Psychometric evaluation of the Multi-Dimensional Scale of Perceived Social Support in young adults with chronic health conditions.

INTRODUCTION: The Multi-Dimensional Scale of Perceived Social Support (MSPSS) is one of the most widely employed tools for measuring perceived social support from three sources: family, friends and a significant other. This study aimed to establish the factor structure of the MSPSS in young adults living with chronic health conditions (CHCs). It also aimed to examine the reliability and convergent validity of the tool. METHODS: A cross-sectional quantitative design was applied. Participants (n = 123, 90 females) were students aged 18-25 years recruited from Colleges of Further Education in Ireland (mean age of 20.1 years, s.d. = 2.43). Participants completed the MSPSS and two subscales of the Medical Outcomes Study 36-item Short Form Health Survey that assessed social functioning and emotional well-being. RESULTS: Exploratory factor analysis yielded a three-factor solution of the MSPSS in young adults living with CHCs. The three factors together explained 83% of the variance in MSPSS scores. All the items had high loadings on the factors (0.72-0.94). The MSPSS showed satisfactory reliability and convergent validity. CONCLUSIONS: These findings suggest that the MSPSS is a valid and reliable tool for measuring perceived social support from three sources in young adults living with CHCs. Social support has been associated with positive outcomes in young adults living with CHCs, thus it is imperative for researchers and clinicians to have access to psychometrically sound instruments to evaluate the construct.

Network Meta-Analysis Techniques for Synthesizing Prevention Science Evidence.

Network meta-analysis is a popular statistical technique for synthesizing evidence from studies comparing multiple interventions. Benefits of network meta-analysis, over more traditional pairwise meta-analysis approaches, include evaluating efficacy/safety of interventions within a single framework, increased precision, comparing pairs of interventions that have never been directly compared in a trial, and providing a hierarchy of interventions in terms of their effectiveness. Network meta-analysis is relatively underutilized in prevention science. This paper therefore presents a primer of network meta-analysis for prevention scientists who wish to apply this method or to critically appraise evidence from publications using the method. We introduce the key concepts and assumptions of network meta-analysis, namely, transitivity and consistency, and demonstrate their applicability to the field of prevention science. We then illustrate the method using a network meta-analysis examining the comparative effectiveness of brief alcohol interventions for preventing hazardous drinking among college students. We provide data and code for all examples. Finally, we discuss considerations that are particularly relevant in network meta-analyses in the field of prevention, such as including non-randomized evidence.

Perinatal outcomes for extremely preterm babies in relation to place of birth in England: the EPICure 2 study.

BACKGROUND: Expertise and resources may be important determinants of outcome for extremely preterm babies. We evaluated the effect of place of birth and perinatal transfer on survival and neonatal morbidity within a prospective cohort of births between 22 and 26 weeks of gestation in England during 2006. METHODS: We studied the whole population of 2460 births where the fetus was alive at the admission of the mother to hospital for delivery. Outcomes to discharge were compared between level 3 (most intensive) and level 2 maternity services, with and without transfers, and by activity level of level 3 neonatal unit; ORs were adjusted for gestation at birth and birthweight for gestation (adjusted ORs (aOR)). FINDINGS: Of this national birth cohort, 56% were born in maternity services with level 3 and 34% with level 2 neonatal units; 10% were born in a setting without ongoing intensive care facilities (level 1). When compared with level 2 settings, risk of death in level 3 services was reduced (aOR 0.73 (95% CI 0.59 to 0.90)), but the proportion surviving without neonatal morbidity was similar (aOR 1.27 (0.93 to 1.74)). Analysis by intended hospital of birth confirmed reduced mortality in level 3 services. Following antenatal transfer into a level 3 setting, there were fewer intrapartum or labour ward deaths, and overall mortality was higher for those remaining in level 2 services (aOR 1.44 (1.09 to 1.90)). Among level 3 services, those with higher activity had fewer deaths overall (aOR 0.68 (0.52 to 0.89)). INTERPRETATION: Despite national policy, only 56% of births between 22 and 26 weeks of gestation occurred in maternity services with a level 3 neonatal facility. Survival was significantly enhanced following birth in level 3 services, particularly those with high activity; this was not at the cost of increased neonatal morbidity.

