Publications by authors named "John Grimley Evans"

34 Publications

Rivastigmine for Alzheimer's disease.

Cochrane Database Syst Rev 2015 Sep 22;9:CD001191. Epub 2015 Sep 22.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford, UK, OX3 7LD.

Background: Alzheimer's disease is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and lower risk of adverse effects have since been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA.

Objectives: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type.

Search Methods: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 2 March 2015 using the terms: Rivastigmine OR  exelon OR ENA OR "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries and grey literature sources.

Selection Criteria: We included all unconfounded, double-blind, randomised, controlled trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two formulations of rivastigmine were compared.

Data Collection And Analysis: One review author (JSB) applied the study selection criteria, assessed the quality of studies and extracted data.

Main Results: A total of 13 trials met the inclusion criteria of the review. The trials had a duration of between 12 and 52 weeks. The older trials tested a capsule form with a dose of up to 12 mg/day. Trials reported since 2007 have tested continuous dose transdermal patch formulations delivering 4.6, 9.5 and 17.7 mg/day.Our main analysis compared the safety and efficacy of rivastigmine 6 to 12 mg/day orally or 9.5 mg/day transdermally with placebo.Seven trials contributed data from 3450 patients to this analysis. Data from another two studies were not included because of a lack of information and methodological concerns. All the included trials were multicentre trials and recruited patients with mild to moderate Alzheimer's disease with a mean age of about 75 years. All had low risk of bias for randomisation and allocation but the risk of bias due to attrition was unclear in four studies, low in one study and high in two studies.After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score (mean difference (MD) -1.79; 95% confidence interval (CI) -2.21 to -1.37, n = 3232, 6 studies) and the Mini-Mental State Examination (MMSE) score (MD 0.74; 95% CI 0.52 to 0.97, n = 3205, 6 studies), activities of daily living (SMD 0.20; 95% CI 0.13 to 0.27, n = 3230, 6 studies) and clinician rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (OR 0.68; 95% CI 0.58 to 0.80, n = 3338, 7 studies).Three studies reported behavioural change, and there were no differences compared to placebo (standardised mean difference (SMD) -0.04; 95% CI -0.14 to 0.06, n = 1529, 3 studies). Only one study measured the impact on caregivers using the Neuropsychiatric Inventory-Caregiver Distress (NPI-D) scale and this found no difference between the groups (MD 0.10; 95% CI -0.91 to 1.11, n = 529, 1 study). Overall, participants who received rivastigmine were about twice as likely to withdraw from the trials (odds ratio (OR) 2.01, 95% CI 1.71 to 2.37, n = 3569, 7 studies) or to experience an adverse event during the trials (OR 2.16, 95% CI 1.82 to 2.57, n = 3587, 7 studies).

Authors' Conclusions: Rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, better outcomes were observed for rate of decline of cognitive function and activities of daily living, although the effects were small and of uncertain clinical importance. There was also a benefit from rivastigmine on the outcome of clinician's global assessment. There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers. At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy. The quality of evidence is only moderate for all of the outcomes reviewed because of a risk of bias due to dropouts. All the studies with usable data were industry funded or sponsored. This review has not examined economic data.
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http://dx.doi.org/10.1002/14651858.CD001191.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050299PMC
September 2015

Rivastigmine for Alzheimer's disease.

Cochrane Database Syst Rev 2015 Apr 10(4):CD001191. Epub 2015 Apr 10.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford, UK, OX3 7LD.

Background: Alzheimer's disease is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and lower risk of adverse effects have since been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA.

Objectives: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type.

Search Methods: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 2 March 2015 using the terms: Rivastigmine OR  exelon OR ENA OR "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries and grey literature sources.

Selection Criteria: We included all unconfounded, double-blind, randomised, controlled trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two formulations of rivastigmine were compared.

Data Collection And Analysis: One review author (JSB) applied the study selection criteria, assessed the quality of studies and extracted data.

Main Results: A total of 13 trials met the inclusion criteria of the review. The trials had a duration of between 12 and 52 weeks. The older trials tested a capsule form with a dose of up to 12 mg/day. Trials reported since 2007 have tested continuous dose transdermal patch formulations delivering 4.6, 9.5 and 17.7 mg/day.Our main analysis compared the safety and efficacy of rivastigmine 6 to 12 mg/day orally or 9.5 mg/day transdermally with placebo.Seven trials contributed data from 3450 patients to this analysis. Data from another two studies were not included because of a lack of information and methodological concerns. All the included trials were multicentre trials and recruited patients with mild to moderate Alzheimer's disease with a mean age of about 75 years. All had low risk of bias for randomisation and allocation but the risk of bias due to attrition was unclear in four studies, low in one study and high in two studies.After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score (mean difference (MD) -1.79; 95% confidence interval (CI) -2.21 to -1.37, n = 3232, 6 studies) and the Mini-Mental State Examination (MMSE) score (MD 0.74; 95% CI 0.52 to 0.97, n = 3205, 6 studies), activities of daily living (SMD 0.20; 95% CI 0.13 to 0.27, n = 3230, 6 studies) and clinician rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (OR 0.68; 95% CI 0.58 to 0.80, n = 3338, 7 studies).Three studies reported behavioural change, and there were no differences compared to placebo (standardised mean difference (SMD) -0.04; 95% CI -0.14 to 0.06, n = 1529, 3 studies). Only one study measured the impact on caregivers using the Neuropsychiatric Inventory-Caregiver Distress (NPI-D) scale and this found no difference between the groups (MD 0.10; 95% CI -0.91 to 1.11, n = 529, 1 study). Overall, participants who received rivastigmine were about twice as likely to withdraw from the trials (odds ratio (OR) 2.01, 95% CI 1.71 to 2.37, n = 3569, 7 studies) or to experience an adverse event during the trials (OR 2.16, 95% CI 1.82 to 2.57, n = 3587, 7 studies).

