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Prof. Susie Dunachie has been awarded an NIHR Global Research Professorship. This is a flagship award in applied global health research with a particular focus on underfunded, under-researched areas. It aims to promote effective translation of research into practice by strengthening research leadership.
Regional contribution of vascular dysfunction in white matter dementia: clinical and neuropathological insights.
The maintenance of adequate blood supply and vascular integrity is fundamental to ensure cerebral function. A wide range of studies report vascular dysfunction in white matter dementias, a group of cerebral disorders characterized by substantial white matter damage in the brain leading to cognitive impairment. Despite recent advances in imaging, the contribution of vascular-specific regional alterations in white matter dementia has been not extensively reviewed. First, we present an overview of the main components of the vascular system involved in the maintenance of brain function, modulation of cerebral blood flow and integrity of the blood-brain barrier in the healthy brain and during aging. Second, we review the regional contribution of cerebral blood flow and blood-brain barrier disturbances in the pathogenesis of three distinct conditions: the archetypal white matter predominant neurocognitive dementia that is vascular dementia, a neuroinflammatory predominant disease (multiple sclerosis) and a neurodegenerative predominant disease (Alzheimer's). Finally, we then examine the shared landscape of vascular dysfunction in white matter dementia. By emphasizing the involvement of vascular dysfunction in the white matter, we put forward a hypothetical map of vascular dysfunction during disease-specific progression to guide future research aimed to improve diagnostics and facilitate the development of tailored therapies.
Imiquimod for actinic keratosis: systematic review and meta-analysis.
Benefit and harm associated with treating actinic keratosis (AK) with the immune response modifier imiquimod was assessed using published randomized-controlled trials. Five randomized double-blind trials lasted 12-16 weeks and treated 1,293 patients. Complete clearance occurred in 50% of patients treated with imiquimod, compared to 5% treated with vehicle, and the number needed to treat (NNT) for one patient to have their keratosis completely cleared after 12-16 weeks was 2.2 (95% confidence interval 2.0-2.5). For partial (>/=75%) clearance the NNT was 1.8 (1.7-2.0). The proportion of patients with any adverse event, any local adverse event, or any treatment-related adverse event was substantially higher with imiquimod than with vehicle, and numbers needed to harm for one additional adverse event with imiquimod over 12-16 weeks ranged from 3.2 to 5.9. Particular local adverse events with imiquimod included erythema (27%), scabbing or crusting (21%), flaking (9%), erosion (6%), edema (4%), and weeping (3%). Imiquimod 5% cream was effective in the treatment of AK, preventing potential development of squamous cell carcinoma. Future investigation might be aimed at elucidating optimal dosing to minimize adverse events without detriment to efficacy, and evaluating long-term recurrence.
Cognitive decline and diabetes: a systematic review of the neuropathological correlates accounting for cognition at death.
Given conflicting findings in epidemiologic studies, we determined the relative contributions of different neuropathologies to the excess risk of cognitive decline in diabetes mellitus (DM) through a systematic review of the literature. Included studies compared subjects with and without DM and reported neuropathological outcomes accounting for cognition at death. Data on Alzheimer's disease (AD) pathology, cerebrovascular disease and non-vascular, non-AD pathology were extracted from each study. Eleven studies (n=6 prospective cohorts, n=5 retrospective post-mortem series, total n=6330) met inclusion criteria. All 11 studies quantified AD changes and 10/11 measured cerebrovascular disease: macroscopic lesions (n=9), microinfarcts (n=8), cerebral amyloid angiopathy (CAA, n=7), lacunes (n=6), white matter disease (n=5), haemorrhages (n=4), microbleeds (n=1), hippocampal microvasculature (n=1). Other pathology was infrequently examined. No study reported increased AD pathology in DM, three studies showed a decrease (n=872) and four (n= 4018) showed no difference, after adjustment for cognition at death. No study reported reduced cerebrovascular pathology in DM. Three studies (n=2345) reported an increase in large infarcts, lacunes and microinfarcts. One study found lower cognitive scores in DM compared to non-DM subjects despite similar cerebrovascular and AD-pathology load suggesting contributions from other neuropathological processes. In conclusion, lack of an association between DM and AD-related neuropathology was consistent across studies, irrespective of methodology. In contrast to AD, DM was associated with increased large and small vessel disease. Data on other pathologies such as non-AD neurodegeneration, and blood-brain-barrier breakdown were lacking. Further studies evaluating relative contributions of different neuropathologies to the excess risk of DM are needed.
