1,000 journals and publishers have adopted. The National Academies have focused on reproducibility and replicability* challenges through several recent initiatives leading to consensus reports, including Reproducibility and Replicability in Science (12), Open Science by Design: Realizing a Vision for 21st Century Research (13), and Fostering Integrity in Research (14). Each of these reports concludes that lack of reporting transparency is one factor which contributes to these systemic problems. Building on these findings, the National Academies convened a public workshop in September 2019 titled “Enhancing Scientific Reproducibility in Biomedical Research Through Transparent Reporting.” The workshop was designed to discuss the current state of transparency in reporting biomedical research and to explore the possibility of improving the harmonization of guidelines across journals and funding agencies. During this workshop, we provided … [↵][1]1To whom correspondence may be addressed: Email: Malcolm.Macleod{at}ed.ac.uk (correspondence regarding the development and evaluation of the guideline) or mellor.david{at}gmail.com (for further information about implementation and stewardship). [1]: #xref-corresp-1-1

Therapeutic hypothermia was a mainstay of severe traumatic brain injury (TBI) management for half a century. Recent trials have suggested that its effect on long-term functional outcome is neutral or negative, despite apparently promising pre-clinical data. Systematic review and meta-analysis is a useful tool to collate experimental data and investigate the basis of its conclusions. We searched three online databases to identify studies testing systemic hypothermia as monotherapy for treatment of animals subjected to a TBI. Data pertaining to TBI paradigm, animal subjects, and hypothermia management were extracted as well as those relating to risk of bias. We pooled outcome data where sufficient numbers allowed and investigated heterogeneity in neurobehavioral outcomes using multi-variate meta-regression. We identified 90 publications reporting 272 experiments testing hypothermia in animals subject to TBI. The subjects were mostly small animals, with well-established models predominating. Target temperature was comparable to clinical trial data but treatment was initiated very early. Study quality was low and there was some evidence of publication bias. Delay to treatment, comorbidity, and blinded outcome assessment appeared to predict neurobehavioral outcome on multi-variate meta-regression. Therapeutic hypothermia appears to be an efficacious treatment in experimental TBI, which differs from the clinical evidence. The pre-clinical literature showed limitations in quality and design and these both appeared to affect neurobehavioral experiment outcome. These should be acknowledged when designing and interpreting pre-clinical TBI studies in the future.

Background Elderly patients are at high risk of complications after stroke, such as infections and fever. The occurrence of these complications has been associated with an increased risk of death or dependency. Hypothesis: Prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first four days after stroke onset will improve functional outcome at 90 days in elderly patients with acute stroke. Design International, 3 × 2-factorial, randomised-controlled, open-label clinical trial with blinded outcome assessment (PROBE) in 3800 patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and an NIHSS score ≥ 6. Patients will be randomly allocated to any combination of oral, rectal, or intravenous metoclopramide (10 mg thrice daily); intravenous ceftriaxone (2000 mg once daily); oral, rectal, or intravenous paracetamol (1000 mg four times daily); or usual care, started within 24 h after symptom onset and continued for four days or until complete recovery or discharge from hospital, if earlier. Outcome: The primary outcome measure is the score on the modified Rankin Scale at 90 days (± 14 days), as analysed with multiple regression. Summary: This trial will provide evidence for a simple, safe and generally available treatment strategy that may reduce the burden of death or disability in patients with stroke at very low costs. Planning: First patient included in May 2016; final follow-up of the last patient by April 2020. Registration: ISRCTN, ISRCTN82217627, https://doi.org/10.1186/ISRCTN82217627

Helping every scientist to improve is more effective than ferreting out a few frauds. Helping every scientist to improve is more effective than ferreting out a few frauds.

Background and Purpose— Because the new era of preclinical stroke research demands improvements in validity and generalizability of findings, moving from single site to multicenter studies could be pivotal. However, the conduct of magnetic resonance imaging (MRI) in stroke remains ill-defined. We sought to assess the variability in the use of MRI for evaluating lesions post stroke and to examine the possibility as an alternative to gold standard histology for measuring the infarct size. Methods— We identified animal studies of ischemic stroke reporting lesion sizes using MRI. We assessed the degree of heterogeneity and reporting of scanning protocols, postprocessing methods, study design characteristics, and study quality. Studies performing histological evaluation of infarct size were further selected to compare with corresponding MRI using meta-regression. Results— Fifty-four articles undertaking a total of 78 different MRI scanning protocols met the inclusion criteria. T 2 -weighted imaging was most frequently used (83% of the studies), followed by diffusion-weighted imaging (43%). Reporting of the imaging parameters was adequate, but heterogeneity between studies was high. Twelve studies assessed the infarct size using both MRI and histology at corresponding time points, with T 2 -weighted imaging–based treatment effect having a significant positive correlation with histology ( ; P Conclusions— Guidelines for standardized use and reporting of MRI in preclinical stroke are urgently needed. T 2 -weighted imaging could be used as an effective in vivo alternative to histology for estimating treatment effects based on the extent of infarction; however, additional studies are needed to explore the effect of individual parameters.