Diversity and stability of cultured vaginal lactobacilli in pregnant women from a multi-ethnic urban UK population.

AIM: To determine the diversity and stability of cultured vaginal lactobacilli in a multi-ethnic population of pregnant women. METHODS AND RESULTS: A single-centre, prospective, cohort study was performed in a tertiary perinatal centre in East London, UK. Self-collected vaginal swabs at 13 and 20 weeks gestation were obtained from women attending for routine antenatal care and cultured for lactobacilli. In women who provided both swabs, 37 of 203 (18%) had no lactobacilli cultured at either time. Only 53 (26%) had the same species at both times. Black women were less likely to have lactobacilli cultured at 13 weeks (P = 0·014), and Black and Asian women were less likely to have lactobacilli cultured at 20 weeks (P = 0·002) compared with those in the White and Other groups. CONCLUSIONS: Significant differences exist between ethnic groups in the carriage and stability of vaginal lactobacilli. SIGNIFICANCE AND IMPACT OF THE STUDY: These differences have implications for the design of interventions aimed at normalizing the vaginal microbiota in pregnant women.

Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment.

Specific language impairment (SLI) is a neurodevelopmental disorder that affects linguistic abilities when development is otherwise normal. We report the results of a genome-wide association study of SLI which included parent-of-origin effects and child genotype effects and used 278 families of language-impaired children. The child genotype effects analysis did not identify significant associations. We found genome-wide significant paternal parent-of-origin effects on chromosome 14q12 (P = 3.74 × 10(-8)) and suggestive maternal parent-of-origin effects on chromosome 5p13 (P = 1.16 × 10(-7)). A subsequent targeted association of six single-nucleotide-polymorphisms (SNPs) on chromosome 5 in 313 language-impaired individuals and their mothers from the ALSPAC cohort replicated the maternal effects, albeit in the opposite direction (P = 0.001); as fathers' genotypes were not available in the ALSPAC study, the replication analysis did not include paternal parent-of-origin effects. The paternally-associated SNP on chromosome 14 yields a non-synonymous coding change within the NOP9 gene. This gene encodes an RNA-binding protein that has been reported to be significantly dysregulated in individuals with schizophrenia. The region of maternal association on chromosome 5 falls between the PTGER4 and DAB2 genes, in a region previously implicated in autism and ADHD. The top SNP in this association locus is a potential expression QTL of ARHGEF19 (also called WGEF) on chromosome 1. Members of this protein family have been implicated in intellectual disability. In summary, this study implicates parent-of-origin effects in language impairment, and adds an interesting new dimension to the emerging picture of shared genetic etiology across various neurodevelopmental disorders.

Is breastfeeding in infancy predictive of child mental well-being and protective against obesity at 9 years of age?

BACKGROUND: Preventing child mental health problems and child obesity have been recognized as public health priorities. The aim of the present study was to examine whether being breastfed (at all or exclusively) in infancy was a predictor of mental well-being and protective against risk of obesity at age 9. METHODS: Cross-sectional data from a large, nationally representative cohort study in the Republic of Ireland was used (n = 8357). Data on breastfeeding were retrospectively recalled. Child mental well-being was assessed using a parent-completed Strengths and Difficulties Questionnaire (SDQ). Child's height and weight were measured using scientifically calibrated instruments. RESULTS: Logistic regression analyses indicated that, after controlling for a wide range of potential confounding variables, being breastfed in infancy was associated with a 26% (P < 0.05) reduction in the risk of an abnormal SDQ score at 9 years. Being breastfed remained a significant predictor of child mental well-being when child obesity was controlled for, indicating that being breastfed, independent of child obesity, is a predictor of child mental well-being. The results of a second logistic regression indicated that, after controlling for a wide range of potential confounding variables, being breastfed for between 11 and 25 weeks was associated with a 36% (P < 0.05) reduction in the risk of obesity at 9 years, while being breastfed for 26 weeks or longer was associated with a 48% (P < 0.01) reduction in the risk of obesity at 9 years. CONCLUSIONS: Breastfeeding in infancy may protect against both poor mental well-being and obesity in childhood.