Stroke: management and prevention
Acute stroke treatment requires clear protocols to rapidly triage patients – using appropriate investigations – for mechanical thrombectomy and intravenous thrombolysis. Computed tomography (CT) excludes haemorrhage, CT angiography locates the occluded vessel, and CT perfusion and perfusion magnetic resonance imaging identify viable tissue. An organized approach to stroke care in a specialist environment reduces disability and saves lives. Adoption of a ‘care bundle’ approach, including the active management of pyrexia and hyperglycaemia, and early screening for swallowing difficulties, is beneficial. Tailored secondary prevention, including assessment of the carotid arteries, is urgent as, for eligible patients, carotid endarterectomy should be done within two weeks. Anticoagulation in elderly individuals with atrial fibrillation is safer than is often assumed, and direct oral anticoagulants have changed the landscape of secondary prevention.
Transdermal fentanyl for cancer pain.
BACKGROUND: Opioid drugs have been used for many years to relieve pain. Transdermal fentanyl offers one option for delivering and maintaining pain relief in patients with moderate or severe cancer pain. OBJECTIVES: To determine the analgesic efficacy of transdermal fentanyl for relief of cancer pain, and to assess the adverse events associated with the use of transdermal fentanyl for relief of cancer pain. SEARCH METHODS: The following databases were searched: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 4 of 12); MEDLINE (1966 to May 2013); EMBASE (1974 to May 2013; CANCERLIT (PubMED) (November 2012); and ClinicalTrials.gov (May 2013). SELECTION CRITERIA: Published randomised controlled trials (RCTs) using placebo or active comparators reporting on the analgesic effect of transdermal fentanyl in adults and children with cancer pain. Studies with fewer than 10 participants were excluded. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two review authors. We extracted any available data on the number or proportion of patients with 'no worse than mild pain' or treatment success (very satisfied, or very good or excellent on patient global impression scales), together with information about adverse events and withdrawals. MAIN RESULTS: We identified nine studies meeting the inclusion criteria, including a Turkish study that is awaiting formal translation. There were 1244 participants randomised in classically designed RCTs, of whom 1197 had evaluable data, and 138 patients enrolled in an enriched enrolment, randomised withdrawal (EERW) trial. Overall, 600 participants were treated with transdermal fentanyl patches, 382 with various formulations of morphine, 36 with methadone, and 221 with paracetamol plus codeine. There were major sources of potential bias, including lack of blinding, small size, high levels of attrition, and inconsistent reporting.We could not compare data in a meaningful analysis regarding adverse events such as nausea, abdominal pain, gastrointestinal bleeding, and confusion. These events may have been attributable to the underlying disease process.There were insufficient comparable data for meta-analysis to be undertaken or to produce numbers needed to treat (NNT) for the analgesic effect. In seven studies with 461 participants reporting pain intensity results after about two weeks, the mean or median pain scores were on the borderline of mild and moderate pain. Most participants would have had no worse than mild pain on treatment. Another reported that 77% of participants using transdermal fentanyl had an undefined successful outcome. Fewer participants experienced constipation with transdermal fentanyl (28%) than with oral morphine (46%), giving a risk ratio of 0.61 (95% CI 0.47 to 0.78); the NNT to prevent constipation was 5.5 (95% CI 3.8 to 10). AUTHORS' CONCLUSIONS: The randomised trial literature for effectiveness of transdermal fentanyl is limited, but it is an important medicine. Most studies recruited fewer than 100 participants and did not provide data appropriate for meta-analysis. Only a few reported how many patients had good pain relief but, where data were reported, a majority had no worse than mild pain within a reasonably short time period. The evidence pointed to a useful and significant reduction in complaints about constipation for transdermal fentanyl compared with oral morphine.
Stroke: management and prevention
Acute stroke treatment requires clear protocols to rapidly triage patients – using appropriate investigations – for endovascular thrombectomy and intravenous thrombolysis. Computed tomography (CT) excludes haemorrhage, CT angiography locates the occluded vessel, and perfusion magnetic resonance imaging identifies viable tissue. An organized approach to stroke care in a specialist environment reduces disability and saves lives. Adoption of a ‘care bundle’ approach including the active management of pyrexia and hyperglycaemia, and early screening for swallowing difficulties, is beneficial. Tailored secondary prevention, including assessment of the carotid arteries, is urgent as, for eligible patients, carotid endarterectomy should be done within 2 weeks. Anticoagulation in elderly individuals with atrial fibrillation is safer than is often assumed, and direct oral anticoagulants have changed the landscape of secondary prevention.
