The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial.:the results of the LRF AML14 trial

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m(2) vs. 35 mg/m(2); (ii) Cytarabine 200 mg/m(2) vs. 400 mg/m(2) in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m(2) were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

Low-fat versus low-carbohydrate weight reduction diets:Effects on weight loss, insulin resistance, and cardiovascular risk: a randomized control trial

OBJECTIVE Low-fat hypocaloric diets reduce insulin resistance and prevent type 2 diabetes in those at risk. Low-carbohydrate, high-fat diets are advocated as an alternative, but reciprocal increases in dietary fat may have detrimental effects on insulin resistance and offset the benefits of weight reduction.

RESEARCH DESIGN AND METHODS We investigated a low-fat (20% fat, 60% carbohydrate) versus a low-carbohydrate (60% fat, 20% carbohydrate) weight reduction diet in 24 overweight/obese subjects ([mean ± SD] BMI 33.6 ± 3.7 kg/m2, aged 39 ± 10 years) in an 8-week randomized controlled trial. All food was weighed and distributed, and intake was calculated to produce a 500 kcal/day energy deficit. Insulin action was assessed by the euglycemic clamp and insulin secretion by meal tolerance test. Body composition, adipokine levels, and vascular compliance by pulse-wave analysis were also measured.

RESULTS Significant weight loss occurred in both groups (P < 0.01), with no difference between groups (P = 0.40). Peripheral glucose uptake increased, but there was no difference between groups (P = 0.28), and suppression of endogenous glucose production was also similar between groups. Meal tolerance–related insulin secretion decreased with weight loss with no difference between groups (P = 0.71). The change in overall systemic arterial stiffness was, however, significantly different between diets (P = 0.04); this reflected a significant decrease in augmentation index following the low-fat diet, compared with a nonsignificant increase within the low-carbohydrate group.

CONCLUSIONS This study demonstrates comparable effects on insulin resistance of low-fat and low-carbohydrate diets independent of macronutrient content. The difference in augmentation index may imply a negative effect of low-carbohydrate diets on vascular risk.

LDL particle size in habitual exercisers, lean sedentary men and abdominally obese sedentary men

Habitual exercisers enjoy considerable protection from coronary heart disease (CHD). Often, however, only modest differences in traditional CHD risk factors are apparent between habitual exercisers and their sedentary counterparts. For this reason, there is increasing interest in novel predictors of CHD, such as a preponderance of small, dense low-density lipoprotein (LDL) particles. Polyacrylamide gel electrophoresis was used to separate lipoprotein subfractions in 32 lean exercisers, 36 lean sedentary men and 21 obese sedentary men aged 30-45 years. Well-validated equations were used to determine LDL concentration and peak particle diameter. Waist girth was used to identify lean (<100 cm) and obese ( >= 100cm) individuals. LDL concentration was lower in lean exercisers than in lean sedentary men (2.64 +/- 0.44 vs. 3.76 +/- 0.79 mmol.l(-1), p <0.001), suggesting that habitual exercise influences this risk factor. In contrast, there were no significant differences in LDL peak particle diameter between lean exercisers, lean sedentary men and obese sedentary men (27.92 +/- 0.67, 28.09 +/- 0.62 and 27.77 +/- 0.77 nm, respectively). In multiple linear regression analysis, triglyceride concentration was the only significant predictor of LDL PPD. These data suggest that habitual exercise influences LDL concentration but does not influence LDL particle size in men aged 30-45 years.

A Profile of Adolescent Cocaine Use in Northern Ireland.

Background: The image of cocaine as a 'party' drug used by more affluent members of society has begun to change as the levels of use of the drug rise amongst school aged young people. Methods: Cocaine use patterns amongst young people aged 13-16 years who were participating in the Belfast Youth Development Study, a longitudinal study of adolescent drug use was explored. Data was collected through an annual datasweep in participating schools. This paper includes data collected in years 3, 4 and 5 of the study. Results: The results show higher levels of cocaine use amongst this age group than reported in much of the existing harm reduction literature. Lifetime use was 3.8% at age 13-14 years, rising to 7.5% at 15-16 years. The profile indicated that adolescent cocaine users were more likely to be female, live in disrupted families and experience social deprivation which is similar to existing adolescent drug use profiles. There was also some evidence of experimental cocaine use amongst the sample. Conclusions: These findings provide further evidence for the development of age appropriate school focused harm reduction initiatives and continued monitoring of contemporary trends of use of cocaine amongst school aged young people.

