Health gains, costs and cost-effectiveness of a population-based screening programme for abdominal aortic aneurysms.

BACKGROUND: Abdominal aortic aneurysm (AAA) rupture carries a high fatality rate. AAAs can be detected before rupture by abdominal ultrasound imaging, allowing elective repair. Population-based screening for AAA in older men reduces AAA-related mortality by about 40 per cent. The UK began an AAA screening programme offering one-off scans to men aged 65 years in 2009. Sweden has a similar programme. Currently, there is no AAA screening programme in New Zealand. This cost-utility analysis aimed to assess the cost-effectiveness of a UK-style screening programme in the New Zealand setting. METHODS: The analysis compared a formal AAA screening programme (one-off abdominal ultrasound imaging for about 20 000 men aged 65 years in 2011) with no systematic screening. A Markov macrosimulation model was adapted to estimate the health gains (in quality-adjusted life-years, QALYs), health system costs and cost-effectiveness in New Zealand. A health system perspective and lifetime horizon was adopted. RESULTS: With New Zealand-specific inputs, the adapted model produced an estimate of about NZ $15 300 (€7746) per QALY gained, with a 95 per cent uncertainty interval (UI) of NZ $8700 to 31 000 (€4405 to 15 694) per QALY gained. Health gains were estimated at 117 (95 per cent UI 53 to 212) QALYs. Health system costs were NZ $1·68 million (€850 535), with a 95 per cent UI of NZ $820 200 to 3·24 million (€415 243 to €1·65 million). CONCLUSION: Using New Zealand's gross domestic product per capita (about NZ $45 000 or €22 100) as a cost-effectiveness threshold, a UK-style AAA screening programme would be cost-effective in New Zealand.

Heavy Drinkers and the Potential Impact of Minimum Unit Pricing-No Single or Simple Effect?

AIMS: To explore the potential impact of a minimum unit price (MUP: 50 pence per UK unit) on the alcohol consumption of ill Scottish heavy drinkers. METHODS: Participants were 639 patients attending alcohol treatment services or admitted to hospital with an alcohol-related condition. From their reported expenditure on alcohol in their index week, and assuming this remained unchanged, we estimated the impact of a MUP (50 ppu) on future consumption. (Around 15% purchased from both the more expensive on-sale outlets (hotels, pubs, bars) and from off-sales (shops and supermarkets). For them we estimated the change in consumption that might follow MUP if (i) they continued this proportion of 'on-sales' purchasing or (ii) their reported expenditure was moved entirely to off-sale purchasing (to maintain consumption levels)). RESULTS: Around 69% of drinkers purchased exclusively off-sale alcohol at <50 ppu. Their drinking, post MUP, may reduce by a mean of 33%. For this group, from a population of very heavy, ill consumers, we were unable to show a differential effect across multiple deprivation quintiles. For other drinkers there might be no reduction, especially if after MUP there were many products priced close to 50 ppu. Moving away from on-sales purchases could support, for some, an increase in consumption. CONCLUSIONS: While a proportion of our harmed, heavy drinkers might be able to mitigate the impact of MUP by changing purchasing habits, the majority are predicted to reduce purchasing. This analysis, focusing specifically on harmed drinkers, adds a unique dimension to the evidence base informing current pricing policy. SHORT SUMMARY: From drink purchasing data of heavy drinkers, we estimated the impact of legislating £0.50 minimum unit price. Over two thirds of drinkers, representing all multiple deprivation quintiles, were predicted to decrease alcohol purchasing; remainder, hypothetically, could maintain consumption. Our data address an important gap within the evidence base informing policy.

Systematic review and meta-analysis: Prevalence and possible causes of vitamin D deficiency and insufficiency in pediatric cancer patients.