Fatigue is ubiquitous but it is more common and more severe in patients with acute and chronic conditions, including stroke. The reported proportion of people with fatigue after stroke ranges from 23% to 75%.1 The variation in proportion between studies reflects the heterogeneity in the studied populations, time since stroke, and assessment methods for fatigue. Fatigue is common immediately after stroke, and it tends to persist in most but not all patients. It contributes to lower quality of life and a higher risk of death.2,3 How to manage and prevent fatigue is ranked by stroke survivors and health professionals among the top 10 research priorities relating to life after stroke.4 However, there is no effective treatment, which is partly because of our lack of knowledge of its mechanisms. Fatigue after stroke may share some common underlying mechanisms with other conditions. For example, Zedlitz and colleagues found that the psychosocial profiles of stroke patients with fatigue were similar to those reported in patients with cancer, multiple sclerosis, and chronic fatigue syndrome.5 Several fatigue models have been developed for patients with other conditions; a myriad of biological,6,7 psychosocial,8,9 and behavioral factors,9 as well as other symptoms, such as pain and sleep problems,10 are involved. In this review, we explored whether these factors contribute to fatigue after stroke. We systematically reviewed studies of post-stroke fatigue (PSF) and discussed the definition of PSF, its natural history, and its associations. By drawing on literature of fatigue in other conditions alongside evidence from stroke studies, we propose a conceptual model of PSF. This model is potentially useful in understanding the mechanisms of PSF and informing the development of its treatment. In stroke studies, PSF is usually defined by cut-off scores on fatigue …

Correctable weaknesses in the design, conduct, and analysis of biomedical and public health research studies can produce misleading results and waste valuable resources. Small effects can be difficult to distinguish from bias introduced by study design and analyses. An absence of detailed written protocols and poor documentation of research is common. Information obtained might not be useful or important, and statistical precision or power is often too low or used in a misleading way. Insufficient consideration might be given to both previous and continuing studies. Arbitrary choice of analyses and an overemphasis on random extremes might affect the reported findings. Several problems relate to the research workforce, including failure to involve experienced statisticians and methodologists, failure to train clinical researchers and laboratory scientists in research methods and design, and the involvement of stakeholders with conflicts of interest. Inadequate emphasis is placed on recording of research decisions and on reproducibility of research. Finally, reward systems incentivise quantity more than quality, and novelty more than reliability. We propose potential solutions for these problems, including improvements in protocols and documentation, consideration of evidence from studies in progress, standardisation of research efforts, optimisation and training of an experienced and non-conflicted scientific workforce, and reconsideration of scientific reward systems.

Pain can significantly decrease the quality of life of patients with advanced cancer. Current treatment strategies often provide inadequate analgesia and unacceptable side effects. Animal models of bone cancer pain are used in the development of novel pharmacological approaches. Here we conducted a systematic review and meta-analysis of publications describing in vivo modelling of bone cancer pain in which behavioural, general health, macroscopic, histological, biochemical, or electrophysiological outcomes were reported and compared to appropriate controls. In all, 150 publications met our inclusion criteria, describing 38 different models of bone cancer pain. Reported methodological quality was low; only 31% of publications reported blinded assessment of outcome, and 11% reported random allocation to group. No publication reported a sample size calculation. Studies that reported measures to reduce bias reported smaller differences in behavioural outcomes between tumour-bearing and control animals, and studies that presented a statement regarding a conflict of interest reported larger differences in behavioural outcomes. Larger differences in behavioural outcomes were reported in female animals, when cancer cells were injected into either the tibia or femur, and when MatLyLu prostate or Lewis Lung cancer cells were used. Mechanical-evoked pain behaviours were most commonly reported; however, the largest difference was observed in spontaneous pain behaviours. In the spinal cord astrocyte activation and increased levels of Substance P receptor internalisation, c-Fos, dynorphin, tumor necrosis factor-α and interleukin-1β have been reported in bone cancer pain models, suggesting several potential therapeutic targets. However, the translational impact of animal models on clinical pain research could be enhanced by improving methodological quality.