An investigation into the reporting and management of late terminations of pregnancy (between 22 +0 and 26 +6 weeks of gestation) within NHS Hospitals in England in 2006: the EPICure preterm cohort study.

OBJECTIVE: To review all late terminations of pregnancy, between 22(+0) and 26(+6) weeks of gestation, collected as part of the EPICure2 study. DESIGN: Prospective cohort study. SETTING: All National Health Service (NHS) hospitals providing perinatal services for extremely preterm infants. POPULATION: All births between 22(+0) and 26(+6) weeks of gestation in England during 2006. METHODS: Data were collected for the defined cohort of births, including terminations of pregnancy, by designated unit staff using a standardised questionnaire. Rigorous validation processes were established to ensure comprehensive data collection. Gestational age was validated using a hierarchical classification of scan dates, certain date of last menstrual period and working gestation. Data for terminations of pregnancy (TOPs) were categorised into two groups, terminations for fetal abnormality and for maternal or fetal compromise, and were analysed in terms of their reporting, management and outcomes. MAIN OUTCOME MEASURES: Classification, rate of feticide and outcome following TOP. RESULTS: Of 3782 births between 22(+0) and 26(+6) weeks of gestation, 647 (17.1%) were TOPs; of these 584 (90.3%) were for fetal abnormality and 63 (9.7%) for maternal or fetal compromise. Feticide was carried out in 489 of 584 (83.7%) TOPs for fetal abnormality, and in 38 of 63 (60.3%) of the TOPs for maternal or fetal compromise. Live births resulted following 2.2% TOPs for fetal abnormality and 4.8% TOPs for maternal or fetal compromise. CONCLUSION: Terminations of pregnancy represent a relatively large proportion of very preterm births. Fetal abnormalities are the main cause for these terminations, and most include feticide. Better screening strategies are required to avoid the need for late terminations of pregnancy for fetal abnormalities.

Relationship between CCL5 and transforming growth factor-ß1 (TGFß1) in breast cancer.

PURPOSE: Investigate circulating CCL5 in breast cancer patients and healthy controls, along with gene expression levels in corresponding tumour tissue and isolated primary stromal cells. Hormonal control of CCL5, and a potential relationship with TGFß1, was also investigated. METHODS: Circulating levels of CCL5 and TGFß1 were measured in 102 breast cancer patients and 66 controls using ELISA. Gene expression levels (CCL5, CCR5, TGFß1, TGFßRII) were quantified in corresponding tumour tissue (n = 43), normal tissue (n = 16), and isolated tumour (n = 22) and normal (n = 3) stromal cells using RQ-PCR. CCL5 and circulating menstrual hormones (LH, FSH, Oestradiol, Progesterone) were analysed in serum samples from healthy, premenopausal volunteers (n = 60). RESULTS: TGFß1 was significantly higher in breast cancer patients (Mean(SEM) 27.4(0.9)ng/ml) compared to controls (14.9(0.9)ng/ml). CCL5 levels decreased in the transition from node negative (59.6(3.7)ng/ml) to node positive disease (40.5(6.3)ng/ml) and increased again as the number of positive lymph nodes increased (⩾3 positive 50.95(9.8)ng/ml). A significant positive correlation between circulating CCL5 and TGFß1 (r = 0.423, p<0.0001) was observed, and mirrored at the gene expression level in tumour tissue from the same patients (r = 0.44, p<0.001). CCL5, CCR5 and TGFß1 expression was significantly higher in tumour compared to normal breast tissue (p < 0.001). A significant negative correlation was observed between circulating CCL5, Oestradiol and Progesterone (r = -0.50, r = -0.39, respectively, p < 0.05). CONCLUSION: CCL5 expression is elevated in the tumour microenvironment. The data support a role for hormonal control of circulating CCL5 and also highlight a potentially important relationship between CCL5 and TGFß1 in breast cancer.