A method of inducing global cerebral ischemia
The four-vessel occlusion (4-VO) method of global forebrain cerebral ischemia mimics the human clinical condition of cardiac arrest. It results in selective neuronal damage and is a useful experimental system to dissect underlying mechanisms behind ischemic phenomena such as the differential susceptibility of CA1 compared to the CA3 region of the hippocampus. It also provides a "proof-of-principle" system for testing out potential agents for neuroprotection. © 2014 Springer Science+Business Media New York.
Importance of preclinical research in the development of neuroprotective strategies for ischemic stroke.
IMPORTANCE: Preclinical stroke research has had a remarkably low translational success rate, and the clinical need for novel neuroprotective therapeutics has gone largely unmet, especially in light of the severe underuse of thrombolysis in acute ischemic stroke. OBJECTIVE: In this review, we aim to provide a brief overview of the commonly used stroke models, their merits and shortcomings, and how these have contributed to translational failures. We review some recent developments in preclinical stroke, providing examples of how improved study quality and the use of novel methods can facilitate translation into the clinical setting. EVIDENCE REVIEW: This is a narrative review of ischemic stroke neuroprotection based on electronic database searches, references of previous publications, and personal libraries. FINDINGS: The stroke research community has not been complacent in its response to criticism: preclinical stroke studies now demonstrate considerable rigor, standardization, and emphasis on minimization of experimenter bias. In addition, numerous innovative methods and strategies are providing novel avenues for investigating neuroprotection, as well as more extensive characterization of established models. CONCLUSIONS AND RELEVANCE: The improvements in preclinical stroke models and methods will make stroke research a good example for preclinical medicine, in general, and will hopefully instill greater confidence in the clinical community regarding which compounds are worthy of further investigation in a clinical setting.
Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy.
Previous attempts to identify neuroprotective targets by studying the ischemic cascade and devising ways to suppress it have failed to translate to efficacious therapies for acute ischemic stroke. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia and the tolerance conferred by ischemic preconditioning (IPC), would reveal new neuroprotective targets. We found that the product of the tuberous sclerosis complex 1 gene (TSC1), hamartin, is selectively induced by ischemia in hippocampal CA3 neurons. In CA1 neurons, hamartin was unaffected by ischemia but was upregulated by IPC preceding ischemia, which protects the otherwise vulnerable CA1 cells. Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo increased the vulnerability of neurons to cell death following oxygen glucose deprivation (OGD) and ischemia. In vivo, suppression of TSC1 expression increased locomotor activity and decreased habituation in a hippocampal-dependent task. Overexpression of hamartin increased resistance to OGD by inducing productive autophagy through an mTORC1-dependent mechanism.
How useful are systematic reviews for informing palliative care practice? Survey of 25 Cochrane systematic reviews.
BACKGROUND: In contemporary medical research, randomised controlled trials are seen as the gold standard for establishing treatment effects where it is ethical and practical to conduct them. In palliative care such trials are often impractical, unethical, or extremely difficult, with multiple methodological problems. We review the utility of Cochrane reviews in informing palliative care practice. METHODS: Published reviews in palliative care registered with the Cochrane Pain, Palliative and Supportive Care Group as of December 2007 were obtained from the Cochrane Database of Systematic Reviews, issue 1, 2008. We reviewed the quality and quantity of primary studies available for each review, assessed the quality of the review process, and judged the strength of the evidence presented. There was no prior intention to perform any statistical analyses. RESULTS: 25 published systematic reviews were identified. Numbers of included trials ranged from none to 54. Within each review, included trials were heterogeneous with respect to patients, interventions, and outcomes, and the number of patients contributing to any single analysis was generally much lower than the total included in the review. A variety of tools were used to assess trial quality; seven reviews did not use this information to exclude low quality studies, weight analyses, or perform sensitivity analysis for effect of low quality. Authors indicated that there were frequently major problems with the primary studies, individually or in aggregate. Our judgment was that the reviewing process was generally good in these reviews, and that conclusions were limited by the number, size, quality and validity of the primary studies.We judged the evidence about 23 of the 25 interventions to be weak. Two reviews had stronger evidence, but with limitations due to methodological heterogeneity or definition of outcomes. No review provided strong evidence of no effect. CONCLUSION: Cochrane reviews in palliative care are well performed, but fail to provide good evidence for clinical practice because the primary studies are few in number, small, clinically heterogeneous, and of poor quality and external validity. They are useful in highlighting the weakness of the evidence base and problems in performing trials in palliative care.
