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Showing papers by "Clinical Trial Service Unit published in 2013"


Journal ArticleDOI
TL;DR: Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease, and the increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years.
Abstract: Background Radiotherapy for breast cancer often involves some incidental exposure of the heart to ionizing radiation. The effect of this exposure on the subsequent risk of ischemic heart disease is uncertain. Methods We conducted a population-based case-control study of major coronary events (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease) in 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001 in Sweden and Denmark; the study included 963 women with major coronary events and 1205 controls. Individual patient information was obtained from hospital records. For each woman, the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from her radiotherapy chart. Results The overall average of the mean doses to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray (95% confidence interval, 2.9 to 14.5; P Conclusions Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women. (Funded by Cancer Research UK and others.).

2,885 citations


Journal ArticleDOI
21 May 2013-BMJ
TL;DR: The increased incidence of cancer after CT scan exposure in this cohort was mostly due to irradiation, and future CT scans should be limited to situations where there is a definite clinical indication, with every scan optimised to provide a diagnostic CT image at the lowest possible radiation dose.
Abstract: Objective To assess the cancer risk in children and adolescents following exposure to low dose ionising radiation from diagnostic computed tomography (CT) scans. Design Population based, cohort, data linkage study in Australia. Cohort members 10.9 million people identified from Australian Medicare records, aged 0-19 years on 1 January 1985 or born between 1 January 1985 and 31 December 2005; all exposures to CT scans funded by Medicare during 1985-2005 were identified for this cohort. Cancers diagnosed in cohort members up to 31 December 2007 were obtained through linkage to national cancer records. Main outcome Cancer incidence rates in individuals exposed to a CT scan more than one year before any cancer diagnosis, compared with cancer incidence rates in unexposed individuals. Results 60 674 cancers were recorded, including 3150 in 680 211 people exposed to a CT scan at least one year before any cancer diagnosis. The mean duration of follow-up after exposure was 9.5 years. Overall cancer incidence was 24% greater for exposed than for unexposed people, after accounting for age, sex, and year of birth (incidence rate ratio (IRR) 1.24 (95% confidence interval 1.20 to 1.29); P Conclusions The increased incidence of cancer after CT scan exposure in this cohort was mostly due to irradiation. Because the cancer excess was still continuing at the end of follow-up, the eventual lifetime risk from CT scans cannot yet be determined. Radiation doses from contemporary CT scans are likely to be lower than those in 1985-2005, but some increase in cancer risk is still likely from current scans. Future CT scans should be limited to situations where there is a definite clinical indication, with every scan optimised to provide a diagnostic CT image at the lowest possible radiation dose.

1,655 citations


Journal ArticleDOI
TL;DR: Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status, and a further reduction in recurrence and mortality, particularly after year 10.

1,637 citations



Journal ArticleDOI
TL;DR: The results suggest that among UK women born around 1940, two-thirds of all deaths of smokers in their 50s, 60s, and 70s are caused by smoking; smokers lose at least 10 years of lifespan.

626 citations


Journal ArticleDOI
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) as mentioned in this paper examined the patterns of health loss in the UK, the leading preventable risks that explain some of these patterns, and how UK outcomes compare with a set of comparable countries in the European Union and elsewhere in 1990 and 2010.

527 citations


Journal ArticleDOI
30 Jul 2013-PLOS ONE
TL;DR: In this article, the effects of major metabolic risk factors on the risk of cardiovascular diseases (CVD) and diabetes by age and sex were investigated in a large cohort pooling project.
Abstract: Background The effects of systolic blood pressure (SBP), serum total cholesterol (TC), fasting plasma glucose (FPG), and body mass index (BMI) on the risk of cardiovascular diseases (CVD) have been established in epidemiological studies, but consistent estimates of effect sizes by age and sex are not available. Methods We reviewed large cohort pooling projects, evaluating effects of baseline or usual exposure to metabolic risks on ischemic heart disease (IHD), hypertensive heart disease (HHD), stroke, diabetes, and, as relevant selected other CVDs, after adjusting for important confounders. We pooled all data to estimate relative risks (RRs) for each risk factor and examined effect modification by age or other factors, using random effects models. Results Across all risk factors, an average of 123 cohorts provided data on 1.4 million individuals and 52,000 CVD events. Each metabolic risk factor was robustly related to CVD. At the baseline age of 55–64 years, the RR for 10 mmHg higher SBP was largest for HHD (2.16; 95% CI 2.09–2.24), followed by effects on both stroke subtypes (1.66; 1.39–1.98 for hemorrhagic stroke and 1.63; 1.57–1.69 for ischemic stroke). In the same age group, RRs for 1 mmol/L higher TC were 1.44 (1.29–1.61) for IHD and 1.20 (1.15–1.25) for ischemic stroke. The RRs for 5 kg/m2 higher BMI for ages 55–64 ranged from 2.32 (2.04–2.63) for diabetes, to 1.44 (1.40–1.48) for IHD. For 1 mmol/L higher FPG, RRs in this age group were 1.18 (1.08–1.29) for IHD and 1.14 (1.01–1.29) for total stroke. For all risk factors, proportional effects declined with age, were generally consistent by sex, and differed by region in only a few age groups for certain risk factor-disease pairs. Conclusion Our results provide robust, comparable and precise estimates of the effects of major metabolic risk factors on CVD and diabetes by age group.