A RCT of peer-mentoring for first-time mothers in socially disadvantaged areas (the moments study)

Objective: Interventions to reduce health inequalities for young children and their mothers are important: involving peers is recommended, but evidence of value for this approach is limited. The authors aimed to examine the effect of an innovative tailored peer-mentoring programme, based on perceived needs, for first-time mothers in socio-economically deprived communities. Design: Randomised controlled trial; parallel qualitative study with purposive samples using semistructured interviews. Setting: Socio-economically disadvantaged areas, Belfast. Participants: Primigravidae, aged 16-30 years, without significant co-morbidity. Intervention: Peer-mentoring by a lay-worker fortnightly during pregnancy and monthly for the following year, tailored to participants' wishes (home visits/telephone contacts), additional to usual care. Main outcome measures: Infant psychomotor and mental development (Bayley Scales of Infant Development (BSID-II)) at 1 year, assessed by an observer blinded to group allocation. Mothers' health at 1 year postnatal (SF-36). Results: Of 534 women invited, 343(64%) participated; 85%, with their children, completed outcome assessments (140 of 172 intervention; 152 of 171 controls). Intervention and control groups did not differ in BSID-II psychomotor (mean difference 1.64, 95% CI -0.94 to 4.21) or mental (-0.81, -2.78 to 1.16) scores, nor SF-36 physical functioning (-5.4, -11.6 to 0.7) or mental health (-1.8, -6.1 to 2.6). Women valued advice given in context of personal experience of child-rearing. Mentors gained health-related knowledge, personal skills and new employment opportunities. Conclusions: Despite possible longer-term social advantage, this peer-mentoring programme showed no benefit for infant development or maternal health at 1 year. Further rigorous evaluation of important outcomes of complex interventions promoting health for children in socially disadvantaged communities is warranted. Trial registration no: ISRCTN 55055030.

Efficacy of a standard meticillin-resistant Staphylococcus aureus decolonisation protocol in routine clinical practice

Summary

Decolonisation may reduce the risk of meticillin-resistant Staphylococcus aureus (MRSA) infection in individual carriers and prevent transmission to other patients. The aims of this prospective cohort study were to determine the long-term efficacy of a standardised decolonisation regimen and to identify factors associated with failure. Patients colonised with MRSA underwent decolonisation, which was considered to be successful if there was no growth in three consecutive sets of site-specific screening swabs obtained weekly post treatment. If patients were successfully decolonised, follow-up cultures were performed 6 and 12 months later. Of 137 patients enrolled, 79 (58%) were successfully decolonised. Of these 79, 53 (67%) and 44 (56%) remained decolonised at 6 and 12 months respectively. Therefore only 44/137 (32%) patients who completed decolonisation were MRSA negative 12 months later. Outcome was not associated with a particular strain of MRSA. Successful decolonisation was less likely in patients colonised with a mupirocin-resistant isolate (adjusted odds ratio: 0.08; 95% confidence interval: 0.02–0.30), in patients with throat colonisation (0.22; 0.07–0.68) and in patients aged >80 years (0.30; 0.10–0.93) compared with those aged 60–80 years. These findings suggest that although initially successful in some cases, the protocol used did not result in long-term clearance of MRSA carriage for most patients.

Disparities in breast cancer mortality trends between 30 European countries: Retrospective trend analysis of WHO mortality database