The prevalence, associations, and natural history of pain in multiple sclerosis (MS) are poorly understood. The objective of this work was to study the prevalence of pain syndromes in MS both cross-sectionally, and longitudinally during the MS disease course. We systematically identified prospective studies detailing pain prevalence in definite MS. We used pooled prevalence estimates, explored heterogeneity using meta-regression, and analysed prevalence during the disease course using both estimates at disease milestones and longitudinal studies. Twenty-eight articles (7101 subjects) describing overall pain, or pain syndromes, met inclusion criteria. Pooled overall pain prevalence (17 studies, 5319 subjects) was 63% (95% confidence interval [CI] 55-70%). Marked heterogeneity in this estimate was not significantly explained by selected study design variables (use of outpatient sample, timeframe prior to study over which pain was assessed) or sample demographic variables (mean Expanded Disability Status Scale, mean disease duration, proportion of female sex, and proportion with progressive MS). We quantified prevalence of headache (43%; 95% CI 33-52%), neuropathic extremity pain (26%; 95% CI 7-53%), back pain (20%; 95% CI 13-28%), painful spasms (15%; 95% CI 8.5-23%), Lhermitte sign (16%; 95% CI 10-25%), and trigeminal neuralgia (3.8%; 95% CI 2-6%) in included studies. Prevalence of pain at MS disease milestones (prior to onset, at onset, and at relapse) and during longitudinal follow-up was poorly described. Pain is common in MS, as are specific pain syndromes. The clinical associations and natural history of pain in MS require clarification. Future study could be enhanced by standardised study design.

Clear reporting of research is crucial to the scientific process. Poorly designed and reported studies are damaging not only to the efforts of individual researchers, but also to science as a whole. Standardised reporting methods, such as those already established for reporting randomised clinical trials, have led to improved study design and facilitated the processes of clinical systematic review and meta-analysis. Such standards were lacking in the pre-clinical field until the development of the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines. These were prompted following a survey which highlighted a widespread lack of robust and consistent reporting of pre-clinical in vivo research, with reports frequently omitting basic information required for study replication and quality assessment. The resulting twenty item checklist in ARRIVE covers all aspects of experimental design with particular emphasis on bias reduction and methodological transparency. Influential publishers and research funders have already adopted ARRIVE. Further dissemination and acknowledgement of the importance of these guidelines is vital to their widespread implementation. Conclusions and implications Wide implementation of the ARRIVE guidelines for reporting of in vivo preclinical research, especially pain research, are essential for a much needed increased transparency and quality in publishing such research. ARRIVE will also positively influence improvements in experimental design and quality, assist the conduct of accurate replication studies of important new findings and facilitate meta-analyses of preclinical research.

Background: Malignant glioma is an aggressive tumour commonly associated with a dismal outcome despite optimal surgical and radio-chemotherapy. Since 2005 temozolomide has been established as first-line chemotherapy. We investigate the role of in vivo glioma models in predicting clinical efficacy.Methods: We searched three online databases to systematically identify publications testing temozolomide in animal models of glioma. Median survival and number of animals treated were extracted and quality was assessed using a 12-point scale; random effects meta-analysis was used to estimate efficacy. We analysed the impact of study design and quality and looked for evidence of publication bias.Results: We identified 60 publications using temozolomide in models of glioma, comprising 2443 animals. Temozolomide prolonged survival by a factor of 1.88 (95% CI 1.74-2.03) and reduced tumour volume by 50.4% (41.8-58.9) compared with untreated controls. Study design characteristics accounted for a significant proportion of between-study heterogeneity, and there was evidence of a significant publication bias.Conclusion: These data reflect those from clinical trials in that temozolomide improves survival and reduces tumour volume, even after accounting for publication bias. Experimental in vivo glioma studies of temozolomide differ from those of other glioma therapies in their consistent efficacy and successful translation into clinical medicine.

Traumatic brain injury (TBI) is a major cause of death and permanent disability. Systemic hypothermia, a treatment used in TBI for many decades, has recently been found to be associated with neutral or unfavourable clinical outcomes despite apparently promising preclinical research. Systematic review and meta‐analysis is a tool to summarize literature and observe trends in experimental design and quality that underpin its general conclusions. Here we aim to use these techniques to describe the use of hypothermia in animal TBI models, collating data relating to outcome and both study design and quality. From here we intend to observe correlations between features and attempt to explain any discrepancies found between animal and clinical data. This protocol describes the relevant methodology in detail.

The mortality and morbidity associated with stroke makes the development of new drugs a research priority. Recent unsuccessful clinical trials have reduced enthusiasm for the development of neuroprotective drugs. Here, we use empirical evidence derived from systematic reviews of stroke drug development to identify stages of drug development which might be improved. We then propose exemplar strategies which may be helpful, along with some basic economic modelling of what the impact of such strategies might be. This suggests that relatively straightforward measures might reduce the costs of drug development by $5.8 bn or 31%.

