A comparison of self and proxy quality of life ratings for people with dementia and their carers: a European prospective cohort study.

Objectives: To identify correlates of self-rated and proxy-rated quality of life (QoL) in people with dementia on (i) a dementia-specific and (ii) a capability-wellbeing QoL measure at baseline and 12-month follow-up, and to consider such factors in the context of QoL intervention development.Method: Prospective clinical and demographic data were collected from 451 community-dwelling dyads (mild-moderate dementia) across eight European countries. QoL was measured using the QOL-AD and the ICECAP-O. Multivariate modelling identified correlates of self- and proxy-rated QoL at baseline and at 12-month follow-up.Results: Carer's proxy-ratings of QoL were significantly lower than self-ratings at all time-points for both measures. Proxy-ratings declined over time, but self-ratings remained stable. Baseline predictors of greater self-rated QoL were education, and greater functional ability and relationship quality. Greater proxy-rated QoL was associated with education and greater functional ability, relationship quality, carer social support and carer QoL, lower carer anxiety/depression and less severe neuropsychiatric symptoms in people with dementia. At follow-up, greater self-rated QoL was predicted by greater functional ability, relationship quality, carer social support and having a spousal carer. Greater proxy-rated QoL at follow-up was associated with the same factors as at baseline; however, the dyad living together was an additional predictive factor.Conclusion: Both proxy-ratings and self-ratings of QoL should be interpreted with caution and in the context of each individual caregiving relationship. Different functional, psychosocial, relational and contextual factors influence self- and proxy-ratings, and both sets of factors should be considered in the context of QoL intervention development for the dyad.

Access to community care for people with dementia and their informal carers : Case vignettes for a European comparison of structures and common pathways to formal care.

BACKGROUND: People with dementia and their informal carers often do not receive appropriate professional support or it is not received at the right time. OBJECTIVES: Description and comparison of common pathways to formal community dementia care in eight European countries as a part of the transnational Actifcare project. MATERIALS AND METHODS: The German team was responsible for creating an individual case scenario as a starting point. The research teams in Ireland, Italy, the Netherlands, Norway, Portugal, Sweden, and the United Kingdom were then asked to describe a common pathway to formal dementia care by writing their own vignette using the provided individual case scenario. RESULTS: A transnational qualitative content analysis was used to identify the following categories as being the most important: involved professionals, dementia-specific and team-based approaches, proactive roles, and financial aspects. General practitioners (GPs) are described as being the most important profession supporting the access to formal care in all the involved countries. In some countries other professionals take over responsibility for the access procedure. Dementia-specific approaches are rarely part of standard care; team-based approaches have differing significances in each of the countries. Informal carers are mainly proactive in seeking formal care. The Nordic countries demonstrate how financial support enhances access to the professional system. CONCLUSION: Enhanced cooperation between GPs and other professions might optimize access to formal dementia care. Team-based approaches focusing on dementia care should be developed further. Informal carers should be supported and relieved in their role. Financial barriers remain which should be further investigated and reduced.

Progress in the management of retrorectal tumours.

AIM: Tumours in the retrorectal space are rare and pathologically heterogeneous. The roles of imaging and preoperative biopsy, nonoperative management and the indications for surgical resection are controversial. This study investigated a series of retrorectal tumours treated in a single institution with the aim of producing a modern improved management algorithm. METHOD: A retrospective analysis was conducted of the management of all retrorectal lesions identified between 1998 and 2013 from a radiology database search. Patient demographics, presenting symptoms, imaging, biopsy, management and the results were recorded. Descriptive statistics were used and Kaplan-Meier survival analysis was performed. RESULTS: Sixty-nine patients with a confirmed retrorectal tumour were identified. The median age was 50 (36-67 interquartile range) and 42 (56%) were female. Twenty (29%) of the tumours were malignant: 4 of 41 cystic lesions were malignant (12.9%) vs. 16 of 28 solid (or heterogeneous) lesions (57.1%) (P < 0.0001). Imaging demonstrated a 95% sensitivity and 64% specificity for differentiating benign from malignant tumours. Magnetic resonance imaging (MRI) was significantly better at distinguishing between benign and malignant tumours than computed tomography (94% vs. 64%, P = 0.03). Percutaneous biopsy was performed in 16 patients and only 27 underwent resection. There was no evidence of local recurrence associated with biopsy. Solid lesions were associated with a nonsignificant decreased overall survival (P = 0.348). CONCLUSION: This study demonstrated that MRI should be the investigation of choice for retrorectal lesions. Biopsy of solid lesions is safe and useful for guiding neoadjuvant and surgical therapy. Cystic lesions without suspicious radiological features can be followed by serial imaging without resection.

Consumer and clinician perspectives on personalising breast cancer prevention information.