486 citations


Journal ArticleDOI
TL;DR: In this paper, the authors assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification and found no significant difference in EFS between the groups given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5, 92·8-98·2; unadjusted odds ratio 1·00, 95 percent CI 0·43-2·31; twosided p=0·99).
Abstract: Summary Background Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification. Methods Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1–24 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD [less than 0·01%] at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119. Findings Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42–72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1–97·7) and that given two delayed intensifications (95·5%, 92·8–98·2; unadjusted odds ratio 1·00, 95% CI 0·43–2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI −5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3–8·9) given one delayed intensification and six (2·4%, 0·2–4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0–2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one ( Interpretation Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy. Funding Medical Research Council and Leukaemia and Lymphoma Research.

381 citations


Journal ArticleDOI
TL;DR: Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment, and there was no significant effect of folic Acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site.

286 citations


Journal ArticleDOI
TL;DR: In this population of women diagnosed with breast cancer during 1973–2008, the radiation-related risks were larger in the third decade after exposure than during the first two decades.
Abstract: Radiation-related mortality from heart disease and lung cancer more than 20 years after radiotherapy for breast cancer

243 citations


Journal ArticleDOI
TL;DR: In adult Chinese, physical activity varies substantially by occupation, and lack of physical activity and excess sedentary leisure time are independently and jointly associated with greater adiposity.

Journal ArticleDOI
17 Oct 2013-Nature
TL;DR: GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility tostatin-induced myopathy.
Abstract: Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 060) Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy

Journal ArticleDOI
TL;DR: The aim of PROSPER is to address deficiencies in methodological quality and size by comparing the relative merits of different procedures in rectal prolapse treatment.
Abstract: Aim Rectal prolapse is a profoundly disabling condition, occurring mainly in elderly and parous women. There is no accepted standard surgical treatment, with previous studies limited in methodological quality and size. PROSPER aimed to address these deficiencies by comparing the relative merits of different procedures. Method In a pragmatic, factorial (2 × 2) design trial, patients could be randomised between abdominal and perineal surgery (i), and suture vs resection rectopexy for those receiving an abdominal procedure (ii) or Altemeier's vs Delorme's for those receiving a perineal procedure (iii). Primary outcome measures were recurrence of the prolapse, incontinence, bowel function and quality of life scores (Vaizey, bowel thermometer and EQ-5D) measured up to 3 years. Results Two hundred and ninety-three patients were recruited: 49 were randomised between surgical approaches (i); 78 between abdominal procedures (ii); and 213 between perineal procedures (iii). Recurrence rates were higher than anticipated, but not significantly different in any comparison: Altemeier's vs Delorme's 24/102 (24%) and 31/99 (31%) [hazard ratio (HR) 0.81; 95% CI 0.47, 1.38; P = 0.4]; resection vs suture rectopexy 4/32 (13%) and 9/35 (26%) (HR 0.45; 95% CI 0.14, 1.46; P = 0.2); perineal vs abdominal 5/25 (20%) and 5/19 (26%) (HR 0.83; 95% CI 0.24, 2.86; P = 0.8). Vaizey, bowel thermometer and EQ-5D scores were not significantly different in any of the comparisons. Conclusion No significant differences were seen in any of the randomised comparisons, although substantial improvements from baseline in quality of life were noted following all procedures.

Journal ArticleDOI
TL;DR: DEVTA contradicts the expectation from other trials that vitamin A supplementation would reduce child mortality by 20–30%, but cannot rule out some more modest effect.

Journal ArticleDOI
TL;DR: In this article, the authors explored whether genetic variants associated with end-stage coagulati are associated with the pathogenesis of ischemic stroke and found that they were associated with fibrin structure and function.
Abstract: Objective: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulati ...