MicroRNA-21 and PDCD4 expression in colorectal cancer.

INTRODUCTION: MiRNAs regulate gene expression by binding to target sites and initiating translational repression and/or mRNA degradation. Studies have shown that miR-21 exerts its oncogenic activity by targeting the PDCD4 tumour suppressor 3'-UTR. However, the mechanism of this regulation is poorly understood. In colorectal cancer, loss of PDCD4 has been reported in association with increased tumour aggressiveness and poor prognosis. The purpose of this study was to delineate the interaction between PDCD4 and its oncogenic modulator miR-21 in colorectal cancer. METHODS: A cohort of 48 colorectal tumours, 61 normal tissues and 7 polyps were profiled for miR-21 and PDCD4 gene expression. A subset of 48 specimens (31 tumours and 17 normal tissues) were analysed for PDCD4 protein expression by immunohistochemistry. RESULTS: A significant inverse relationship between miR-21 and PDCD4 gene expression (p < 0.001) was identified by RT-qPCR. In addition, significant reduction of PDCD4 (p < 0.001) expression and reciprocal upregulation of miR-21 (p = 0.005) in a progressive manner from tumour-polyp-normal mucosae was identified. Analysis of protein expression by IHC revealed loss of PDCD4 staining in tumour tissue. Patients with disease recurrence had higher levels of miR-21. CONCLUSION: This study demonstrates the inverse relationship between miR-21 and PDCD4, thus suggesting that miR-21 post-transcriptionally modulates PDCD4 via mRNA degradation. Pharmacological manipulation of the miR-21/PDCD4 axis could represent a novel therapeutic strategy in the treatment of colorectal cancer.

Accuracy of bacterial DNA testing for central venous catheter-associated bloodstream infection in children with cancer.

BACKGROUND: Central venous catheters (CVCs) are widely used for children with cancer and are a major risk factor for bloodstream infection. Early and specific diagnosis of CVC-associated bloodstream infection allows early targeted treatment, reducing the risk of CVC removal and avoiding the operative risks and trauma of reinsertion, but peripheral vein sampling, as used in adults, improves specificity but is not usually acceptable in children. OBJECTIVE: To improve the detection and treatment of CVC-associated bloodstream infection in children (aged 0-18 years) with cancer admitted with fever. METHODS: There were four main studies: (1) evaluation of the diagnostic accuracy of a quantitative molecular method for the detection of bacterial deoxyribonucleic acid (DNA), based solely on blood samples drawn through the CVC; (2) analysis of the prognostic risk of CVC removal and duration of intravenous (i.v.) antibiotic treatment days in relation to presenting clinical features, blood culture results and bacterial DNA test results; (3) systematic reviews of treatment options for CVC-associated infection and a questionnaire survey of current practice in paediatric oncology centres; (4) evaluation of the clinical effectiveness of different test-treatment strategies to reduce i.v. antibiotic treatment days and unnecessary CVC removals. RESULTS: (1) The bacterial DNA test detected two-thirds [95% confidence interval (CI) 44% to 83%] of children classified with probable CVC-associated infection - specificity was 88% (95% CI 84% to 92%). Although high bacterial DNA concentrations were associated with subsequent CVC removal and long duration of i.v. antibiotic treatment, the test did not improve the prediction of these outcomes over and above clinical signs of CVC-associated infection combined with blood culture results. (2) High DNA load was predictive of CVC removal and i.v. treatment duration, before blood culture results became available at 48 hours after sampling. (3) There was limited evidence that antibiotic lock treatment reduces the risk of recurrent CVC-associated infection or CVC removal (pooled relative risk 0.7, 95% CI 0.47 to 1.05), but prophylactic use of antimicrobial locks halved the risk of bloodstream infection (pooled incidence rate ratio 0.43, 95% CI 0.36 to 0.51). Contrary to this, the national survey of paediatric oncology centres found that locks are being used for treatment rather than prevention and that problems related to the formulation of lock solutions currently impede a shift to their prophylactic use in children. (4) Most i.v. treatment days would be saved by early stopping of treatment for children at low risk of infection. LIMITATIONS: The accuracy study was limited primarily by the lack of an adequate reference standard, and the main limitation of the series of systematic reviews was the poor quality of included studies and lack of randomised controlled trials of CVC removal or antimicrobial locks for treatment of infection. CONCLUSIONS: There is strong evidence to support the use of antimicrobial locks for prevention of CVC-associated infection; however, few of these studies involved children with cancer. The analysis does not support routine bacterial DNA testing on admission to detect CVC-associated infection, but repeated testing (as a marker of microbial load) should be evaluated in high-risk groups. Further research should determine the effectiveness of antibiotic locks for treating CVC-associated infection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN68138140. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 7. See the HTA programme website for further project information.