Authors' Conclusions: Rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, better outcomes were observed for rate of decline of cognitive function and activities of daily living, although the effects were small and of uncertain clinical importance. There was also a benefit from rivastigmine on the outcome of clinician's global assessment. There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers. At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy. The quality of evidence is only moderate for all of the outcomes reviewed because of a risk of bias due to dropouts. All the studies with usable data were industry funded or sponsored. This review has not examined economic data.
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http://dx.doi.org/10.1002/14651858.CD001191.pub3DOI Listing
April 2015

Questionnaire study of the association between patient numbers and regular visiting by general practitioners in care homes.

Age Ageing 2012 Mar 17;41(2):269-72. Epub 2012 Jan 17.

Green Templeton College, University of Oxford, 4, Gracious Street, Whittlesey, Peterborough PE7 1AP, UK.

Background: regular visiting in care homes enables proactive care. Surveys of managers found variation in medical care yet little is known about factors influencing general practitioners (GPs) visiting patterns. We examined whether practice factors including numbers of registered patients are associated with regular visiting.

Design And Setting: postal questionnaires sent to 73 care homes of European Care Group and separate questionnaires to visiting practices.

Methods: information on regularity of visiting was requested from homes and practices. Practices were asked for numbers of doctors and training status. As data were not normally distributed, non-parametric tests were used to compare practices regularly visiting with those visiting only on request in terms of numbers of registered care home patients.

Results: forty-seven (64%) of homes responded, with care provided for 1,867 patients by 162 practices. Practices visiting regularly had significantly more patients than practices that did not [median (IQR) 32 (28) versus 3 (5), P < 0.001]. Ninety-five (31%) of practices responded showing a similar association of registrations with regular visiting [median (IQR) 20 (37) versus 4 (4), P < 0.001]. There was no association between numbers of doctors or training status on regular visiting.

Conclusion: the number of registered patients is strongly associated with regular care home visiting. Aligning practices with care homes thereby increasing registered patients per practice could encourage proactive care.
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http://dx.doi.org/10.1093/ageing/afr183DOI Listing
March 2012

Geriatrics.

Clin Med (Lond) 2011 Apr;11(2):166-8

University of Oxford.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922742PMC
http://dx.doi.org/10.7861/clinmedicine.11-2-166DOI Listing
April 2011

Psychogenic pseudo-Tourette syndrome: one of Dr Johnson's maladies?

J R Soc Med 2010 Dec;103(12):500-2

Green Templeton College Oxford OX2 6HG England.

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http://dx.doi.org/10.1258/jrsm.2010.100208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996528PMC
December 2010

Association of depression with subsequent mortality, cardiovascular morbidity and incident dementia in people aged 80 and over and suffering from hypertension. Data from the Hypertension in the Very Elderly Trial (HYVET).

Age Ageing 2010 Jul 23;39(4):439-45. Epub 2010 May 23.

Imperial College London, UK.

Background: depression is common in elderly people and may be associated with increased cardiovascular risk and incident dementia.

Method: participants in the Hypertension in the Very Elderly Trial (HYVET) completed a depression screening instrument, the Geriatric Depression Score (GDS), at baseline and annually. We examined the association of GDS score with incident stroke, mortality and dementia using Cox proportional hazards models (hazard ratios, HR and 95% confidence intervals, CI) adjusted for treatment group and other potential confounders.

Results: 2,656 HYVET participants completed the GDS. The mean follow-up was 2.1 years. A GDS score > or =6 was associated with increased risks of all-cause (HR 1.8, 95% CI 1.4-2.3) and cardiovascular mortality (HR 2.10, 95% CI 1.5-3.0), all stroke (HR 1.8, 95% CI 1.2-2.8) and all cardiovascular events (HR 1.6, 95% CI 1.2-2.1). Risk of incident dementia also tended to be increased (HR 1.28, 95% CI 0.95-1.73). Each additional GDS point at baseline also gave rise to a significantly increased risk of fatal and non-fatal cardiovascular events, all-cause mortality and dementia.

Conclusion: there was a strong association between baseline depression scores and later fatal and non-fatal cardiovascular endpoints over a mean follow-up of 2 years in a hypertensive very elderly group. The mechanism of this association warrants further study.
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http://dx.doi.org/10.1093/ageing/afq042DOI Listing
July 2010

Rivastigmine for Alzheimer's disease.

Cochrane Database Syst Rev 2009 Apr 15(2):CD001191. Epub 2009 Apr 15.

Centre for Statistics in Medicine, University of Oxford, Wolfson College, Linton Road, Oxford, UK, OX2 6UD.

Background: Alzheimer's disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and low risk of adverse effects, have now been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA.

Objectives: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type.

Search Strategy: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 27 March 2008 using the terms: Rivastigmine OR exelon OR ENA OR "SDZ ENA 713" . The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many clinical trials registries and grey literature sources.

Selection Criteria: All unconfounded, double-blind, randomized trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for more than two weeks and its effects compared with those of placebo in a parallel group of patients.

Data Collection And Analysis: One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data.