Journal ArticleDOI
TL;DR: Patients with NAFLD, particularly those with NASH, have a higher prevalence and incidence of clinically manifested cardiovascular disease, independently of classical cardiometabolic risk factors.
Abstract: Non-alcoholic fatty liver disease (NAFLD) currently represents the most common liver disease in Western countries, being found in 25-30% of the general population. NAFLD embraces a wide range of metabolic hepatic damage characterised by steatosis and, in some cases, associated non-alcoholic steatohepatitis (NASH). The long-term hepatic prognosis of NAFLD patients depends on the histological stage at diagnosis: simple steatosis has a favourable outcome, whereas patients with NASH can develop cirrhosis and other liver-related complications, including hepatocellular carcinoma. Progression of fibrosis is thought to develop in up to one third of NASH patients, including the development of cirrhosis, but regression is also possible in pre-cirrhotic stages. Independent predictors of fibrosis are older age, diabetes, obesity, hypertension, and the degree of insulin resistance. Patients with NAFLD, particularly those with NASH, have a higher prevalence and incidence of clinically manifested cardiovascular disease, independently of classical cardiometabolic risk factors. Hepatocellular carcinoma (HCC) is usually diagnosed at a late stage, but it may also occur in non-cirrhotic NASH, as obesity and diabetes both independently increases the risk of developing HCC. Liver-related mortality is increased up to ten-fold in patients with NASH.

Journal ArticleDOI
TL;DR: The prevalence and patterns of drinking in China differ greatly by age, sex and geographical region, and drinking alcohol was positively correlated with regular smoking, blood pressure and heart rate and was associated with 2 mmHg higher systolic blood pressure.
Abstract: Background Drinking alcohol has a long tradition in Chinese culture. However, data on the prevalence and patterns of alcohol consumption in China, and its main correlates, are limited. Methods During 2004–08 the China Kadoorie Biobank recruited 512 891 men and women aged 30–79 years from 10 urban and rural areas of China. Detailed information on alcohol consumption was collected using a standardized questionnaire, and related to socio-demographic, physical and behavioural characteristics in men and women separately. Results Overall, 76% of men and 36% of women reported drinking some alcohol during the past 12 months, with 33% of men and 2% of women drinking at least weekly; the prevalence of weekly drinking in men varied from 7% to 51% across the 10 study areas. Mean consumption was 286 g/week and was higher in those with less education. Most weekly drinkers habitually drank spirits, although this varied by area, and beer consumption was highest among younger drinkers; 37% of male weekly drinkers (12% of all men) reported weekly heavy drinking episodes, with the prevalence highest in younger men. Drinking alcohol was positively correlated with regular smoking, blood pressure and heart rate. Among male weekly drinkers, each 20 g/day alcohol consumed was associated with 2 mmHg higher systolic blood pressure. Potential indicators of problem drinking were reported by 24% of male weekly drinkers. Conclusion The prevalence and patterns of drinking in China differ greatly by age, sex and geographical region. Alcohol consumption is associated with a number of unfavourable health behaviours and characteristics.

Journal ArticleDOI
10 Jan 2013-Blood
TL;DR: It is concluded that matched sibling donor myeloablative HCT improves survival only for younger patients, with an absolute benefit of approximately 10% at 5 years, and improved chemotherapy outcomes and reduced nonrelapse mortality associated with allogeneic HCT may change the relative effects of these treatments in the future.

Journal ArticleDOI
TL;DR: The authors, who are experienced clinical trialists, propose a framework for expediting the conduct of clinical trials and reducing what they perceive as unnecessary bureaucracy in current trial regulations.
Abstract: The authors, who are experienced clinical trialists, propose a framework for expediting the conduct of clinical trials and reducing what they perceive as unnecessary bureaucracy in current trial regulations.

Journal ArticleDOI
TL;DR: Existing ICDS village staff can be organised to deliver simple pre- school interventions sustainably for many years at low cost, but regular deworming had little effect on mortality in this lightly infected pre-school population of north India.

Journal ArticleDOI
01 Jan 2013-Leukemia
TL;DR: Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy.
Abstract: Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes (NOTCH1(WT)FBXW7(WT)), 38% single NOTCH1 mutant (NOTCH1(Single)FBXW7(WT)), 3% just FBXW7 mutant (NOTCH1(WT)FBXW7(MUT)) and 24% either double NOTCH1 mutant (NOTCH1(Double)FBXW7(WT)) or mutant in both genes (NOTCH1(MUT)FBXW7(MUT)), hereafter called as NOTCH1±FBXW7(Double). There was no difference between groups in early response to therapy, but NOTCH1±FBXW7(Double) patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1(WT)FBXW7(WT) patients (71% versus 40%, P=0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1(WT)FBXW7(WT), NOTCH1(Single)FBXW7(WT) and NOTCH1±FBXW7(Double) patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1±FBXW7(Double) patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy.