BACKGROUND AND AIMS: Vitamin D inadequacy is now an internationally recognized health problem and pediatric cancer patients may be at even higher risk than healthy children. We aimed to evaluate primary research to establish the prevalence of vitamin D inadequacy and to explore its possible causes in pediatric cancer patients. METHODS: Electronic databases were searched (no restriction-Aug 2013) with no language restrictions and keywords related to cancer and vitamin D. We included studies of patients aged <18 years, diagnosed with and treated for cancer and reporting plasma vitamin D status. Evidence was critically appraised employing the CASP tool. Meta-analysis was performed when appropriate. RESULTS: We included 19 studies, which were mainly of moderate-quality and heterogeneous in the definitions of vitamin D deficiency and insufficiency. The median (range) prevalence of vitamin D deficiency was 14% (0-61.5%) and insufficiency 23% (0-83%). Finally, a significant effect of younger age with vitamin D inadequacy was shown (effect size: -0.132; 95%CI -0.203, -0.060). CONCLUSION: There is a possibility of a high prevalence of vitamin D inadequacy in pediatric cancer patients, especially older children, urging the need for high-quality population-based longitudinal studies using standard definitions.

Single- and repeat-dose toxicity of IDX14184, a nucleotide prodrug with antiviral activity for hepatitis C viral infection, in mice, rats, and monkeys.

The single- and repeat-dose toxicity profile of IDX14184, a novel guanosine nucleotide prodrug with antiviral activity against hepatitis C viral infection, was characterized following once daily oral administration for durations up to 13, 26, and 32 weeks in mouse, rat, and cynomolgus monkey, respectively. The heart, liver, kidney, skeletal muscles, and lower gastrointestinal tract (cecum, colon, and/or rectum) were identified as the primary toxicity targets in these nonclinical species. The mouse was relatively insensitive to IDX14184-induced cardiac toxicity and hepatotoxicity. The rat was very sensitive to IDX14184-induced skeletal muscle, liver, heart, and lower gastrointestinal tract toxicity but relatively insensitive to kidney toxicity. The monkey is a good animal species to detect IDX14184-induced toxicity in the cardiac and skeletal muscles, and in the liver and kidney, but not lower gastrointestinal tract toxicity. The toxicity profile of IDX14184 was most appropriately characterized in rats and monkeys. The conduct of a series of cardiac size and function assessments during a non-rodent toxicology study using echocardiography proved great utility in this work. IDX14184 clinical development was eventually terminated due to suboptimal efficacy and regulatory concerns on potential heart and kidney injury in patients, as seen with a different guanosine nucleotide prodrug, BMS-986094.

Alcohol purchasing by ill heavy drinkers; cheap alcohol is no single commodity.

OBJECTIVES: Potential strategies to address alcohol misuse remain contentious. We aim to characterise the drink purchases of one population group: heavy drinkers in contact with Scottish health services. We contrast our findings with national sales data and explore the impact of socio-economic status on purchasing behaviour. STUDY DESIGN: Cross-sectional study comparing alcohol purchasing and consumption by heavy drinkers in Edinburgh and Glasgow during 2012. METHODS: 639 patients with serious health problems linked to alcohol (recruited within NHS hospital clinics (in- and out-patient settings) 345 in Glasgow, 294 in Edinburgh) responded to a questionnaire documenting demographic data and last week's or a 'typical' weekly consumption (type, brand, volume, price, place of purchase). Scottish Index of Multiple Deprivation quintile was derived as proxy of sociodemographic status. RESULTS: Median consumption was 184.8 (IQR = 162.2) UK units/week paying a mean of 39.7 pence per alcohol unit (£0.397). Off-sales accounted for 95% of purchases with 85% of those <50 pence (£0.5 UK) per alcohol unit. Corresponding figures for the Scottish population are 69% and 60%. The most popular low-priced drinks were white cider, beer and vodka with the most common off-sales outlet being the corner shop, despite supermarkets offering cheaper options. Consumption levels of the cheapest drink (white cider) were similar across all quintiles apart from the least deprived. CONCLUSIONS: Heavy drinkers from all quintiles purchase the majority of their drinks from off-sale settings seeking the cheapest drinks, often favouring local suppliers. While beer was popular, recent legislation impacting on the sale of multibuys may prevent the heaviest drinkers benefiting from the lower beer prices available in supermarkets. Non-etheless, drinkers were able to offset higher unit prices with cheaper drink types and maintain high levels of consumption. Whilst price is key, heavy drinkers are influenced by other factors and adapt their purchasing as necessary.

Selective transfection of microglia in the brain using an antibody-based non-viral vector.