Main Results: Nine trials, involving 4775 participants, were included in the analyses. Use of rivastigmine in high doses was associated with statistically significant benefits on several measures. High-dose rivastigmine (6 to 12 mg daily) was associated with a two-point improvement in cognitive function on the ADAS-Cog score compared with placebo (weighted mean difference -1.99, 95% confidence interval -2.49 to -1.50, on an intention-to-treat basis) and a 2.2 point improvement in activities of daily living assessed on the Progressive Deterioration Scale (weighted mean difference -2.15, 95% confidence interval -3.16 to -1.13, on an intention-to-treat basis) at 26 weeks. At lower doses (4 mg daily or lower) differences were in the same direction but were statistically significant only for cognitive function. There were statistically significantly higher numbers of events of nausea, vomiting, diarrhoea, anorexia, headache, syncope, abdominal pain and dizziness among patients taking high-dose rivastigmine than among those taking placebo. There was some evidence that adverse events might be less common with more frequent, smaller doses of rivastigmine. The 2008 update includes a new study testing two types of rivastigmine transdermal patch, one delivering a higher dose than previously tested (17.4 mg/day) and a smaller patch delivering 9.6 mg/day. The efficacy of the smaller patch was not significantly different compared with the capsules of similar daily dose, but was associated with significantly fewer adverse events of nausea, vomiting, dizziness and asthenia. The efficacy of the larger patch was not significantly different compared with the smaller patch, but the smaller patch was associated with significantly fewer adverse events of nausea, vomiting, weight loss and dizziness. There appears to be advantages associated with the smaller patch compared with both the higher dose patch and the 6-12 mg/day capsules.

Authors' Conclusions: Rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, improvements were seen in the rate of decline of cognitive function, activities of daily living, and severity of dementia with daily doses of 6 to 12 mg. Adverse events were consistent with the cholinergic actions of the drug. A transdermal patch has been tested in one trial, and there is evidence that the lower dose smaller patch is associated with fewer side effects than the capsules or the higher dose larger patch and has comparable efficacy to both. This review has not examined economic data.
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http://dx.doi.org/10.1002/14651858.CD001191.pub2DOI Listing
April 2009

Ginkgo biloba for cognitive impairment and dementia.

Cochrane Database Syst Rev 2009 Jan 21(1):CD003120. Epub 2009 Jan 21.

Centre for Statistics in Medicine, University of Oxford, Wolfson College, Linton Road, Oxford, UK, OX2 6UD.

Background: Extracts of the leaves of the maidenhair tree, Ginkgo biloba, have long been used in China as a traditional medicine for various disorders of health. A standardized extract is widely prescribed for the treatment of a range of conditions including memory and concentration problems, confusion, depression, anxiety, dizziness, tinnitus and headache. The mechanisms of action are thought to reflect the action of several components of the extract and include increasing blood supply by dilating blood vessels, reducing blood viscosity, modification of neurotransmitter systems, and reducing the density of oxygen free radicals.

Objectives: To assess the efficacy and safety of Ginkgo biloba for dementia or cognitive decline.

Search Strategy: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 20 September 2007 using the terms: ginkgo*, tanakan, EGB-761, EGB761, "EGB 761" and gingko*. The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources.

Selection Criteria: Randomized, double-blind studies, in which extracts of Ginkgo biloba at any strength and over any period were compared with placebo for their effects on people with acquired cognitive impairment, including dementia, of any degree of severity.

Data Collection And Analysis: Data were extracted from the published reports of the included studies, pooled where appropriate and the treatment effects or the risks and benefits estimated.

Main Results: 36 trials were included but most were small and of duration less than three months. Nine trials were of six months duration (2016 patients). These longer trials were the more recent trials and generally were of adequate size, and conducted to a reasonable standard. Most trials tested the same standardised preparation of Ginkgo biloba, EGb 761, at different doses, which are classified as high or low. The results from the more recent trials showed inconsistent results for cognition, activities of daily living, mood, depression and carer burden. Of the four most recent trials to report results three found no difference between Ginkgo biloba and placebo, and one found very large treatment effects in favour of Ginkgo biloba.There are no significant differences between Ginkgo biloba and placebo in the proportion of participants experiencing adverse events.A subgroup analysis including only patients diagnosed with Alzheimer's disease (925 patients from nine trials) also showed no consistent pattern of any benefit associated with Ginkgo biloba.

Authors' Conclusions: Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and publication bias cannot be excluded. The evidence that Ginkgo biloba has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable.
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http://dx.doi.org/10.1002/14651858.CD003120.pub3DOI Listing
January 2009

Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people.

Cochrane Database Syst Rev 2008 Oct 8(4):CD004514. Epub 2008 Oct 8.

Department of Psychiatry, Oxfordshire and Buckinghamshire Mental Health Trust, John Radcliffe Hospital (4th Floor, Room 4401C), Headington, Oxford, UK, OX3 9DU.

Background: Folate deficiency can result in congenital neural tube defects and megaloblastic anaemia. Low folate levels may be due to insufficient dietary intake or inefficient absorption, but impaired metabolic utilization also occurs.Because B12 deficiency can produce a similar anaemia to folate deficiency, there is a risk that folate supplementation can delay the diagnosis of B12 deficiency, which can cause irreversible neurological damage. Folic acid supplements may sometimes therefore include vitamin B12 supplements with simultaneous administration of vitamin B12.Lesser degrees of folate inadequacy are associated with high blood levels of the amino acid homocysteine which has been linked with the risk of arterial disease, dementia and Alzheimer's disease. There is therefore interest in whether dietary supplementation can improve cognitive function in the elderly.However, any apparent benefit from folic acid which was given in combination with B12 needs to be "corrected" for any effect of vitamin B12 alone. A separate Cochrane review of vitamin B12 and cognitive function has therefore been published.