Nature and severity of lung function abnormalities in extremely pre-term children at 11 years of age.

Advances in neonatal care have resulted in increased survival of children born extremely pre-term (EP). Nevertheless the incidence of bronchopulmonary dysplasia and long-term respiratory morbidity remains high. We investigated the nature of pathophysiological changes at 11 yrs of age to ascertain whether respiratory morbidity in EP children primarily reflects alterations in the lung periphery or more centralised airway function in this population. Spirometry, plethysmography, diffusing capacity, exhaled nitric oxide, multiple-breath washout, skin tests and methacholine challenge were used during laboratory-based assessments in a subgroup of the 1995 EPICure cohort and in controls. Results were obtained in 49 EP and 52 control children. Lung function abnormalities were found in 78% of EP children, with evidence of airway obstruction, ventilation inhomogeneity, gas trapping and airway hyperresponsiveness. Levels of atopy and exhaled nitric oxide were similar between the groups. Prior wheeze was associated with significant reductions in forced flows and volumes. By contrast, abnormalities of the lung periphery appear to be mediated primarily through EP birth per se. The prevalence of lung function abnormalities, which is largely obstructive in nature and likely to have long-term implications, remains high among 11-yr-old children born EP. Spirometry proved an effective means of detecting these persistent abnormalities.

Development of the Children's Attributions about Psychological Problems in their Peers Scale.

BACKGROUND: Research has shown that children's beliefs about the causes of psychological problems are related to their attitudes and reactions towards affected peers. This study describes the development of the Children's Attributions about Psychological Problems in their Peers (CAPPP) Scale, which assesses children's beliefs about the causes of an internalizing and an externalizing condition. METHODS: The 16 items comprising the CAPPP are derived from previous qualitative research findings. Five hundred and ninety-five young people, drawn from five different age groups spanning early childhood to late adolescence, completed a CAPPP Scale for each of two vignettes describing the behaviour of hypothetical peers with attention deficit hyperactivity disorder (ADHD) and depression. RESULTS: Modifications following consideration of psychometric properties and conceptual fit resulted in a 12-item scale. For both the ADHD and depression conditions, the components that emerged were 'Volition', 'Recent Life Stress', 'Family Factors' and 'School Factors'. CONCLUSIONS: The present study represents the first field trial of the CAPPP. Results suggest that children's and adolescents' beliefs about the causes of psychological problems are multidimensional and incorporate both individual and environmental factors.

Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT).