There are currently few approaches to transiently manipulate the expression of specific proteins in microglia of the brain. An antibody directed against an extracellular epitope of scavenger receptor class B, type I (SR-BI) was found to be selectively taken up by these cells in the brain. Other antibodies tested were not internalised by microglia. A vector was produced by linking the SR-BI antibody to polyethyleneimine and binding a DNA plasmid encoding green fluorescent protein. Infusions of this vector into the hippocampus produced a widespread transfection of cells, more than 80% of which were immunoreactive for microglial/macrophage markers. Transfection was not detected in cells expressing markers for astrocytes or neurons. Reporter gene expression was most prominent near the infusion site but was seen in tissue up to 4mm away. DNA bound to polyethyleneimine alone or to a vector containing a different antibody did not produce transfection in the brain. Single injections of the vector containing the SR-BI antibody into the brain also resulted in transfection of microglia, albeit with lower efficiency. Vector modifications to promote lysis of endosomes or entry of DNA into the nucleus did not increase efficiency. The findings clearly demonstrate the capacity of the SR-BI antibody to selectively target brain microglia. This approach offers considerable potential to deliver DNA and other molecules capable of modifying the function of these cells in vivo.

Delirium in acute stroke: screening tools, incidence rates and predictors: a systematic review.

Delirium is a common complication in acute stroke yet there is uncertainty regarding how best to screen for and diagnose delirium after stroke. We sought to establish how delirium after stroke is identified, its incidence rates and factors predicting its development. We conducted a systematic review of studies investigating delirium in acute stroke. We searched The Cochrane Collaboration, MEDLINE, EMBASE, CINHAL, PsychINFO, Web of Science, British Nursing Index, PEDro and OT Seeker in October 2010. A total of 3,127 citations were screened, full text of 60 titles and abstracts were read, of which 20 studies published between 1984 and 2010 were included in this review. The methods most commonly used to identify delirium were generic assessment tools such as the Delirium Rating Scale (n = 5) or the Confusion Assessment Method (n = 2) or both (n = 2). The incidence of delirium in acute stroke ranged from 2.3-66%, with our meta-analysis random effects approach placing the rate at 26% (95% CI 19-33%). Of the 11 studies reporting risk factors for delirium, increased age, aphasia, neglect or dysphagia, visual disturbance and elevated cortisol levels were associated with the development of delirium in at least one study. The outcomes associated with the condition are increased morbidity and mortality. Delirium is found in around 26% of stroke patients. Difference in diagnostic and screening procedures could explain the wide variation in frequency of delirium. There are a number of factors that may predict the development of the condition.

Services for children with developmental co-ordination disorder: the experiences of parents.

BACKGROUND: Parents provide valuable information on their experiences of engaging with therapy services for their children, which can inform the future development of these services. The aim of this study was to explore the views and experiences of parents who had accessed therapy services for their child with developmental co-ordination disorder (DCD). METHODS: Seven focus groups were conducted incorporating 52 parents who had a child diagnosed with, or fitting the diagnostic criteria for DCD. Focus groups were audiotaped, transcribed and analysed thematically. FINDINGS: Parents reported struggling to gain access to therapy services. When they gained access, they found the services beneficial for their child but continued to experience difficulties regarding the quality of service delivery. CONCLUSIONS/IMPLICATIONS: The study suggests that parents thought some health-care professionals lacked knowledge and understanding of DCD, which they believed impacted upon early recognition and access to services. They perceived that therapy at an early age was vital for children's development, and indicated that a clearer path for accessing these services was necessary in addition to improved service quality. They called for an increase in awareness of DCD by all therapy service professionals to aid early recognition and improved treatment.

The impact of MRSA infection in the airways of children with cystic fibrosis; a case-control study.

The prevalence of Methicillin Resistant Staphylococcus Aureus (MRSA) in patients with Cystic Fibrosis (CF) has risen dramatically over the past 10 years. The clinical significance of MRSA in CF patients remains undetermined. We conducted a review of patients with CF infected with MRSA over a 10 year period at Our Lady's Children's Hospital, Crumlin between 1999 and 2009. We collected data from 24 patients infected with MRSA and 24 control patients without MRSA There was a significant difference between the two groups in the rate of decline in percentage FEV1 two years after MRSA infection (Difference: -17.4, 95% CI: -30.48, -4.31, p = 0.01). A similar trend was seen for FVC% and FEF25-75% predicted. This study suggests that persistent MRSA infection in the airways of children with CF is associated with diminished lung function two years post acquisition, when compared to a matched control cohort without MRSA.