Objective: To examine changes in temporal trends in breast cancer mortality in women living in 30 European countries.
Design: Retrospective trend analysis.
Data source: WHO mortality database on causes of deaths
Subjects reviewed: Female deaths from breast cancer from 1989 to 2006
Main outcome measures: Changes in breast cancer mortality for all women and by age group (<50, 50-69, and >= 70 years) calculated from linear regressions of log transformed, age adjusted death rates. Joinpoint analysis was used to identify the year when trends in all age mortality began to change.
Results: From 1989 to 2006, there was a median reduction in breast cancer mortality of 19%, ranging from a 45% reduction in Iceland to a 17% increase in Romania. Breast cancer mortality decreased by >= 20% in 15 countries, and the reduction tended to be greater in countries with higher mortality in 1987-9. England and Wales, Northern Ireland, and Scotland had the second, third, and fourth largest decreases of 35%, 29%, and 30%, respectively. In France, Finland, and Sweden, mortality decreased by 11%, 12%, and 16%, respectively. In central European countries mortality did not decline or even increased during the period. Downward mortality trends usually started between 1988 and 1996, and the persistent reduction from 1999 to 2006 indicates that these trends may continue. The median changes in the age groups were -37% (range -76% to -14%) in women aged <50, -21% (-40% to 14%) in 50-69 year olds, and -2% (-42% to 80%) in >= 70 year olds.
Conclusions: Changes in breast cancer mortality after 1988 varied widely between European countries, and the UK is among the countries with the largest reductions. Women aged <50 years showed the greatest reductions in mortality, also in countries where screening at that age is uncommon. The increasing mortality in some central European countries reflects avoidable mortality.

Adolescent men's attitudes and decision-making in relation to an unplanned pregnancy. Responses to an interactive video drama

This study confronts a gender bias in research on adolescent pregnancy by exploring adolescent men’s decisions relating to a hypothetical unplanned pregnancy. A cross-sectional survey was conducted with adolescent men (N = 360) aged between 14 and 18 years attending schools in the Republic of Ireland. The study, the first of its kind in Europe, extends the small body of evidence on adolescent men and pregnancy decision-making by developing and examining reactions to an interactive video drama used in a comparable study in Australia. In addition, we tested a more comprehensive range of sociological and psychological determinants of adolescent men’s decisions regarding an unplanned pregnancy. Results showed that adolescent men were more likely to choose to keep the baby in preference to abortion or adoption. Adolescent men’s choice to continue the pregnancy (keep or adopt) in preference to abortion was significantly associated with anticipated feelings of regret in relation to abortion, perceived positive attitudes of own mother to keeping the baby and a feeling that a part of them might want a baby. Religiosity was also shown to underlie adolescent men’s views on the perceived consequences of an abortion in their lives.

Birth order and childhood type 1 diabetes risk: A pooled analysis of 31 observational studies

Background: The incidence rates of childhood onset type 1 diabetes are almost universally increasing across the globe but the aetiology of the disease remains largely unknown. We investigated whether birth order is associated with the risk of childhood diabetes by performing a pooled analysis of previous studies. Methods: Relevant studies published before January 2010 were identified from MEDLINE, Web of Science and EMBASE. Authors of studies provided individual patient data or conducted pre-specified analyses. Meta-analysis techniques were used to derive combined odds ratios (ORs), before and after adjustment for confounders, and investigate heterogeneity. Results: Data were available for 6 cohort and 25 case-control studies, including 11 955 cases of type 1 diabetes. Overall, there was no evidence of an association prior to adjustment for confounders. After adjustment for maternal age at birth and other confounders, a reduction in the risk of diabetes in second-or later born children became apparent [fully adjusted OR=0.90 95% confidence interval (CI) 0.83-0.98; P=0.02] but this association varied markedly between studies (I 2=67%). An a priori subgroup analysis showed that the association was stronger and more consistent in children <5years of age (n=25 studies, maternal age adjusted OR=0.84 95% CI 0.75, 0.93; I 2=23%). Conclusion: Although the association varied between studies, there was some evidence of a lower risk of childhood onset type 1 diabetes with increasing birth order, particularly in children aged <5 years. This finding could reflect increased exposure to infections in early life in later born children. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2010; all rights reserved.

Age-related changes in energy efficiency of gait, activity, and participation in children with cerebral palsy

Aim
The aim of this study was to use a prospective longitudinal study to describe age-related trends in energy efficiency during gait, activity, and participation in ambulatory children with cerebral palsy (CP).

Method
Gross Motor Function Measure (GMFM), Paediatric Evaluation of Disability Inventory (PEDI), and Lifestyle Assessment Questionnaire-Cerebral Palsy (LAQ-CP) scores, and energy efficiency (oxygen cost) during gait were assessed in representative sample of 184 children (112 male; 72 female; mean age 10y 9mo; range 4–16y) with CP. Ninety-four children had unilateral spastic CP, 84 bilateral spastic CP, and six had other forms of CP. Fifty-seven were classified as Gross Motor Function Classification System (GMFCS) level I, 91 as level II, 22 as level III, and 14 as level IV). Assessments were carried out on two occasions (visit 1 and visit 2) separated by an interval of 2 years and 7 months. A total of 157 participants returned for reassessment.