Introduction: A proximal myopathy develops in some patients with muscle channelopathies, but the causative molecular mechanisms are unknown. Methods: We reviewed retrospectively all clinical and muscle biopsy findings of 3 patients with channelopathy and additional myositis. Direct DNA sequencing was performed. Results: Pathogenic mutations were identified in each case. Biopsies demonstrated inflammatory infiltrates. Conclusions: Clinicians should consider muscle biopsy in channelopathy patients with severe myalgia and/or subacute weakness and accompanying elevated creatine kinase. Chance association of myositis and channelopathy is statistically unlikely. An alternative hypothesis suggests that inflammatory insults could contribute to myopathy in some patients. Muscle Nerve 44: 283-288, 2011

Background: Parkinson’s disease (PD) can be a severely disabling condition in spite of therapies currently available. Systematic review and meta-analysis can provide an overview of a field of research and identify potential sources of bias and limits to efficacy. In this study we use these tools to describe the reported efficacy of dopamine agonists in animal models of PD. Methods: Publications were identified by electronic searching of three online databases. Data were extracted for neurobehavioural outcome, for study design and for the reporting of measures to avoid bias. Standardised mean difference meta-analysis was used to provide summary estimates of efficacy, with the effects of study quality and study design explored using stratified meta-analysis. Results: 253 publications reported the use of a dopamine agonist in an animal model of PD; of these 121 reported data suitable for inclusion in meta-analysis. 47 interventions were tested in 601 experiments using 4181 animals. Overall, neurobehavioural outcome was improved by 1.08 standard deviations (SD; 95% Confidence Interval (CI) 0.97e1.19). Reporting of measures to reduce bias was low and publications which reported the blinded assessment of outcome had significantly smaller effect sizes (0.85, 95% CI 0.64 to 1.07) than those which did not (1.18, 95% CI 1.05 to 1.31, p < 0.005). Conclusions: While dopamine agonists do appear to have efficacy in animal models of PD the low prevalence of reporting of measures to avoid bias is of concern. Systematic review of individual interventions may be helpful in the design of future preclinical and clinical trials.

Background: In other neurological diseases, the failure to translate pre-clinical findings to effective clinical treatments has been partially attributed to bias introduced by shortcomings in the design of animal experiments. Objectives: Here we evaluate published studies of interventions in animal models of multiple sclerosis for methodological design and quality and to identify candidate interventions with the best evidence of efficacy. Methods: A systematic review of the literature describing experiments testing the effectiveness of interventions in animal models of multiple sclerosis was carried out. Data were extracted for reported study quality and design and for neurobehavioural outcome. Weighted mean difference meta-analysis was used to provide summary estimates of the efficacy for drugs where this was reported in five or more publications. Results: The use of a drug in a pre-clinical multiple sclerosis model was reported in 1152 publications, of which 1117 were experimental autoimmune encephalomyelitis (EAE). For 36 interventions analysed in greater detail, neurobehavioural score was improved by 39.6% (95% CI 34.9—44.2%, p < 0.001). However, few studies reported measures to reduce bias, and those reporting randomization or blinding found significantly smaller effect sizes. Conclusions: EAE has proven to be a valuable model in elucidating pathogenesis as well as identifying candidate therapies for multiple sclerosis. However, there is an inconsistent application of measures to limit bias that could be addressed by adopting methodological best practice in study design. Our analysis provides an estimate of sample size required for different levels of power in future studies and suggests a number of interventions for which there are substantial animal data supporting efficacy.

Translating experimental findings into clinically effective therapies is one of the major bottlenecks of modern medicine. As this has been particularly true for cerebrovascular research, attention has turned to the quality and validity of experimental cerebrovascular studies. We set out to assess the study design, statistical analyses, and reporting of cerebrovascular research. We assessed all original articles published in the Journal of Cerebral Blood Flow and Metabolism during the year 2008 against a checklist designed to capture the key attributes relating to study design, statistical analyses, and reporting. A total of 156 original publications were included (animal, in vitro, human). Few studies reported a primary research hypothesis, statement of purpose, or measures to safeguard internal validity (such as randomization, blinding, exclusion or inclusion criteria). Many studies lacked sufficient information regarding methods and results to form a reasonable judgment about their validity. In nearly 20% of studies, statistical tests were either not appropriate or information to allow assessment of appropriateness was lacking. This study identifies a number of factors that should be addressed if the quality of research in basic and translational biomedicine is to be improved. We support the widespread implementation of the ARRIVE (Animal Research Reporting In Vivo Experiments) statement for the reporting of experimental studies in biomedicine, for improving training in proper study design and analysis, and that reviewers and editors adopt a more constructively critical approach in the assessment of manuscripts for publication. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1064-1072; doi: 10.1038/jcbfm.2010.217; published online 15 December 2010

Background and Purpose— At least part of the failure in the transition from experimental to clinical studies in stroke has been attributed to the imprecision introduced by problems in the design of experimental stroke studies. Using a metaepidemiologic approach, we addressed the effect of randomization, blinding, and use of comorbid animals on the estimate of how effectively therapeutic interventions reduce infarct size. Methods— Electronic and manual searches were performed to identify meta-analyses that described interventions in experimental stroke. For each meta-analysis thus identified, a reanalysis was conducted to estimate the impact of various quality items on the estimate of efficacy, and these estimates were combined in a meta–meta-analysis to obtain a summary measure of the impact of the various design characteristics. Results— Thirteen meta-analyses that described outcomes in 15 635 animals were included. Studies that included unblinded induction of ischemia reported effect sizes 13.1% (95% CI, 26.4% to 0.2%) greater than studies that included blinding, and studies that included healthy animals instead of animals with comorbidities overstated the effect size by 11.5% (95% CI, 21.2% to 1.8%). No significant effect was found for randomization, blinded outcome assessment, or high aggregate CAMARADES quality score. Conclusions— We provide empirical evidence of bias in the design of studies, with studies that included unblinded induction of ischemia or healthy animals overestimating the effectiveness of the intervention. This bias could account for the failure in the transition from bench to bedside of stroke therapies.