Objectives: To examine the effects of folic acid supplementation, with or without vitamin B12, on elderly healthy or demented people, in preventing cognitive impairment or retarding its progress.

Search Strategy: Trials were identified from a search of the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 10 October 2007 using the terms: folic acid, folate, vitamin B9, leucovorin, methyltetrahydrofolate, vitamin B12, cobalamin and cyanocobalamin. This Register contains references from all major health care databases and many ongoing trials databases. In addition MEDLINE, EMBASE, CINAHL, PsychINFO and LILACS were searched (years 2003-2007) for additional trials of folate with or without vitamin B12 on healthy elderly people.

Selection Criteria: All double-blind, placebo-controlled, randomized trials, in which supplements of folic acid with or without vitamin B12 were compared with placebo for elderly healthy people or people with any type of dementia or cognitive impairment.

Data Collection And Analysis: The reviewers independently applied the selection criteria and assessed study quality. One reviewer extracted and analysed the data. In comparing intervention with placebo, weighted mean differences and standardized mean difference or odds ratios were estimated.

Main Results: Eight randomized controlled trials fulfilled the inclusion criteria for this review. Four trials enrolled healthy older people, and four recruited participants with mild to moderate cognitive impairment or dementia with or without diagnosed folate deficiency. Pooling the data was not possible owing to heterogeneity in sample selections, outcomes, trial duration, and dosage. Two studies involved a combination of folic acid and vitamin B12.There is no adequate evidence of benefit from folic acid supplementation with or without vitamin B12 on cognitive function and mood of unselected healthy elderly people. However, in one trial enrolling a selected group of healthy elderly people with high homocysteine levels, 800 mcg/day folic acid supplementation over three years was associated with significant benefit in terms of global functioning (WMD 0.05, 95% CI 0.004 to 0.096, P = 0.033); memory storage (WMD 0.14, 95% CI 0.04 to 0.24, P = 0.006) and information-processing speed (WMD 0.09, 95% CI 0.02 to 0.16, P = 0.016).Four trials involved people with cognitive impairment. In one pilot trial enrolling people with Alzheimer's disease, the overall response to cholinesterase inhibitors significantly improved with folic acid at a dose of 1mg/day (odds ratio: 4.06, 95% CI 1.22 to 13.53; P = 0.02) and there was a significant improvement in scores on the Instrumental Activities of Daily Living and the Social Behaviour subscale of the Nurse's Observation Scale for Geriatric Patients (WMD 4.01, 95% CI 0.50 to 7.52, P = 0.02). Other trials involving people with cognitive impairment did not show any benefit in measures of cognitive function from folic acid, with or without vitamin B12.Folic acid plus vitamin B12 was effective in reducing serum homocysteine concentrations (WMD -5.90, 95% CI -8.43 to -3.37, P < 0.00001). Folic acid was well tolerated and no adverse effects were reported.

Authors' Conclusions: The small number of studies which have been done provide no consistent evidence either way that folic acid, with or without vitamin B12, has a beneficial effect on cognitive function of unselected healthy or cognitively impaired older people. In a preliminary study, folic acid was associated with improvement in the response of people with Alzheimer's disease to cholinesterase inhibitors. In another, long-term use appeared to improve the cognitive function of healthy older people with high homocysteine levels. More studies are needed on this important issue.
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http://dx.doi.org/10.1002/14651858.CD004514.pub2DOI Listing
October 2008

Folate and vitamin B12 status in relation to cognitive impairment and anaemia in the setting of voluntary fortification in the UK.

Br J Nutr 2008 Nov 17;100(5):1054-9. Epub 2008 Mar 17.

Clinical Trial Service Unit, University of Oxford, Oxford, UK.

Concerns about risks for older people with vitamin B12 deficiency have delayed the introduction of mandatory folic acid fortification in the UK. We examined the risks of anaemia and cognitive impairment in older people with low B12 and high folate status in the setting of voluntary fortification in the UK. Data were obtained from two cross-sectional studies (n 2403) conducted in Oxford city and Banbury in 1995 and 2003, respectively. Associations (OR and 95 % CI) of cognitive impairment and of anaemia with low B12 status (holotranscobalamin < 45 pmol/l) with or without high folate status (defined either as serum folate >30 nmol/l or >60 nmol/l) were estimated after adjustment for age, sex, smoking and study. Mean serum folate levels increased from 15.8 (sd 14.7) nmol/l in 1995 to 31.1 (sd 26.2) nmol/l in 2003. Serum folate levels were greater than 30 nmol/l in 9 % and greater than 60 nmol/l in 5 %. The association of cognitive impairment with low B12 status was unaffected by high v. low folate status (>30 nmol/l) (OR 1.50 (95 % CI 0.91, 2.46) v. 1.45 (95 % CI 1.19, 1.76)), respectively. The associations of cognitive impairment with low B12 status were also similar using the higher cut-off point of 60 nmol/l for folate status ((OR 2.46; 95 % CI 0.90, 6.71) v. (1.56; 95 % CI 1.30, 1.88)). There was no evidence of modification by high folate status of the associations of low B12 with anaemia or cognitive impairment in the setting of voluntary fortification, but periodic surveys are needed to monitor fortification.
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http://dx.doi.org/10.1017/S0007114508958001DOI Listing
November 2008

Low vitamin B-12 status and risk of cognitive decline in older adults.