Bone marrow-derived mesenchymal stem cells (MSCs) are known to specifically migrate to and engraft at tumour sites. Understanding interactions between cancer cells and MSCs has become fundamental to determining whether MSC-tumour interactions should be harnessed for delivery of therapeutic agents or considered a target for intervention. Breast Cancer Cell lines (MDA-MB-231, T47D & SK-Br3) were cultured alone or on a monolayer of MSCs, and retrieved using epithelial specific magnetic beads. Alterations in expression of 90 genes associated with breast tumourigenicity were analysed using low-density array. Expression of markers of epithelial-mesenchymal transition (EMT) and array results were validated using RQ-PCR. Co-cultured cells were analysed for changes in protein expression, growth pattern and morphology. Gene expression and proliferation assays were also performed on indirect co-cultures. Following direct co-culture with MSCs, breast cancer cells expressed elevated levels of oncogenes (NCOA4, FOS), proto-oncogenes (FYN, JUN), genes associated with invasion (MMP11), angiogenesis (VEGF) and anti-apoptosis (IGF1R, BCL2). However, universal downregulation of genes associated with proliferation was observed (Ki67, MYBL2), and reflected in reduced ATP production in response to MSC-secreted factors. Significant upregulation of EMT specific markers (N-cadherin, Vimentin, Twist and Snail) was also observed following co-culture with MSCs, with a reciprocal downregulation in E-cadherin protein expression. These changes were predominantly cell contact mediated and appeared to be MSC specific. Breast cancer cell morphology and growth pattern also altered in response to MSCs. MSCs may promote breast cancer metastasis through facilitation of EMT.

Academic attainment and special educational needs in extremely preterm children at 11 years of age: the EPICure study.

AIM: To assess academic attainment and special educational needs (SEN) in extremely preterm children in middle childhood. METHODS: Of 307 extremely preterm (< or =25 weeks) survivors born in the UK and Ireland in 1995, 219 (71%) were re-assessed at 11 years of age and compared to 153 classmates born at term, using standardised tests of cognitive ability and academic attainment and teacher reports of school performance and SEN. Multiple imputation was used to correct for selective dropout. RESULTS: Extremely preterm children had significantly lower scores than classmates for cognitive ability (-20 points; 95% CI -23 to -17), reading (-18 points; -22 to -15) and mathematics (-27 points; -31 to -23). Twenty nine (13%) extremely preterm children attended special school. In mainstream schools, 105 (57%) extremely preterm children had SEN (OR 10; 6 to 18) and 103 (55%) required SEN resource provision (OR 10; 6 to 18). Teachers rated 50% of extremely preterm children as having below average attainment compared with 5% of classmates (OR 18; 8 to 41). Extremely preterm children who entered compulsory education an academic year early due to preterm birth had similar academic attainment but required more SEN support (OR 2; 1.0 to 3.6). CONCLUSIONS: Extremely preterm survivors remain at high risk for learning impairments and poor academic attainment in middle childhood. A significant proportion require full-time specialist education and over half of those attending mainstream schools require additional health or educational resources to access the national curriculum. The prevalence and impact of SEN are likely to increase as these children approach the transition to secondary school.

Relevance of basal serum FSH to IVF outcome varies with patient age.

Live birth rate (LBR), age and basal serum FSH values were analysed in 1589 women undergoing their first cycle of IVF. Four age groups (<30, 30-34, 35-38, 39-45 years) and three FSH groups (<5, 5-9.9, > or =10 IU/l) were established. Logistic regression analysis was used to determine the effect of age and FSH on live birth. A model to predict the probability of a live birth suggests that an additional 10 years of age reduces the odds for live birth (OR = 0.66, 95% CI 0.48-0.91); an increase of FSH by 5 IU/l reduces the probability of live birth (OR = 0.75, 95% CI 0.61-0.92); women > or =39 years have an additional reduction in probability of live birth (OR = 0.58, 95% CI 0.61-0.92). Analysis by age and FSH categories showed that pregnancy rate (PR) did not change significantly with rising FSH for women <35 years old. In cycles started with serum FSH <5 IU/l, increasing age did not effect PR and LBR. Cycles started with serum FSH > or =10 IU/l had a PR and LBR of 23.6 and 16.9% respectively. The clinical relevance of elevated FSH varies according to age; younger women with elevated FSH and older women with low FSH still have an acceptable LBR.