The development of stroke drugs has been characterized by success in animal studies and subsequent failure in clinical trials. Animal studies might have overstated efficacy, or clinical trials might have understated efficacy; in either case we need to better understand the reasons for failure. Techniques borrowed from clinical trials have recently allowed the impact of publication and study-quality biases on published estimates of efficacy in animal experiments to be described. On the basis of these data, we propose minimum standards for the range and quality of pre-clinical animal data. We believe the adoption of these standards will lead to improved effectiveness and efficiency in the selection of drugs for clinical trials in stroke and in the design of those trials.

The care of the elderly physicians from another hospital asked us to take over the management of an 87-year-old man who lived alone. Other than osteoarthritis mainly affecting his left knee, surgery for prostatic hypertrophy four years earlier, a reducible right inguinal hernia and moderately high alcohol consumption, he had no significant medical history. He had smoked 15 cigarettes a day for many years. Remarkably, he had only used senna for occasional constipation and paracetamol for joint pain in the preceding few years. He did the Scotsman cryptic crossword daily. He had attended the elderly care out-patient clinic about 10 weeks before admission complaining of poor balance and new onset of falling. He attributed the falls to tripping rather than poor balance, and had no associated loss of consciousness. Three weeks before his transfer to neurology, he had been admitted to the elderly care ward following a night-time fall. He had become tangled in his duvet and fallen to the floor where he remained, unable to get up, until morning when a neighbour found him. He had not lost consciousness or experienced other symptoms prior to or during the fall, and he could not recall hitting his head. He felt that poor balance, stiff legs, and a recent onset (3–4 weeks) of double vision caused the fall. On examination at the time, his Mini-Mental State Examination score was 20 out of 30 and he had a right VI nerve palsy. The physicians thought his left leg was slightly weaker than the right, but found it difficult to be sure because of his knee pain. His reflexes were all normal and his plantar responses were flexor. The remainder of his examination was normal. He had a normal full blood …

The nuclear mineralocorticoid receptor (MR), a high-affinity receptor for glucocorticoids, is highly expressed in the hippocampus where it underpins cognitive, behavioural and neuroendocrine regulation. Increased neuronal MR expression occurs early in the response to cellular injury in vivo and in vitro and is associated with enhanced neuronal survival. To determine whether increased neuronal MR might be causal in protecting against ischaemic damage in vivo we generated a forebrain-specific MR-overexpressing transgenic mouse (MR-Tg) under the control of the CamKII alpha promoter, and subjected mice to transient cerebral global ischaemia induced by bilateral common carotid artery occlusion for 20 min. We also separately assessed the effects of MR overexpression on hypothalamic-pituitary-adrenal (HPA) axis activity and cognitive and affective functions in noninjured animals. Our results showed that MR-Tg mice had significantly reduced neuronal death following transient cerebral global ischaemia compared to wild-type littermates. This effect was not associated with alterations in basal or poststress HPA axis function or in arterial blood pressure. MR-Tg mice also demonstrated improved spatial memory retention, reduced anxiety and altered behavioural response to novelty. The induction of neuronal MR appears to offer a protective response which has potential therapeutic implications in cerebral ischaemia and cognitive and affective disorders.

Mineralocorticoid receptor expression is increased following neuronal injury, and this is associated with increased neuronal survival. Here we demonstrate a causal link between overexpression of MR in PC12 cells and protection against death induced by staurosporine and oxygen-glucose deprivation. This survival effect is abrogated by MR antagonism. Drugs which upregulate MR may form the basis for a novel therapeutic approach in conditions such as stroke and head injury.