Am J Clin Nutr 2007 Nov;86(5):1384-91

Clinical Trial Service Unit, University of Oxford,, University of Oxford, Oxford, United Kingdom.

Background: Elevated total homocysteine (tHcy) concentrations have been associated with cognitive impairment, but it is unclear whether low vitamin B-12 or folate status is responsible for cognitive decline.

Objective: We examined the associations of cognitive decline with vitamin B-12 and folate status in a longitudinal cohort study performed from 1993 to 2003 in Oxford, United Kingdom.

Design: Cognitive function was assessed with the Mini-Mental State Examination on >/=3 occasions during 10 y and related to serum concentrations of vitamin B-12, holotranscobalamin (holoTC), tHcy, methylmalonic acid (MMA), and folate with the use of linear mixed models in 1648 participants who provided blood in 1995.

Results: Cognitive function declined abruptly at younger ages in some participants but remained intact in others until very old age. In multivariate regression analyses after adjustment for established risk factors, concentrations of holoTC (a marker of reduced vitamin B-12 status), tHcy, and MMA predicted cognitive decline, but folate did not. A doubling in holoTC concentrations (from 50 to 100 pmol/L) was associated with a 30% slower rate of cognitive decline (-0.137 to -0.083), whereas a doubling in tHcy (from 10 to 20 micromol/L) or MMA (from 0.25 to 0.50 micromol/L) was associated with >50% more rapid cognitive decline (-0.090 to -0.169) and (-0.104 to -0.169), respectively. After adjustment for all vitamin markers simultaneously, the associations of cognitive decline with holoTC and MMA remained significant.

Conclusions: Low vitamin B-12 status was associated with more rapid cognitive decline. Randomized trials are required to determine the relevance of vitamin B-12 supplementation for prevention of dementia.
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http://dx.doi.org/10.1093/ajcn/86.5.1384DOI Listing
November 2007

Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin.

Clin Chem 2007 May 15;53(5):963-70. Epub 2007 Mar 15.

Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom.

Background: Impaired vitamin B(12) function and decreased vitamin B(12) status have been associated with neurological and cognitive impairment. Current assays analyze total vitamin B(12) concentration, only a small percentage of which is metabolically active. Concentrations of this active component, carried on holotranscobalamin (holoTC), may be of greater relevance than total vitamin B(12).

Methods: We compared the utility of serum holoTC with conventional vitamin B(12) for detection of vitamin B(12) deficiency in a population-based study of older people, using increased methylmalonic acid (MMA) concentrations as a marker of metabolic vitamin B(12) deficiency in the overall population (n = 2403) and in subsets with normal (n = 1651) and abnormal (n = 752) renal function.

Results: Among all participants, 6% had definite (MMA >0.75 micromol/L) and 16% had probable (MMA >0.45 micromol/L) metabolic vitamin B(12) deficiency. In receiver operating characteristic curves for detection of definite vitamin B(12) deficiency, holoTC had a greater area under the curve (AUC) compared with vitamin B(12) in all participants (0.85 vs 0.76; P <0.001) and in subsets with normal (AUC: 0.87 vs 0.79; P <0.001) and abnormal (AUC: 0.85 vs 0.74; P = 0.002) renal function. Similar findings were observed for detection of moderate vitamin B(12) deficiency. Whereas the positive predictive value for both holoTC and vitamin B(12) was greater for detection of probable than definite vitamin B(12) deficiency, both tests were associated with more false-positive than true-positive test results.

Conclusions: HoloTC has a modestly superior diagnostic accuracy compared with conventional vitamin B(12) for the detection of vitamin B(12) deficiency, but neither test can be recommended to screen asymptomatic populations.
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http://dx.doi.org/10.1373/clinchem.2006.080382DOI Listing
May 2007

Absence of relationship between MTTP haplotypes and longevity.

J Gerontol A Biol Sci Med Sci 2007 Feb;62(2):202-5

Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK.

Background: Polymorphisms for the microsomal triglyceride transfer protein (MTTP) gene have been associated with longevity and with lower risk for cardiovascular mortality. However, the association of MTTP with longevity has been contested in a large German collection of nonagenarians and centenarians.

Methods: We made a detailed characterization of MTTP haplotype carrier status in a cohort of 1398 old men and women (mean age 78 years) and a population-based cohort (n = 777) of younger controls (mean age 40 years) in Oxford, England.

Results: There were no significant differences in haplotypes for MTTP gene between the younger and older age groups.

Conclusion: This study, which adopted a more detailed genetic analysis of the MTTP gene in a large case-control study of older people provides reliable evidence against any significant association of the MTTP gene with longevity.
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http://dx.doi.org/10.1093/gerona/62.2.202DOI Listing
February 2007

Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study.

Age Ageing 2006 Jul 18;35(4):416-22. Epub 2006 May 18.

Hightown Surgery, Hightown Gardens, Banbury, UK.

Background: low vitamin B12 concentrations are common in older people, but the clinical relevance of biochemical evidence of vitamin B12 deficiency in the absence of anaemia is uncertain.

Objective: to examine associations of cognitive impairment, depression and neuropathy with blood measurements of vitamin B12 and folate status in older people.

Design: cross-sectional study in general practice in Banbury, England.

Participants: a total of 1,000 individuals aged 75 years or older living in the community.