Results
Significant improvements in mean raw scores for GMFM, PEDI, and LAQ-CP were recorded; however, mean raw oxygen cost deteriorated over time. Age-related trends revealed gait to be most inefficient at the age of 12 years, but GMFM scores continued to improve until the age of 13 years, and two PEDI subscales to age 14 years, before deteriorating (p<0.05). Baseline score was consistently the single greatest predictor of visit 2 score. Substantial agreement in GMFCS ratings over time was achieved (?lw=0.74–0.76).

Interpretation
These findings have implications in terms of optimal provision and delivery of services for young people with CP to maximize physical capabilities and maintain functional skills into adulthood.

Patterns of substance use among young people attending colleges of further education in Northern Ireland

Aims: The aim of this article was to investigate the factors associated with ecstasy use in school-aged teenagers. Methods: This was a longitudinal study of adolescent drug use, which was undertaken in three towns in Northern Ireland. A questionnaire was administered annually to participants. In this article ecstasy use patterns amongst a cohort of young people aged 14–16 years participating in the Belfast Youth Development Study (BYDS) was explored. Findings: The percentage of those who had used ecstasy at least once increased from 7% when aged 14 years to 9% at 15 and 13% at 16 years. Female gender, delinquency, problem behaviours at school and the number of evenings spent out with friends each week were found to be significant variables predicting ‘ever use’ of ecstasy in all 3 years by logistic regression. Conclusions: The findings suggest that ecstasy use patterns may be changing from their historical perception as a ‘party’ drug, as the demographic profile ecstasy of users in this study reflected the traditional profile of illicit drug use during adolescence, which raises challenges for addressing the problems associated with this drug.

Increasing incidence of Barrett's oesophagus: a population-based study

Oesophageal adenocarcinoma, a highly fatal cancer, has risen in incidence in Western societies, but it is unclear whether this is due to increasing incidence of its pre-cursor condition, Barrett's oesophagus (BO) or whether the proportion of BO patients undergoing malignant progression has increased in the face of unchanged BO incidence. Data from population-based studies of BO incidence is limited, with equivocal results to date difficult to distinguish from changes in endoscopic practices. The aim of this study was to assess population trends in Barrett's oesophagus (BO) diagnoses in relation to endoscopy and biopsy rates over a 13 year period. The Northern Ireland Barrett's oesophagus Register (NIBR) is a population-based register of all 9,329 adults diagnosed with columnar epithelium of the oesophagus in Northern Ireland between 1993 and 2005, of whom 58.3% were male. European age-standardised annual BO incidence rates were calculated per 100,000 of the population, per 100 endoscopies and per 100 endoscopies including an oesophageal biopsy. Average annual BO incidence rates rose by 159% during the study period, increasing from 23.9/100,000 during 1993-1997 to 62.0/100,000 during 2002-2005. This elevation far exceeded corresponding increases in rates of endoscopies and oesophageal biopsies being conducted. BO incidence increased most markedly in individuals aged <60 years, and most notably amongst males aged <40 years. This study points towards a true increase in the incidence of BO which would appear to be most marked in young males. These findings have significant implications for future rates of oesophageal adenocarcinoma and surveillance programmes. © 2011 Springer Science+Business Media B.V.

Improved detection of acute myocardial infarction in patients with chest pain and significant left main stem coronary stenosis.

Background: Non-invasive diagnosis of acute myocardial infarction (AMI) associated with significant left main stem (LMS) stenosis remains challenging.

Methods: Consecutive patients presenting with acute ischaemic-type chest pain from 2000 to 2010 were analysed. Entry criteria: 12-lead ECG and Body Surface Potential Map (BSPM) at presentation, cardiac troponin T (cTnT) =12?h and coronary angiography during admission. cTnT =0.03?µg/l defined AMI. ECG abnormalities assessed: STEMI by Minnesota criteria; ST elevation (STE) aVR =0.5?mm; ST depression (STD) =0.5?mm in =2 contiguous leads (CL); T-wave inversion (TWI) =1?mm in =2 CL. BSPM STE was =2?mm in anterior, =1?mm in lateral, inferior, right ventricular or high right anterior and =0.5?mm in posterior territories. Significant LMS stenosis was =70%.