Objective: To investigate the association between gender and deprivation and rates of admission to a national neurorehabilitation facility following subarachnoid haemorrhage or traumatic brain injury. Design: Retrospective analysis of hospital activity data. Setting: Lothian Health Board hospital activity; national neurorehabilitation centre. Subjects: Patients with subarachnoid haemorrhage or traumatic brain injury. Methods: We obtained data for hospital discharge for subarachnoid haemorrhage and traumatic brain injury for patients living in the Lothian Health Board area for the five years 1995 to 1999 by age (15 and over), sex and deprivation category of home residence from nationally held data sets. Similar data were extracted for discharges from the national neurorehabilitation unit. Main measures: Rates of neurorehabilitation admission per 1000 hospital admissions. Chi-squared testing was used to assess statistical significance. Results: Data for 13 338 hospital admissions and 329 neurorehabilitation admissions were available. We observed higher than expected rates of rehabilitation admission for men with subarachnoid haemorrhage and for patients from more affluent postcode sectors with traumatic brain injury. Conclusion: Higher rehabilitation rates are seen among men following subarachnoid haemorrhage and may indicate a focus on return-to-work in the referral or assessment of those suitable for or requiring neurorehabilitation. Higher rehabilitation rates in head injury in those from Carstairs Deprivation Category (DepCat) 2 postcode sectors may represent a bias favouring those from affluent areas in the interaction between the individual and the health service in this group.

Atrial fibrillation and severe carotid-artery stenosis are well-characterised risk factors for stroke; each is present in about a fifth of patients. The identification of such risk factors in patients is important because their presence calls for specific secondary prevention strategies. One region of the circulation that has received limited attention as a source of thrombus is the aortic arch. However, aortic arch atheroma is a common post-mortem finding, and it seems reasonable to speculate that atheroma might give rise to thrombi with distal embolism to the arterial tree, including the cerebral circulation. Here we review the evidence for aortic-arch atheroma as an important independent risk factor for stroke, and show that studies of the risk of stroke indicate a four times greater odds of stroke in patients with severe arch atheroma.

Although the macrolide immunosuppressant tacrolimus (FK506) is neuroprotective in animal models of focal and global cerebral ischaemia, the mechanism of this action is not known. FK506 inhibits the protein phosphatase calcineurin, whose substrates can include nitric oxide synthase (NOS), and the neuroprotective effect of FK506 has been attributed to inhibition of NOS activity. We have examined nitric oxide-mediated cyclic guanosine monophosphate (cGMP) accumulation in neonatal rat cerebellar prisms. As expected, N-methyl-D-aspartate (NMDA) induced a rapid, concentration dependent accumulation of cGMP that was inhibited by the NMDA receptor antagonist dizocilpine (MK801) and the NOS inhibitor L-nitro-arginine methyl ester. Phosphoserine immunopositivity following NMDA exposure was increased in the presence of FK506, confirming inhibition of calcineurin. However, FK506 had no effect on NMDA-stimulated cGMP accumulation. These findings suggest that the neuroprotective effect of FK506 may be mediated by mechanisms other than increased NOS phosphorylation.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling pain condition resulting from chemotherapy for cancer. Severe acute CIPN may require chemotherapy dose reduction or cessation. There is no effective CIPN prevention strategy; treatment of established chronic CIPN is limited, and the prevalence of CIPN is not known. Here we used a systematic review to identify studies reporting the prevalence of CIPN. We searched Embase, Medline, CAB Abstracts, CINAHL, PubMed central, Cochrane Library, and Web of Knowledge for relevant references and used random-effects meta-regression to estimate overall prevalence. We assessed study quality using the CONSORT and STROBE guidelines, and we report findings according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. We provide a qualitative summary of factors reported to alter the risk of CIPN. We included 31 studies with data from 4179 patients in our analysis. CIPN prevalence was 68.1% (57.7–78.4) when measured in the first month after chemotherapy, 60.0% (36.4–81.6) at 3months and 30.0% (6.4–53.5) at 6months or more. Different chemotherapy drugs were associated with differences in CIPN prevalence, and there was some evidence of publication bias. Genetic risk factors were reported in 4 studies. Clinical risk factors, identified in 4 of 31 studies, included neuropathy at baseline, smoking, abnormal creatinine clearance, and specific sensory changes during chemotherapy. Although CIPN prevalence decreases with time, at 6months 30% of patients continue to suffer from CIPN. Routine CIPN surveillance during post-chemotherapy follow-up is needed. A number of genetic and clinical risk factors were identified that require further study.

The pharmaceutical industry is in the doldrums. Food and Drug Administration drug approvals per year are falling steadily,1 and the costs of drug development are steadily increasing.2 However, although neuroscience as a whole may not be delivering the returns on investment we would like, the state of stroke medicine has never been better. Although changing lifestyles for the better often seems intractable, pharmacotherapy has delivered effective primary prevention. Control of blood pressure, cholesterol lowering, and control of clotting in atrial fibrillation are all providing benefit. The same approaches are effective in secondary prevention, in which antiplatelet therapies already have a long-established role. We also have even come slowly to the realization that the brain is malleable, and that therapy during the long-term rehabilitative phase of stroke is likely to help patients regain useful function. Despite this, we are still struggling to make gains in acute stroke treatment. Thrombolysis was first introduced in the 1990s after the National Institute of Neurological Disorders and Stroke (NINDS) trial in a period that saw intensive evaluation of a range of lytic approaches. However, only a small proportion of the patients who might benefit from this powerful treatment receive it.3 Surprisingly, despite the clear benefit of tissue-type plasminogen activator, we have still to complete the analysis of novel thrombolytics, such as desmoteplase and tenecteplase.3 Moreover, we seem to be on the verge of abandoning neuroprotection, one of the most extensively studied concepts in neuroscience.4 For all intents and purposes, Big Pharma has already done so despite convincing proof of concept in humans; neuroprotection by hypothermia is in routine use to prevent the neurological consequences of cardiac arrest in adults5 and hypoxic-ischemic encephalopathy in neonates.6 The pessimism within the pharmacological industry seems reasonable. More than 100 clinical trials of …