The human G93A-superoxide dismutase-1 mutation, mitochondrial glutathione and apoptotic cell death.

Mutations in Cu/Zn superoxide dismutase are a cause of motor neuron death in about 20% of cases of familial amyotrophic lateral sclerosis (ALS). Although the molecular mechanism of which these mutations induce motor neuron cell death is to a large extent unknown, there is significant evidence that effects on mitochondrial function and development of oxidative stress make a major contribution to the selective death of motor neurons in this disease. In this overview article we review the current understanding of mutant SOD1-mediated motor neuron degeneration in ALS with focus on oxidative damage and mitochondrial dysfunction. We also present novel information on the role of mitochondrial glutathione for the survival of NSC-34 cells stably transfected with the human SOD1(G93A) mutation, putting forward the hypothesis that this antioxidant pool provides a potentially useful target for therapeutic intervention.

CD 271 (P75 neurotrophin receptor).

P75NTR (or CD271) is a member of the Tumor Necrosis Factor receptor (TNFR) super family of transmembrane proteins that share significant homology in their extracellular domains. Subsets of TNF receptors, including CD271, have a cytoplasmic death domain, although CD271 has unique intracellular structure and downstream signaling partners. CD271 is also differentiated from other members of the TNFR receptor family in that it binds pro and mature neurotrophins and affects the growth, differentiation and death of the nervous system. The ligands for CD271 are neurotrophins, which are Nerve Growth Factor (NGF), Brain-Derived Growth factor (BDNF), Neurotrophin 3 (NT3) and Neurotrophin 4/5 (NT4/5). Recent studies have provided evidence that CD271 also serves as a receptor for the pro-forms of these neurotrophins.

Targeted silencing of TrkA expression in rat forebrain neurons via the p75 receptor.

Basal forebrain neurons express the neurotrophin receptors, p75NTR and tyrosine kinase receptor A (TrkA). We tested the hypothesis that impairment of memory in rats could be achieved by RNA interference (RNAi) -induced silencing of TrkA specifically within these neurons. A novel fusogenic, karyophilic immunoporter (fkAb(p75)-ipr) was constructed from the antibody, MC192 (monoclonal antibody to the rat neurotrophin receptor p75NTR, Ab(p75)), poly-l-lysine together with the hemagglutinin 2 and VP1 nuclear localization peptides of influenza and SV40 virus, respectively. Plasmid DNA constructs containing short hairpin sequences inhibitory to tyrosine kinase receptor A expression (TrkAi) and the gene encoding cGFP (green fluorescent protein from coral fish) was produced. These TrkAi plasmids were mixed with the immunoporter, forming the immunogene, TrkAi-fkAb(p75). A control TrkAsc complexed with fkAb(p75) (TrkAsc-fkAb(p75)) immunogene was constructed from a scrambled sequence (TrkAsc) and fkAb(p75)-ipr. Rats were infused using an osmotic mini-pump into the third ventricle with either TrkAi-fkAb(p75) or TrkAsc-fkAb(p75). Naive rats were also included as additional controls. After 7 days, examination of gene expression on forebrain sections of some rats revealed cGFP expression in TrkA neurons. Fifteen to 19 days after infusion, rats were tested in a Morris water maze apparatus. Animals that received TrkAi-fkAb(p75) showed significantly impaired spatial memory learning ability compared with naive or TrkAsc-fkAb(p75)-treated rats. Western blot and immunofluorescence analysis showed that TrkA protein levels and numbers of TrkA positive neurons were reduced by 60% and 55% respectively in TrkAi-fkAb(p75)-infused rats compared with infused controls or naive animals. We conclude that p75-receptor-mediated RNAi-induced silencing of genes offers a novel and powerful way to study the function of specific endogenous genes within distinct neuronal subpopulations of the brain.

Clinically relevant fatigue in cancer outpatients: the Edinburgh Cancer Centre symptom study.