Journal ArticleDOI
TL;DR: Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid responses.
Abstract: Aims Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response. Methods and results A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1 , and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE , and SLCO1B1 . The largest and most significant effects were with LPA and APOE , but were only 2–3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response. Conclusions Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited.

Journal ArticleDOI
TL;DR: Despite strong inverse and apparently independent associations of 25(OH)D with vascular and non-vascular mortality, causality remains uncertain and large-scale randomized trials are required to assess the clinical relevance of these associations.
Abstract: We examined associations of plasma concentrations of 25(OH)D and cause-specific mortality in a prospective study of older men living in the UK and included findings in meta-analyses of similar studies identified by a systematic search reporting on vascular and all-cause mortality. In a 13-year follow-up of 5409 men (mean baseline age 77 years), 1358 died from vascular and 1857 from non-vascular causes. Median season-adjusted baseline 25(OH)D concentration was 56 (interquartile range: 45-67) nmol/L. After adjustment for age and seasonality, higher concentrations of 25(OH)D were inversely and approximately linearly (log-log scale) associated with vascular and non-vascular mortality throughout the range 40-90 nmol/L. After additional adjustment for prior disease and cardiovascular risk factors, a doubling in 25(OH)D concentration was associated with 20% (95% confidence interval (CI): 9-30%) lower vascular and 23% (95% CI: 14-31%) lower non-vascular mortality. In meta-analyses of prospective studies, individuals in the top vs. bottom quarter of 25(OH)D concentrations had 21% (95% CI: 13-28%) lower vascular and 28% (95% CI: 24-32%) lower all-cause mortality.

Journal ArticleDOI
TL;DR: There was little inter-observer variation in the estimated dose of the heart and left anterior descending coronary artery, especially when guidelines were used, and for the LADCA there was substantial variation inThe estimated dose, which was not reduced with guidelines.


Journal ArticleDOI
23 Oct 2013-Trials
TL;DR: The ATTILA trial meets a pressing need for robust, generalisable evidence to either justify continuing investment or reappraise the appropriate scale of ATT use, as there is an absence of robust evidence for the cost-effectiveness and benefit of using assistive technology and telecare.
Abstract: Background: Assistive technology and telecare (ATT) are relatively new ways of delivering care and support to people with social care needs. It is claimed that ATT reduces the need for community care, prevents unnecessary hospital admission, and delays or prevents admission into residential or nursing care. The current economic situation in England has renewed interest in ATT instead of community care packages. However, at present, the evidence base to support claims about the impact and effectiveness of ATT is limited, despite its potential to mitigate the high financial cost of caring for people with dementia and the social and psychological cost to unpaid carers. Method/design: ATTILA (Assistive Technology and Telecare to maintain Independent Living At Home for People with Dementia) is a pragmatic, multi-centre, randomised controlled trial over 104 weeks that compares outcomes for people with dementia who receive ATT and those who receive equivalent community services but not ATT. The study hypothesis is that fewer people in the ATT group will go into institutional care over the 4-year period for which the study is funded. The study aims to recruit 500 participants, living in community settings, with dementia or significant cognitive impairment, who have recently been referred to social services. Primary outcome measures are time in days from randomisation to institutionalisation and cost effectiveness. Secondary outcomes are caregiver burden, health-related quality of life in carers, number and severity of serious adverse events, and data on acceptability, applicability and reliability of ATT intervention packages. Assessments will be undertaken in weeks 0 (baseline), 12, 24, 52 and 104 or until institutionalisation or withdrawal of the participant from the trial. Discussion: In a time of financial austerity, CASSRs in England are increasingly turning to ATT in the belief that it will deliver good outcomes for less money. There is an absence of robust evidence for the cost-effectiveness and benefit of using assistive technology and telecare. The ATTILA trial meets a pressing need for robust, generalisable evidence to either justify continuing investment or reappraise the appropriate scale of ATT use.

Journal ArticleDOI
TL;DR: GAD is associated with both clinically-identified and screen-detected type 2 diabetes mellitus (T2DM), and the relationship between MD and T2DM is strongest among those who are not obese.