Results: low vitamin B12 concentrations were identified in 13% of older people and were associated with memory impairment and depression. After adjustment for age, sex and smoking, individuals with vitamin B12 or holotranscobalamin (holoTC) in the bottom compared with top quartiles had a 2-fold risk (OR = 2.17; 95% CI 1.11-4.27) and a 3-fold risk (OR = 3.02; 95% CI 1.31-6.98) of cognitive impairment, respectively. Low vitamin B12 status was also associated with missing ankle tendon jerks but not with depression. Treatment with vitamin B12 for 3 months corrected the biochemical abnormalities but had no effect on any of the clinical measurements.

Conclusions: low vitamin B12 concentrations are associated with cognitive impairment and missing ankle tendon jerks in older people in the absence of anaemia. Large-scale trials of vitamin B12 supplementation are required to assess the clinical significance of these associations.
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http://dx.doi.org/10.1093/ageing/afl033DOI Listing
July 2006

Interactions among polymorphisms in folate-metabolizing genes and serum total homocysteine concentrations in a healthy elderly population.

Am J Clin Nutr 2006 Mar;83(3):708-13

Department of Internal Medicine, University of California, Davis, Davis, CA, USA.

Background: Homocysteine concentrations are influenced by vitamin status and genetics, especially several polymorphisms in folate-metabolizing genes.

Objective: We examined the interactions and associations with serum total homocysteine (tHcy) and folate concentrations of polymorphisms in the following folate-metabolizing genes: methylenetetrahydrofolate reductase (MTHFR), reduced folate carrier 1 (RFC1), and glutamate carboxypeptidase II (GCPII).

Design: Healthy volunteers (436 men and 606 women; mean age: 77.9 y) were randomly selected from among residents of Oxford, United Kingdom. We determined the individual effects and interactions of the MTHFR 677C-->T, MTHFR 1298A-->C, RFC1 80G-->A, and GCPII 1561C-->T polymorphisms on serum tHcy and folate concentrations.

Results: Subjects with the MTHFR 677TT genotype had higher serum tHcy concentrations than did those with the MTHFR 677CC genotype (P < 0.001), and this effect was greater in subjects with low serum folate status (P for interaction = 0.026). The MTHFR 1298A-->C, RFC1 80G-->A, and GCPII 1561C-->T polymorphisms had no individual effects on serum tHcy or folate concentrations. There was no interactive effect of the MTHFR 677C-->T and MTHFR 1298A-->C polymorphisms on tHcy concentrations. An interaction (P = 0.05) was observed between the MTHFR 677TT and RFC1 80GG genotypes, whereby persons with this genotype combination had a mean (+/-SEM) serum tHcy concentration (18.5 +/- 1.2 micromol/L) that was 5.1 micromol/L greater than the mean value of 13.4 +/- 0.2 micromol/L for the whole population.

Conclusions: Folate and tHcy concentrations were not affected individually by the MTHFR 1298A-->C, RFC1 80G-->A, or GCPII 1561C-->T polymorphisms or by combinations of the MTHFR 677C-->T and MTHFR 1298A-->C genotypes. An interaction between the MTHFR 677TT and RFC1 80GG genotypes was observed whereby persons with this combination had higher serum tHcy.
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http://dx.doi.org/10.1093/ajcn.83.3.708DOI Listing
March 2006

Candidate gene association studies of genes involved in neuronal cholinergic transmission in Alzheimer's disease suggests choline acetyltransferase as a candidate deserving further study.

Am J Med Genet B Neuropsychiatr Genet 2005 Jan;132B(1):5-8

Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK

Consistent deficits in the cholinergic system are evident in the brains of Alzheimer's Disease (AD) patients, including reductions in the activities of acetylcholine, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT), increased butyrylcholinesterase (BChE) activity, and a selective loss of nicotinic acetylcholine receptors (nAChRs). Accordingly, we have analyzed polymorphisms in the genes encoding AChE, ChAT, BChE, and several of the subunit genes from neuronal nAChRs, for genetic associations with late-onset AD. A significant association for disease was detected for a non-coding polymorphism in ChAT (allele chi(1) (2) = 12.84, P = 0.0003; genotype chi(2) (2) = 11.89, P = 0.0026). Although replication analysis did not confirm the significance of this finding when the replication samples were considered alone (allele chi(1) (2) = 1.02, P = 0.32; genotype chi(2) (2) = 1.101, P = 0.58) the trends were in the correct direction and a significant association remained when the two sample sets were pooled (allele chi(1) (2) = 12.37, P = 0.0004; genotype chi(2) (2) = 11.61, P = 0.003). Previous studies have reported significant disease associations for both the K-variant of BChE and the coding ChAT rs3810950 polymorphism with AD. Replication analyses of these two loci failed to detect any significant association for disease in our case-control samples.
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http://dx.doi.org/10.1002/ajmg.b.30068DOI Listing
January 2005

Candidate gene association study of solute carrier family 11a members 1 (SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease.

Neurosci Lett 2005 Feb;374(2):124-8

Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Rd., Cambridge CB2 2XY, UK.

Divalent cations are strongly implicated in Alzheimer's disease (AD) pathogenesis, and can regulate amyloid beta-peptide aggregation. The proton-divalent cation transporters encoded by SLC11A1 (formerly NRAMP1) on chromosome 2q35, and SLC11A2 (also known as DCT1 and DMT1) on chromosome 12q13, are expressed in the brain and regulate ion homeostasis from endosomal compartments. SLC11A1 also has pleiotropic effects on pro-inflammatory responses that may be important in AD. We analyzed seven informative polymorphisms in the SLC11A1 and SLC11A2 genes encoding these divalent cation transporters in a sample of 216 late-onset AD cases and 323 age-matched controls. We found only borderline evidence (p=0.08) for an allelic association between SNP rs407135 at SLC11A2 and AD, in which the variant allele was protective (odd ratio (OR) 0.77; 95% CI 0.56-1.04) relative to the more common allele. There was no interaction with apolipoprotein E (APOE) varepsilon4, but stratification by gender showed that all of the effect of SLC11A2 was in the male patient group. No other associations with AD were observed at SLC11A1 or SLC11A2, indicating no major effect of either gene for the occurrence of AD.
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http://dx.doi.org/10.1016/j.neulet.2004.10.038DOI Listing
February 2005

Commentary: geriatrics in the United kingdom: what happened next.