Respiratory health in pre-school and school age children following extremely preterm birth.

RATIONALE: Increasing survival at extremely low gestational ages is associated with very high rates of bronchopulmonary dysplasia (BPD) but is rarely quantified. OBJECTIVES: To identify respiratory morbidity and risk factors in the EPICure cohort over the first 6 years of life. METHODS: 308 babies born at < or =25 weeks' gestation in 1995 were followed up at 30 months and 6 years of age. Respiratory outcome was evaluated using clinical assessment, parental questionnaire and peak expiratory flow (PEF) at 6 years. RESULTS: 74% of this population received supplemental oxygen at 36 weeks postmenstrual age and 36% were discharged with supplemental oxygen which continued for a median of 2.5 months (75th percentile: 8.5 months). 236 children were followed to 6 years. Respiratory symptoms and medication use were more prevalent at 30 months and 6 years in children with BPD compared to those without. Children without BPD (n = 56) were not significantly different from their classmates but had consistently higher prevalence of poor respiratory health. Symptoms, need for hospital admission and medication use declined between 30 months and 6 years. 200 index children completed three PEF measures; PEF was lower than in classmates (mean adjusted difference: 39 l/min (95% CI 30 to 47)) and was lowest in children discharged home with oxygen and in those with BPD. Gestational age, BPD and maternal smoking at home and in pregnancy were independent risk factors for symptoms, but BPD was the only independent associate of PEF. CONCLUSION: Extremely preterm children have a continuum of poor respiratory health over the first 6 years, which is exacerbated by smoking during pregnancy and in the home.

Topical or oral ibuprofen for chronic knee pain in older people. The TOIB study.

OBJECTIVES: To determine whether GPs should advise their older patients with chronic knee pain to use topical or oral non-steroidal anti-inflammatory drugs (NSAIDs). DESIGN: An equivalence study was designed to compare the effect of advice to use preferentially oral or topical ibuprofen (an NSAID) on knee pain and disability, NSAID-related adverse effects and NHS/societal costs, using a randomised controlled trial (RCT) and a patient preference study (PPS). Reasons for patient preferences for topical or oral preparations, and attitudes to adverse effects, were explored in a qualitative study. SETTING: Twenty-six general practices in the UK. PARTICIPANTS: Participants comprised 585 people with knee pain, aged 50 years or over; 44% were male, mean age 64 years. The RCT had 282 participants: 144 in the oral group and 138 in the topical group. The PPS had 303 participants: 79 in the oral group and 224 in the topical group. INTERVENTIONS: Advice to use preferentially oral or topical NSAIDs for knee pain. OUTCOME MEASURES: The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcome measures were the Short Form with 36 Items (SF-36), perceived troublesomeness of knee pain, satisfaction with health status, major adverse effects (unplanned hospital admissions and deaths) and minor adverse events over 12 months. The health economic analysis measured the comparative cost per quality-adjusted life-year (QALY) from both an NHS and a societal perspective over 1 and 2 years. RESULTS: Changes in the global WOMAC score at 12-months were equivalent in both studies: topical - oral, RCT difference=2 [95% confidence interval (CI) -2 to 6], PPS difference=1 (95% CI -4 to 6). There were no differences in the secondary outcomes, except for a suggestion, in the RCT, that those in the topical group were more likely to have more severe overall pain and disability as measured by the chronic pain grade, and more likely to report changing treatment because of inadequate pain relief. There were no differences in the rate of major adverse effects but some differences in the number of minor ones. In the RCT, 17% and 10% in the oral and the topical group, respectively, had a defined respiratory adverse effect (95% CI of difference -17% to -2.0%); after 12 months, the change in serum creatinine was 3.7 mmol/l (95% CI 0.9 to 6.5) less favourable in the oral than in the topical group, and 11% of those in the oral group reported changing treatment because of adverse effects compared with 1% in the topical group (p=0.02). None of these differences were seen in the PPS. Oral NSAIDs cost the NHS 191 pounds and 72 pounds more per participant over 1 year in the RCT and PPS respectively. In the RCT the cost per QALY in the oral group, from an NHS perspective, was in the range 9000-12,000 pounds. In the PPS it was 2564 pounds over 1 year, but over 2 years the oral route was more cost-effective. Patient preference for medication type was affected by previous experience of medication (including adverse reactions), other illness, pain elsewhere, anecdotes, convenience, severity of pain and perceived degree of degeneration. Lack of understanding about knee pain and the action of medication led to increased tolerance of symptoms. Potentially important symptoms may inadvertently have been disregarded, increasing participants' risk of suffering a major adverse effect. CONCLUSIONS: Advice to use either oral or topical preparations has an equivalent effect on knee pain, but oral NSAIDs appear to produce more minor adverse effects than topical NSAIDs. Generally, these results support advising older people with knee pain to use topical rather than oral NSAIDS. However, for patients who prefer oral NSAID preparations rather than a topical NSAID, particularly those with more widespread or severe pain, the oral route is a reasonable treatment option, provided that patients are aware of the risks of potentially serious adverse effects from oral medication. Further research is needed into strategies to change prescribing behaviour and ensure that older patients are aware of the potential risks and benefits of using NSAIDs. Observational studies are needed to estimate rates of different predefined minor adverse effects associated with the use of oral NSAIDs in older people as are long-term studies of topical NSAIDs in those for whom oral NSAIDs are not appropriate.