Interventions that improve functional outcome after acute intracerebral hemorrhage (ICH) in animals might benefit humans. Therefore, we systematically reviewed the literature to find studies of nonsurgical treatments tested in animal models of ICH.In July 2009 we searched Ovid Medline (from 1950), Embase (from 1980), and ISI Web of Knowledge (from 1969) for controlled animal studies of nonsurgical interventions given after the induction of ICH that reported neurobehavioral outcome. We assessed study quality and performed meta-analysis using a weighted mean difference random effects model.Of 13,343 publications, 88 controlled studies described the effects of 64 different medical interventions (given a median of 2 hours after ICH induction) on 38 different neurobehavioral scales in 2,616 treated or control animals (median 14 rodents per study). Twenty-seven (31%) studies randomized treatment allocation, and 7 (8%) reported allocation concealment; these studies had significantly smaller effect sizes than those without these attributes (p0.001). Of 64 interventions stem cells, calcium channel blockers, anti-inflammatory drugs, iron chelators, and estrogens improved both structural outcomes and neurobehavioral scores in1 study. Meta-regression revealed that together, structural outcome and the intervention used accounted for 65% of the observed heterogeneity in neurobehavioral score (p0.001, adjusted r(2) = 0.65).Further animal studies of the interventions that we found to improve both functional and structural outcomes in animals, using better experimental designs, could target efforts to translate effective treatments for ICH in animals into randomized controlled trials in humans.

The recent meta-analysis of NXY-059 in experimental stroke models using individual animal data found the drug to be an effective neuroprotective agent. However, the failure of translation of both this compound and many others from preclinical studies to the clinic indicates that new approaches must be used in drug discovery so that animal models become more reflective of the clinical situation, and studies using animal models of stroke mimic the design of studies performed in humans, as far as possible. In this review, we suggest that a fundamental paradigm shift is needed away from performing preclinical studies in individual laboratories to performing them in an organised group of independent laboratories. Studies should be run by a steering committee and should be supported by a coordinating centre, external data monitoring committee and outcome adjudication committee. This structure will mimic the practice of multicentre clinical trials. By doing so, future studies will minimise potential sources of bias including randomisation, concealment of allocation, blinding of surgery and outcome assessment and ensure publication of all data. It is likely that individual studies will involve increased heterogeneity and therefore will need to be larger. However, regular independent monitoring of data will allow development of interventions to be ceased immediately if neutral or negative data are obtained. The additional costs involved should be seen as reasonable when compared with the resources that would have been expended in running a clinical trial that subsequently proved negative.

The nuclear mineralocorticoid receptor (MR), a high-affinity receptor for glucocorticoids, is highly expressed in the hippocampus where it underpins cognitive, behavioural and neuroendocrine regulation. Increased neuronal MR expression occurs early in the response to cellular injury in vivo and in vitro and is associated with enhanced neuronal survival. To determine whether increased neuronal MR might be causal in protecting against ischaemic damage in vivo we generated a forebrain-specific MR-overexpressing transgenic mouse (MR-Tg) under the control of the CamKII alpha promoter, and subjected mice to transient cerebral global ischaemia induced by bilateral common carotid artery occlusion for 20 min. We also separately assessed the effects of MR overexpression on hypothalamic-pituitary-adrenal (HPA) axis activity and cognitive and affective functions in noninjured animals. Our results showed that MR-Tg mice had significantly reduced neuronal death following transient cerebral global ischaemia compared to wild-type littermates. This effect was not associated with alterations in basal or poststress HPA axis function or in arterial blood pressure. MR-Tg mice also demonstrated improved spatial memory retention, reduced anxiety and altered behavioural response to novelty. The induction of neuronal MR appears to offer a protective response which has potential therapeutic implications in cerebral ischaemia and cognitive and affective disorders.