J Gerontol A Biol Sci Med Sci 2004 Nov;59(11):1160-1; discussion 1132-52

Clinical Geratology, University of Oxford, Green College, Oxford OX2 6HG, England.

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http://dx.doi.org/10.1093/gerona/59.11.1160DOI Listing
November 2004

Dangerous jobsworths.

Br J Gen Pract 2004 Nov;54(508):870

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1324931PMC
November 2004

Donepezil for the symptomatic treatment of patients with mild to moderate Alzheimer's disease: a meta-analysis of individual patient data from randomised controlled trials.

Int J Geriatr Psychiatry 2004 Jul;19(7):624-33

The University of Reading, Medical and Pharmaceutical Statistics Research Unit, Reading, UK.

Background: The objective was to evaluate the efficacy and tolerability of donepezil (5 and 10 mg/day) compared with placebo in alleviating manifestations of mild to moderate Alzheimer's disease (AD).

Method: A systematic review of individual patient data from Phase II and III double-blind, randomised, placebo-controlled studies of up to 24 weeks and completed by 20 December 1999. The main outcome measures were the ADAS-cog, the CIBIC-plus, and reports of adverse events.

Results: A total of 2376 patients from ten trials were randomised to either donepezil 5 mg/day (n = 821), 10 mg/day (n = 662) or placebo (n = 893). Cognitive performance was better in patients receiving donepezil than in patients receiving placebo. At 12 weeks the differences in ADAS-cog scores were 5 mg/day-placebo: - 2.1 [95% confidence interval (CI), - 2.6 to - 1.6; p < 0.001], 10 mg/day-placebo: - 2.5 ( - 3.1 to - 2.0; p < 0.001). The corresponding results at 24 weeks were - 2.0 ( - 2.7 to - 1.3; p < 0.001) and - 3.1 ( - 3.9 to - 2.4; p < 0.001). The difference between the 5 and 10 mg/day doses was significant at 24 weeks (p = 0.005). The odds ratios (OR) of improvement on the CIBIC-plus at 12 weeks were: 5 mg/day-placebo 1.8 (1.5 to 2.1; p < 0.001), 10 mg/day-placebo 1.9 (1.5 to 2.4; p < 0.001). The corresponding values at 24 weeks were 1.9 (1.5 to 2.4; p = 0.001) and 2.1 (1.6 to 2.8; p < 0.001). Donepezil was well tolerated; adverse events were cholinergic in nature and generally of mild severity and brief in duration.

Conclusion: Donepezil (5 and 10 mg/day) provides meaningful benefits in alleviating deficits in cognitive and clinician-rated global function in AD patients relative to placebo. Increased improvements in cognition were indicated for the higher dose.
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http://dx.doi.org/10.1002/gps.1133DOI Listing
July 2004

Evidence-based pharmacotherapy of Alzheimer's disease.

Int J Neuropsychopharmacol 2004 Sep 1;7(3):351-69. Epub 2004 Jul 1.

Cochrane Dementia and Cognitive Improvement Group, University of Oxford, UK.

Dementia is an acquired global impairment of cognitive capacities. Approximately 5% of people aged over 65 yr are affected by dementia, and some 70% of cases are thought to be due primarily to Alzheimer's disease. Descriptions of the clinical manifestations of Alzheimer's disease have been increasingly refined in the last decade but there is no diagnostic test for what remains fundamentally a pathologically defined condition. At the present time interventions for Alzheimer's disease are limited to those that modify the manifestations of the disease, and foremost amongst the candidates available are the cholinesterase inhibitors. The rationale for the use of cholinergic drugs for Alzheimer's disease lies in enhancing the secretion of, or prolonging the half-life of, acetylcholine in the brain. Several potential compounds have been tested, but short half-lives and a high incidence of cholinergic and other adverse effects have eliminated most. Only three are widely licensed for use, donepezil, galantamine and rivastigmine. Their efficacy is relatively modest. These drugs have been tested in 32 randomized, placebo-controlled trials. The trials assess cognitive function primarily, and in addition they may assess global function, activities of daily living, quality of life and behavioural disturbance typically over 3 or 6 months. The performance of each drug is summarized in a Cochrane review, a systematic review carried out according to strict guidelines. There was a significant benefit in favour of treatment compared with placebo for cognition and activities of daily living, but withdrawals due to adverse events were significantly higher for treatment than placebo for all three drugs. There is little evidence from direct comparisons between the three drugs. There are several economic analyses of the cost-effectiveness of these drugs, but the findings cannot be considered robust owing to inadequate data. A range of other pharmacological treatments have been tested, including selegiline, piracetam, vitamin E, Ginkgo biloba, anti-inflammatory drugs and hormone replacement therapy, but, so far, Cochrane reviews have not established the efficacy of these interventions for Alzheimer's disease. A Cochrane review of memantine shows benefits on cognitive and global function of the same order of magnitude as seen for the cholinesterase inhibitors. Memantine has been licensed in Europe for treatment of patients with moderately severe to severe Alzheimer's disease.
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http://dx.doi.org/10.1017/S1461145704004444DOI Listing
September 2004

It is not just the patient...