Prospective matched-pair comparison of outcome after treatment for lobular and ductal breast carcinoma.

BACKGROUND: Whether the prognosis of invasive lobular carcinoma is different from that of other invasive breast cancers is controversial. The aim of this study was to compare the outcome in age- and stage-matched patients with lobular carcinoma and those with invasive breast cancer, and in particular to compare predictors of outcome. METHODS: Data were obtained from a prospectively maintained database that included patients who had breast surgery for invasive cancer. Patients were matched for International Union Against Cancer stage and age at diagnosis within 5 years. Two patients with invasive ductal carcinoma were matched to each patient with invasive lobular carcinoma. RESULTS: There was no significant difference between invasive ductal and lobular carcinomas in terms of overall survival. Oestrogen receptor (ER)-positive invasive ductal carcinoma had a better prognosis than ER-positive invasive lobular carcinoma (P = 0.011). Similarly, ER-negative invasive ductal carcinoma was associated with worse survival than ER-negative invasive lobular carcinoma (P = 0.054). CONCLUSION: These results suggested that the differences in outcome between invasive ductal and lobular carcinomas may be determined by ER status.

Bloodstream infection due to Acinetobacter spp: epidemiology, risk factors and impact of multi-drug resistance.

Acinetobacter spp. are increasingly reported as important causes of human infection. Many isolates exhibit multi-drug resistance, raising concerns over our ability to treat serious infections with these organisms. The impact of infection on clinical outcome as well as the importance of multi-drug resistance is poorly defined. A descriptive retrospective observational study was undertaken of all episodes of Acinetobacter bacteremia occurring in a UK tertiary care centre from 1998-2006. Demographics of infected patients, characteristics and antimicrobial susceptibility of infecting strains were recorded and the impact of antimicrobial therapy on all causes of 30-day mortality assessed. Three hundred ninety-nine episodes of Acinetobacter bacteremia were identified, with A. baumannii being the most frequently isolated species. Most episodes occurred in critical care and were associated with multidrug resistance, with carbapenem resistance rising from 0% in 1998 to 55% in 2006. Although bacteremia due to carbapenem-resistant Acinetobacter and a requirement for critical care were associated with a higher mortality, mortality was not reduced by the administration of appropriate empirical antimicrobial therapy. A prospective study is required to identify both the most effective intervention and those most likely to benefit from treatment.