This article presents a narrative review of the non-medical, medical and endovascular aspects of the management of acute ischaemic stroke in the posterior circulation, a potentially devastating condition with high mortality and substantial disability in many of those who survive. Optimal management requires a combination of supportive measures and specific interventions and is best delivered within a high-dependency or intensive care environment. Non-medical measures include management of physiological parameters, respiratory support where necessary and prompt treatment of complications such as the development of hydrocephalus. Deterioration in conscious state and progression of symptoms may occur some time after initial presentation and after admission to hospital; when such progression is detected, very rapid therapeutic reperfusion may be feasible. Reperfusion strategies include intravenous and intra-arterial thrombolysis (IAT) and mechanical methods to aid reperfusion, including the use of mechanical clot disruption, clot retrieval or stenting devices. The optimal reperfusion strategy, including considerations of whether to use intravenous or intra-arterial thrombolytic approaches, the use of bridging intravenous treatment prior to intra-arterial treatment, and the use of pharmacological or mechanical adjuncts to IAT is not known. However, it seems likely that the important determinant of therapeutic efficacy is the speed and safety with which reperfusion can be achieved. It may also be that the time available to achieve reperfusion is longer than in the anterior circulation.

Glucocorticoids, acting via the mineralocorticoid receptor, are required for granule neuronal survival in the rat dentate gyrus. Whether this mineralocorticoid receptor-mediated neuroprotective effect has more general applicability is unknown. Here we report increased mineralocorticoid receptor expression in rat hippocampal and cortical neurons exposed in vitro to low levels of staurosporine and in rat hippocampal pyramidal neurons exposed in vivo to hypothermic transient global ischaemia. In both the cell culture system and the in vivo system increased mineralocorticoid receptor expression is associated with increased neuronal survival, and this increase is reversed by mineralocorticoid receptor antagonism. Modulation of mineralocorticoid receptor gene expression may therefore be an important target for reduction of brain injury in conditions caused by cerebral ischaemia including brain damage following cardiac arrest and stroke.

Apoptosis is an important route to neuronal death in experimental models of stroke, the leading neurological cause of death and disability. Here we explore a role for ataxia telangiectasia mutated protein (ATM), an activator of p53, in a primary cortical culture model of stroke. NMDA-induced apoptosis was reduced in cultures derived from mice with targeted deletions in the ATM gene. In addition, NMDA-induced caspase-3 activity was abolished in cultures lacking two functioning copies of the ATM gene. These data provide evidence to suggest that, in primary cortical culture, NMDA-induced apoptosis is partially mediated through ATM. They provide further evidence to support the hypothesis that DNA damage is one route to apoptosis following neuronal injury.

Objective. To determine the impact of deprivation and gender on the incidence and emergency management of acute brain disorders. Design. Retrospective database review of mortality, hospital discharge, and ICU discharge data. Setting. Lothian Health Board area, 1995–1999. Patients and participants. All persons over the age of 15 dying or being discharged from hospital with a primary diagnosis of stroke, epilepsy, subarachnoid haemorrhage (SAH) or traumatic brain injury; patients registered in the Scottish Intensive Care Society Audit Database as having been discharged from the supraregional neurosciences intensive care unit with one of these as a primary diagnoses and a home postcode within the Lothian Health Board area. Measurements and results. Standardised ratios were calculated for hospital admission, mortality, and ICU admission by deprivation category and gender. Data were available for 29,205 hospital admissions, 5,227 deaths, and 360 ICU admissions. For all diagnoses, deprivation was associated with higher rates of hospital admission and death. Deprivation was associated with lower rates of ICU admission for traumatic brain injury and stroke. There was a U-shaped relationship between deprivation and ICU admission with epilepsy. There were no gender differences in rates of ICU admission. Males had higher rates of hospital admission for all conditions and of death from epilepsy and SAH, and lower rates of death from stroke. Conclusions. We have demonstrated deprivation- and gender- differences in the incidence and emergency management of four acute brain disorders. The identification of the source(s) of these differences is an important subject for further research.

See related article, pages 1878–1882 Advances in neuroimaging and an increase in the number of neuroimaging procedures performed have created a new management dilemma. Unruptured intracranial aneurysms (UIA) are found in ≈2% of people undergoing digital subtraction angiography1 and in 0.4% of people undergoing an MRI.2 The best risk management strategy in these patients is not known. Such patients are at increased risk for aneurysmal subarachnoid hemorrhage (SAH), but to know how they might best be managed, we need to understand more about the natural history of UIA, about factors that might provoke rupture, and about the risks and potential successes of intervention. In recent years, the Utrecht group,3 whose most recent work appears in this issue of Stroke , has contributed greatly to our understanding of these issues. The best estimate of the risk of rupture probably comes from the prospective arm of International Study of Unruptured Intracranial Aneurysms (ISUIA),4 which suggests an annual rupture risk of ≈0.1% for aneurysms 10 mm and most are in the anterior circulation. Paradoxically, despite this apparently very low rupture risk, most aneurysmal SAH appear to be attributable to rupture of small anterior circulation aneurysms. The most rational explanation, proposed by Wiebers et al5 and strongly supported by detailed mathematical modeling,6 is that most SAH arises from recently formed rather than long-standing aneurysms, although it is …