Lancet 2004 Mar;363(9414):1070

Division of Clinical Gerontology, The Radcliffe Infirmary, Oxford OX2 6HE, UK.

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http://dx.doi.org/10.1016/S0140-6736(04)15845-5DOI Listing
March 2004

Candidate gene association studies of the alpha 4 (CHRNA4) and beta 2 (CHRNB2) neuronal nicotinic acetylcholine receptor subunit genes in Alzheimer's disease.

Neurosci Lett 2004 Mar;358(2):142-6

Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.

Consistent deficits in the cholinergic system are evident in Alzheimer's disease (AD) patients, including selective loss of alpha4beta2 nicotinic acetylcholine receptors in the brains of AD patients. Knockout mice for the beta2 subunit have impaired neuronal survival in ageing. Accordingly, we have analysed polymorphisms in the genes that encode the alpha4 and beta2 subunits, CHRNA4 and CHRNB2 respectively, for genetic associations with late-onset AD. A significant association for disease was observed for a non-coding polymorphism in CHRNB2 (odds ratio=0.57, 95% confidence interval=0.35-0.95, P=0.024). Replication analysis was performed in two further sample sets. While these did not individually yield significant results, a significant association remained when all samples were pooled (odds ratio=0.70, 95% confidence interval=0.52-0.95, P=0.019). These data suggest that this variant warrants further examination in large case-control series.
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http://dx.doi.org/10.1016/j.neulet.2004.01.016DOI Listing
March 2004

Screening for vitamin B-12 and folate deficiency in older persons.

Am J Clin Nutr 2003 May;77(5):1241-7

Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom.

Background: Vitamin B-12 deficiency is usually accompanied by elevated concentrations of serum total homocysteine (tHcy) and methylmalonic acid (MMA). Folate deficiency also results in elevated tHcy. Measurement of these metabolites can be used to screen for functional vitamin B-12 or folate deficiency.

Objective: We assessed the prevalence of vitamin B-12 and folate deficiency in a population-based study (n = 1562) of older persons living in Oxford City, United Kingdom.

Design: We postulated that, as vitamin B-12 or folate concentrations declined from adequate to impaired levels, tHcy (or MMA) concentrations would increase. Individuals were classified as being at high risk of vitamin B-12 deficiency if they had low vitamin B-12 (< 150 pmol/L) or borderline vitamin B-12 (150-200 pmol/L) accompanied by elevated MMA (> 0.35 micromol/L) or tHcy (> 15.0 micromol/L). Individuals were classified as being at high risk of folate deficiency if they had low folate (< 5 nmol/L) or borderline folate (5-7 nmol/L) accompanied by elevated tHcy (> 15 micromol/L).

Results: Cutoffs of 15.0 micro mol/L for tHcy and 0.35 micro mol/L for MMA identified persons with normal or elevated concentrations. Among persons aged 65-74 and >or= 75 y, respectively, approximately 10% and 20% were at high risk of vitamin B-12 deficiency. About 10% and 20%, respectively, were also at high risk of folate deficiency. About 10% of persons with vitamin B-12 deficiency also had folate deficiency.

Conclusion: Use of tHcy or MMA among older persons with borderline vitamin concentrations may identify those at high risk of vitamin B-12 deficiency who should be considered for treatment.
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http://dx.doi.org/10.1093/ajcn/77.5.1241DOI Listing
May 2003

Drugs and falls in later life.

Lancet 2003 Feb;361(9356):448

Green College, OX2 6HE, Oxford, UK.

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http://dx.doi.org/10.1016/S0140-6736(03)12502-0DOI Listing
February 2003

The gifts reserved for age.

Int J Epidemiol 2002 Aug;31(4):792-5

University of Oxford, Green College, Oxford OX2 6HG, UK.

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http://dx.doi.org/10.1093/ije/31.4.792DOI Listing
August 2002

Neuromuscular stimulation of the quadriceps muscle after hip fracture: a randomized controlled trial.

Arch Phys Med Rehabil 2002 Aug;83(8):1087-92

Interdisciplinary Research Centre in Health, Coventry University, UK.

Objective: To study the feasibility and effect of neuromuscular stimulation on recovery of mobility after surgical fixation for hip fracture.

Design: Double-blind study with stratified randomization.

Setting: Home-based rehabilitation program.

Participants: Twenty-four women over the age of 75 years with hip fracture.

Interventions: Neuromuscular or placebo stimulation of the quadriceps muscle of the fractured leg, applied for 3 hours a day, for 6 weeks, commencing 1 week after surgery.

Main Outcome Measures: Recovery of walking speed and ability, postural stability, lower-limb muscle power, and pain at 7 and 13 weeks after surgery.

Results: Women in the neuromuscular stimulation group showed faster recovery of mobility. Of the women receiving stimulation, 9 of 12 recovered their prior levels of indoor mobility ability by 13 weeks compared with 3 of 12 in the placebo group (Fisher exact test, P=.046). There were no differences in recovery of walking speed in the first 7 weeks, but women in the stimulation group had greater recovery between 7 and 13 weeks (mean difference=-.13m/s; 95% confidence interval, -.23 to -.01).

Conclusions: Neuromuscular stimulation at home is feasible and may be effective in speeding recovery of mobility after surgical fixation of hip fracture.
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http://dx.doi.org/10.1053/apmr.2002.33645DOI Listing
August 2002