Suppression of the inflammatory response by diphenyleneiodonium after transient focal cerebral ischemia.
Diphenyleneiodonium (DPI), a NADPH oxidase inhibitor, reduces production of reactive oxygen species (ROS) and confers neuroprotection to focal cerebral ischemia. Our objective was to investigate whether the neuroprotective action of DPI extends to averting the immune response. DPI-induced gene changes were analyzed by microarray analysis from rat brains subjected to 90 min of middle cerebral artery occlusion, treated with NaCl (ischemia), dimethylsulfoxide (DMSO), or DMSO and DPI (DPI), and reperfused for 48 h. The genomic expression profile was compared between groups using ingenuity pathway analysis at the pathway and network level. DPI selectively up-regulated 23 genes and down-regulated 75 genes more than twofold compared with both DMSO and ischemia. It significantly suppressed inducible nitric oxide synthase signaling and increased the expression of methionine adenosyltransferasesynthetase 2A and adenosylmethionine decarboxylase 1 genes, which are involved in increasing the production of the antioxidant glutathione. The most significantly affected gene network comprised genes implicated in the inflammatory response with an expression change indicating an overall suppression. Both integrin- and interleukin-17A-signaling pathways were also significantly associated and suppressed. In conclusion, the neuroprotective effects of DPI are mediated not only by suppressing ischemia-triggered oxidative stress but also by limiting leukocyte migration and infiltration.
Reality of evidence-based practice in palliative care.
There has been a paradigm shift in medicine away from tradition, anecdote and theoretical reasoning from the basic sciences towards evidence-based medicine (EBM). In palliative care however, statistically significant benefits may be marginal and may not be related to clinical meaningfulness. The typical treatment vs. placebo comparison necessitated by 'gold standard' randomised controlled trials (RCTs) is not necessarily applicable. The complex multimorbidity of end of life care involves considerations of the patient's physical, psychological, social and spiritual needs. In addition, the field of palliative care covers a heterogeneous group of chronic and incurable diseases no longer limited to cancer. Adequate sample sizes can be difficult to achieve, reducing the power of studies and high attrition rates can result in inadequate follow up periods. This review uses examples of the management of cancer-related fatigue and death rattle (noisy breathing) to demonstrate the current state of EBM in palliative care. The future of EBM in palliative care needs to be as diverse as the patients who ultimately derive benefit. Non-RCT methodologies of equivalent quality, validity and size conducted by collaborative research networks using a 'mixed methods approach' are likely to pose the correct clinical questions and derive evidence-based yet clinically relevant outcomes.
Neuroprotection in stroke: the importance of collaboration and reproducibility.
Acute ischaemic stroke accounts for 6.5 million deaths per year, and by 2030 will result in the annual loss of over 200 million disability-adjusted life years globally. There have been considerable recent advances in the gold standard of acute ischaemic stroke treatment, some aspects of which-aspirin to prevent recurrence, and treating patients in specialized stroke wards-are widely applicable. Recanalization of the occluded artery through thrombolysis and/or endovascular thrombectomy is restricted to only a small proportion of patients, due to contra-indications and the costs associated with establishing the infrastructure to deliver these treatments. The use of neuroprotective agents in stroke has been a notable failure of translation from medical research into clinical practice. Yet, with the advent of endovascular thrombectomy and the ability to investigate patients in much greater detail through advanced imaging modalities, neuroprotective agents can and should be re-examined as adjunct therapies to recanalization. In parallel, this requires appropriate planning on behalf of the preclinical stroke research community: there is a need to reinvestigate these therapies in a more collaborative manner, to enhance reproducibility through reduced attrition, improved reporting, and adopting an approach to target validation that more closely mimics clinical trials. This review will describe some of the novel strategies being used in stroke research, and focus on a few key examples of neuroprotective agents that are showing newfound promise in preclinical models of stroke therapy. Our primary aim is to give an overview of some of the challenges faced by preclinical stroke research, and suggest potential ways to improve translational success.
Endogenous neuroprotection: hamartin modulates an austere approach to staying alive in a recession.
Tuberous sclerosis complex 1 (hamartin) is an effective endogenous neuroprotectant. Understanding the endogenous mechanism for neuroprotection mediated by hamartin may afford a novel approach to effective treatment of neurological diseases such as stroke, neurodegenerative diseases, and epilepsy, with possible applications to nonneurological conditions.