BACKGROUND: Fatigue is associated with cancer and its treatment but we know little about how many and which patients suffer fatigue of clinical severity. We aimed to determine the prevalence of clinically relevant fatigue (CRF) and its associations in outpatients with various cancer diagnoses. PATIENTS AND METHODS: A survey of outpatients with colorectal, breast, gynaecological, genitourinary, sarcoma, melanoma and miscellaneous tumours at a regional cancer centre. Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) fatigue subscale and the Hospital Anxiety and Depression Scale (HADS). These self-report data were linked to demographic and clinical variables. Data were available on 2867 outpatients. RESULTS: The prevalence of CRF (EORTC fatigue subscale > or =40) was 32% (95% confidence interval 31-34%). The variables independently associated with CRF were primary cancer site, having disease present, type of cancer treatment and emotional distress (total HADS score > or =15). Emotional distress had the strongest association with fatigue but half the cases of CRF were not distressed. CONCLUSION: CRF is common in cancer outpatients and is associated with type of disease and treatment, as well as with emotional distress. The association between CRF and emotional distress is strong but they are not equivalent conditions.

Emotional distress in cancer patients: the Edinburgh Cancer Centre symptom study.

To: (1) estimate the prevalence of clinically significant emotional distress in patients attending a cancer outpatient department and (2) determine the associations between distress and demographic and clinical variables, we conducted a survey of outpatients attending selected clinics of a regional cancer centre in Edinburgh, UK. Patients completed the Hospital Anxiety and Depression Scale (HADS) on touch-screen computers and the scores were linked to clinical variables on the hospital database. Nearly one quarter of the cancer outpatients 674 out of 3071 (22%; 95% confidence interval (CI) 20-23%) met our criterion for clinically significant emotional distress (total HADS score 15 or more). Univariate analysis identified the following statistically significant associations: age<65, female gender, cancer type and extent of disease. Multivariate analysis indicated that age<65 (odds ratio 1.41; 95% CI 1.18-1.69), female gender (odds ratio 1.58; 95% CI 1.31-1.92) and active disease (odds ratio 1.72; 95% CI 1.43-2.05) but not cancer diagnosis, were the independent predictors of clinically significant emotional distress. Services to treat distress in cancer patients should be organised to target patients by characteristics other than their cancer diagnosis.

The initial development of an item bank to assess and screen for psychological distress in cancer patients.

Psychological distress is a common problem among cancer patients. Despite the large number of instruments that have been developed to assess distress, their utility remains disappointing. This study aimed to use Rasch models to develop an item-bank which would provide the basis for better means of assessing psychological distress in cancer patients.An item bank was developed from eight psychological distress questionnaires using Rasch analysis to link common items. Items from the questionnaires were added iteratively with common items as anchor points and misfitting items (infit mean square >1.3) removed, and unidimensionality assessed.A total of 4914 patients completed the questionnaires providing an initial pool of 83 items. Twenty items were removed resulting in a final pool of 63 items. Good fit was demonstrated and no additional factor structure was evident from the residuals. However, there was little overlap between item locations and person measures, since items mainly targeted higher levels of distress. The Rasch analysis allowed items to be pooled and generated a unidimensional instrument for measuring psychological distress in cancer patients. Additional items are required to more accurately assess patients across the whole continuum of psychological distress.

Rasch analysis of the dimensional structure of the Hospital Anxiety and Depression Scale.

The Hospital Anxiety and Depression Scale (HADS) has been used extensively in cancer patients to identify psychological distress. Reports of the factor structure and screening performance of the instrument vary. Rasch models allow an assessment of the structure of a questionnaire by identifying item fit. Removal of misfitting items may improve both the dimensionality and efficacy of screening questionnaires. A Rasch analysis of the HADS-T and subscales was used to explore the factor structure, dimensionality and screening efficacy. A total of 1855 patients completed a touchscreen version of the HADS, including 381 patients who had received a psychiatric interview (SCAN/PSE). These data were analysed using Rasch models, and the screening efficacy at identifying cases of psychological distress and anxiety and depression evaluated. The results demonstrated that the structure of the HADS-T and subscales was unidimensional. Three items from the HADS-T, and one from each of the subscales demonstrated misfit. Screening efficacy for the HADS-T and subscales was modest. However, removal of misfitting items had little impact on screening, demonstrating that items could potentially be omitted, if required. The item range covered a narrow spectrum of psychological distress, predominantly higher levels of distress. Additional items have to be added if screening for moderate to mild distress is to be improved for cancer patients.