Results: Enrolled were 2810 patients (aged 60?±?12 years; 71% male). Of these, 116 (4.1%) had significant LMS stenosis with AMI occurring in 92 (79%). STEMI by Minnesota criteria occurred in 13 (11%) (sensitivity 12%, specificity 92%), STE in lead aVR in 23 (20%) (sensitivity 23%, specificity 92%), TWI in 38 (33%) (sensitivity 34%, specificity 71%) and STD in 51 (44%) (sensitivity 49%, specificity 75%). BSPM STE occurred in 85 (73%): sensitivity 88%, specificity 83%, positive predictive value 95% and negative predictive value 65%. Of those with AMI, 74% had STE in either the high right anterior or right ventricular territories not identified by the 12-lead ECG. C-Statistic for AMI diagnosis using BSPM STE was 0.800 (P?<?0.001).

Conclusion: In patients with significant LMS stenosis presenting with chest pain, BSPM STE has improved sensitivity (88%), with specificity 83%, over 12-lead ECG in the diagnosis of AMI.

Increased diagnosis and detection rates of carcinoma in situ of the breast

The purpose of this study was to identify trends in the diagnosis of carcinoma in situ (CIS) of the breast in the United Kingdom (UK) and the Republic of Ireland (ROI) and to examine the impact of mammography. Data on cases of newly diagnosed CIS of the breast and mode of detection (screen detected or not) were obtained, where available, from regional cancer registries between 1990 and 2007. Age-standardised diagnosis rates for the UK and the ROI, and regional screen detected diagnosis rates were compared by calculating the annual percentage change (APC) over time. The APC of the diagnosis rate amongst women aged 50-64 years (original screening age group) showed a significant 5.9% increase in the UK (1990-2007) and 11.5% increase in the ROI (1994-2007). The rate of diagnosis (50-64 years) stabilized in the UK between 2005 and 2007 and was substantially higher than in other western populations with national screening programmes. The APC of the diagnosis rate amongst those aged 65-69 years showed a significant 12.4% increase in the UK (1990-2007) and 10.3% increase in the ROI (1994-2007). amongst women aged 50-74 years in the UK, approximately 4,300 cases of CIS (˜90% ductal carcinoma in situ) were diagnosed in 2007. Our analyses have shown that screen detected CIS contributed primarily to the increase in diagnosis of CIS of the breast. The high diagnosis rate of screen detected CIS of the breast underlines the need for further research into lesion and patient characteristics that are related to progression of CIS to invasive disease to better target treatment. © 2012 Springer Science+Business Media, LLC.

All-cause mortality and periodontitis in 60-70-year-old men: A prospective cohort study

Objective To investigate the association between periodontitis and mortality from all causes in a prospective study in a homogenous group of 60- to 70-year-old West European men. Methodology A representative sample of 1400 dentate men, (mean age 63.8, SD 3.0 years), drawn from the population of Northern Ireland, had a comprehensive periodontal examination between 2001 and 2003. Men were divided into thirds on the basis of their mean periodontal attachment loss (PAL). The primary endpoint, death from any cause, was analysed using Kaplan-Meier survival plots and Cox's proportional hazards model. Results In total, 152 (10.9%) of the men died during a mean follow-up of 8.9 (SD 0.7) years; 37 (7.9%) men in the third with the lowest PAL (<1.8 mm) died compared with 73 (15.7%) in the third with the highest PAL (>2.6 mm). The unadjusted hazard ratio (HR) for death in the men with the highest level of PAL compared with those with the lowest PAL was 2.11 (95% CI 1.42-3.14), p < 0.0001. After adjustment for confounding variables (age, smoking, hypertension, BMI, diabetes, cholesterol, education, marital status and previous history of a cardiovascular event) the HR was 1.57 (1.04-2.36), p = 0.03. Conclusion The European men in this prospective cohort study with the most severe loss of periodontal attachment were at an increased risk of death compared with those with the lowest loss of periodontal attachment.