Journal ArticleDOI
01 Apr 2013-Brain
TL;DR: Light is cast on the role of HLA-DRB1*15 in disease outcome and the powerful approach of using microscopic pathology to clarify the way in which genes and clinical phenotypes of neurological diseases are linked is highlighted.
Abstract: Clinical heterogeneity in multiple sclerosis is the rule. Evidence suggests that HLA-DRB1*15 may play a role in clinical outcome. Spinal cord pathology is common and contributes significantly to disability in the disease. The influence of HLA-DRB1*15 on multiple sclerosis spinal cord pathology is unknown. A post-mortem cohort of pathologically confirmed cases with multiple sclerosis (n = 108, 34 males) with fresh frozen material available for genetic analyses and fixed material for pathology was used. HLA-DRB1 alleles were genotyped to select a subset of age- and sex-matched HLA-DRB1*15-positive (n = 21) and negative (n = 26) cases for detailed pathological analyses. For each case, transverse sections from three spinal cord levels (cervical, thoracic and lumbar) were stained for myelin, axons and inflammation. The influence of HLA-DRB1*15 on pathological outcome measures was evaluated. Carriage of HLA-DRB1*15 significantly increased the extent of demyelination (global measure 15+: 23.7% versus 15-: 12.16%, P = 0.004), parenchymal (cervical, P < 0.01; thoracic, P < 0.05; lumbar, P < 0.01) and lesional inflammation (border, P = 0.001; periplaque white matter, P < 0.05) in the multiple sclerosis spinal cord. HLA-DRB1*15 influenced demyelination through controlling the extent of parenchymal inflammation. Meningeal inflammation correlated significantly with small fibre axonal loss in the lumbar spinal cord (r = -0.832, P = 0.003) only in HLA-DRB1*15-positive cases. HLA-DRB1*15 significantly influences pathology in the multiple sclerosis spinal cord. This study casts light on the role of HLA-DRB1*15 in disease outcome and highlights the powerful approach of using microscopic pathology to clarify the way in which genes and clinical phenotypes of neurological diseases are linked.

Journal ArticleDOI
TL;DR: The capacity of biomass smoke particles to elicit oxidative stress certainly has the potential to contribute towards negative health impacts associated with traditional domestic fuels in the developing world.
Abstract: More than half the world's population still rely on burning biomass fuels to heat and light their homes and cook food. Household air pollution, a common component of which is inhalable particulate matter (PM), emitted from biomass burning is associated with increased vulnerability to respiratory infection and an enhanced risk of developing chronic obstructive pulmonary disease. In the light of an emerging hypothesis linking chronic PM exposure during childhood and increased vulnerability to respiratory diseases in adulthood, in a chain of events involving oxidative stress, reduced immunity and subsequent infection, the aim of this study was to characterise the oxidative potential (OP) of PM collected during the burning of wood and mixed biomass, whilst cooking food in the Kathmandu Valley, Nepal. Our assessments were based on the capacity of the particles to deplete the physiologically relevant antioxidants from a validated, synthetic respiratory tract lining fluid (RTLF). Incubation of mixed biomass and wood smoke particles suspensions with the synthetic RTLF for 4 h resulted in a mean loss of ascorbate of 64.76 ± 16.83% and 83.37 ± 14.12% at 50 μg/ml, respectively. Reduced glutathione was depleted by 49.29 ± 15.22% in mixed biomass and 65.33 ± 13.01% in wood smoke particles under the same conditions. Co-incubation with the transition metal chelator diethylenetriaminepentaacetate did not inhibit the rate of ascorbate oxidation, indicating a negligible contribution by redox-active metals in these samples. The capacity of biomass smoke particles to elicit oxidative stress certainly has the potential to contribute towards negative health impacts associated with traditional domestic fuels in the developing world.

Journal ArticleDOI
TL;DR: This data indicates that chronic myelogenous leukemia with mild basophilia as the predominant manifestation at presentation in patients seen at a referral centre over a 16-year period is likely to be a cause for concern.
Abstract: S.E. & Rees, R.C. (2009) Tumour antigentargeted immunotherapy for chronic myeloid leukaemia: is it still viable? Cancer Immunology, Immunotherapy, 58, 1489–1499. Savage, D.G., Szydlo, R.M. & Goldman, J.M. (1997) Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period. British Journal of Haematology, 96, 111–116. Waldhauer, I. & Steinle, A. (2008) NK cells and cancer immunosurveillance. Oncogene, 27, 5932– 5943. Yasuda, H., Aritaka, N., Ando, J., Hirama, M., Komatsu, N. & Hirano, T. (2011) Chronic myelogenous leukemia with mild basophilia as the predominant manifestation at presentation. Internal Medicine, 50, 501–502.