WWOX mRNA expression profile in epithelial ovarian cancer supports the role of WWOX variant 1 as a tumour suppressor, although the role of variant 4 remains unclear.

WWOX is a candidate tumour suppressor gene that exhibits LOH or homozygous deletion in several tumour types. As well as the predominant full-length transcript (variant 1) there also exist alternatively spliced transcripts found previously only in malignant tissue. It has been suggested that proteins encoded by these variants may interfere with normal WWOX function in a dominant negative fashion. The most prevalent alternate transcript demonstrated in ovarian cancer is variant 4, which lacks exons 6-8. Here, we report the first comparison of the mRNA expression of WWOX variants 1 and 4 in human ovarian tumours and normal ovaries, and correlate expression with clinical data. We demonstrate significantly lower WWOX variant 1 expression in tumours than in normal ovaries. This reduction was not associated with any specific clinical subgroup. Variant 4 was expressed at low levels, and significantly associated with high grade and advanced stage ovarian cancer. Furthermore, tumours co-expressing variant 4 and relatively high levels of variant 1 showed significantly worse survival than tumours expressing variant 1 alone. However, variant 4 was also frequently identified in non-malignant ovarian tissue. These results support the role of WWOX variant 1 as a suppressor of ovarian tumourigenesis, but the role of variant 4 remains speculative.

Patient satisfaction with two different models of cancer genetic services in south-east Scotland.

There is a need to integrate primary- and secondary-care cancer genetic services, but the most appropriate model of service delivery remains unclear. This study reports patients' expectations of breast cancer genetic services and a comparison of their satisfaction with two service models. In the first model, risk assessment was carried out using mailed family history data. Women estimated as being at high/moderate risk were offered an appointment at the familial breast cancer clinic, and those at low risk were sent a letter of reassurance. In the second model, all women were seen by a genetic nurse specialist, who assessed risk, referred high/moderate-risk women to the above clinic and discharged those at low risk. Over 60% of all women in the study regarded access to breast screening by mammogram and regular check-ups as very important. This underlines the demand for a multidisciplinary service providing both clinical genetic and surgical services. Satisfaction was high with both models of service, although significantly lower among women not at increased cancer risk and thus not offered a clinical check-up and mammography. Increased cancer worry was associated with a greater expressed need for information and for reassurance through follow-up clinical checks and mammography. Better targeting of counselling to the expressed concerns and needs of these women is required to improve the service offered. GPs and patients expressed no clear preference for any specific service location or staffing configuration. The novel community service was less expensive in terms of both staff and patient costs. The potential to decrease health staff/patient contact time and to employ nurse practitioners with both clinical genetic and oncology training should be explored further. The rapidly rising demand for these services suggests that the evaluation of further new models needs to continue to be given priority to guide the development of cancer genetic services.

A randomised controlled trial of a psychoeducational intervention for women at increased risk of breast cancer.

This study aimed to compare the impact of two versions of a psychoeducational written intervention on cancer worry and objective knowledge of breast cancer risk-related topics in women who had been living with an increased risk of familial breast cancer for several years. Participants were randomised to three conditions: scientific and psychosocial information pack (Group 1), scientific information pack only (Group 2) or standard care control (Group 3). They completed postal questionnaires at baseline (n=163) and 4 weeks (n=151). As predicted, there was a significant decrease in cancer worry for Group 1, but not Group 2. Objective knowledge significantly improved for both Group 1 and Group 2 as expected, but not Group 3. However, there was an unpredicted decline in cancer worry for Group 3. This study supports the value of a scientific and psychosocial information pack in providing up-to-date information related to familial risk of breast cancer for long-term attendees of a familial breast cancer clinic. Further research is warranted to determine how the information pack could be incorporated into the existing clinical service, thus providing these women with the type of ongoing psychosocial support that many familial breast cancer clinics are currently lacking.

Management of major depression in outpatients attending a cancer centre: a preliminary evaluation of a multicomponent cancer nurse-delivered intervention.

A novel nurse-delivered multicomponent intervention for major depressive disorder (MDD) in cancer outpatients was compared with usual care alone in a nonrandomised matched group design (n=30 per group). At the final 6-month outcome, 38.5% (95% CI, 5.4-57%) fewer patients in the intervention group still met the criteria for MDD.