BACKGROUND: Personalised prevention of breast cancer has focused on women at very high risk, yet most breast cancers occur in women at average, or moderately increased risk (≤moderate risk). OBJECTIVES: To determine; 1) interest of women at ≤ moderate risk (consumers) in personalised information about breast cancer risk; 2) familial cancer clinicians' (FCCs) perspective on managing women at ≤ moderate risk, and; 3) both consumers' and FCCs reactions to iPrevent, a personalised breast cancer risk assessment and risk management decision support tool. METHODS: Seven focus groups on breast cancer risk were conducted with 49 participants; 27 consumers and 22 FCCs. Data were analysed thematically. RESULTS: Consumers reported some misconceptions, low trust in primary care practitioners for breast cancer prevention advice and frustration that they often lacked tailored advice about breast cancer risk. They expressed interest in receiving personalised risk information using iPrevent. FCCs reported an inadequate workforce to advise women at ≤ moderate risk and reacted positively to the potential of iPrevent to assist. CONCLUSIONS: While highlighting a potential role for iPrevent, several outstanding issues remain. For personalised prevention of breast cancer to extend beyond women at high risk, we must harness women's interest in receiving tailored information about breast cancer prevention and identify a workforce willing to advise women.

Automated Microsampling Technologies and Enhancements in the 3Rs.

Data collected in vivo is essential for advising decisions on drug screening and development and basic research, and animal models are used extensively for acquiring experimental measurements. Traditionally, collection of specimens has been invasive, stressful to animal subjects, labor intensive, time-consuming and costly, and required many animals when using small models with low fluid volumes, such as rats or mice. Utilizing automated microsampling (AMS) alone or in an integrative pharmacology approach to evaluate multiple physiological, pharmacokinetic, and pharmacodynamic endpoints simultaneously in the same animal accomplishes multiple experimental goals. Use of AMS robotics and associated instrumentation can assist in achieving significant reduction and refinement of animal use. Automated robotic instrumentation for specimen collection from living animal models can now be used to provide better quality pharmacokinetic and pharmacodynamic data, reduce time, provide more data with less variability, reduce animal use, and refine animal model use to reduce pain and stress. Instrumentation in common use for automated sampling and dosing is briefly discussed. In parallel with advances in automated instrumentation, recent advances in analytical detection methods complement the use of automated technology for data and specimen collection. Methods requiring much smaller volumes can now be utilized. Microsampling (small biological samples in volumes of 5-100 µL) can facilitate reduction in animal numbers while minimizing stresses associated with excessive fluid volume removal. Innovations in automation, microsampling techniques, and analytical methods have facilitated advances in data collection that allow for more robust and accurate data, reduction in animal use, and refinement in techniques that improve animal welfare. These innovations offer opportunities for wider application in nonclinical investigations by collection of multiple data streams simultaneously from individual animals. Many benefits are achievable through the use integrative pharmacology designs utilizing AMS, including decreased time for completion of composite data collection, decreased personnel resources, lower costs, improved safety, higher quality and multiple data-sets, and improvements in aspects of the 3Rs.

Acute respiratory distress syndrome in a community hospital ICU.

OBJECTIVE: To estimate the incidence of the acute respiratory distress syndrome (ARDS) in an Australian urban community, and to describe the pattern of disease and outcomes in a community hospital intensive care unit (ICU). SETTING: An eight-bed general ICU in a community hospital. DESIGN: Retrospective chart review. PATIENTS: 32 patients identified over a 4-year period as having ARDS. MEASUREMENTS AND RESULTS: The incidence of ARDS in an Australian urban community was estimated to be 7.3-9.3 cases/100,000 population per year. In-hospital mortality was 59%, while ICU mortality was 47%. Sepsis, pneumonia and aspiration were the main aetiological factors accounting for 94% of the patient population. There was no trauma. The Acute Physiology and Chronic Health Evaluation and Murray scores and values for the ratio of the partial pressure of oxygen in arterial blood and fractional inspired oxygen on admission to the ICU were similar between survivors and nonsurvivors, and none of these parameters were reliable predictors of outcome. Mean age, however, was different between survivors (56 +/- 16 years) and non-survivors (69 +/- 9 years) (p < or = 0.01). Mean daily fluid balance was also different between survivors (536 +/- 545 ml/day) and non-survivors (1576 +/- 1255 ml/day) (p < or = 0.02). Haemodynamic data were collected on 21 of the 32 patients within 72 h of the onset of ARDS. None of the haemodynamic parameters reached significance. There was, however, a trend for better cardiac function and oxygen consumption in the survivors. CONCLUSIONS: These data show that for ARDS, at least, mortality outcome can be comparable in a community ICU to a tertiary referral institution. The pattern of disease in an urban Australian community hospital is different to that often reported from tertiary centres. The incidence of ARDS in an Australian urban community is comparable to the reported incidence in North America and Western Europe.

A qualitative investigation of the views of primary care dentists on participating in prospective studies in the North-West of England.

BACKGROUND: There is a poor understanding of to how to recruit and involve primary care dentists in clinical trials. AIM: To use a qualitative paradigm to explore the views of primary care dentists towards participating in clinical trials and develop an understanding of the factors that facilitate and prevent their involvement. DESIGN, SETTING, SUBJECTS AND METHODS: An iterative approach was undertaken using a focus group (n = 6) followed by phased semi-structured interviews (n = 18). Data were analysed using thematic analysis and constant comparative analysis. FINDINGS: The semi-structured interviews generated nine codes which were organised into three themes: technical issues for trials in primary dental care, practical issues for research in primary dental care and primary care dentists as research consumers. Overall, primary care dentists had a poor understanding of research methodology and clinical research. Barriers to participation included loss of clinical freedom and control, practice disruption, patient welfare, staff workload, financial loss and time. CONCLUSIONS: Barriers to primary dental care research need to be overcome through appropriate protocols, funding, training and support. Joint working of primary dental care teams and academic researchers is essential, along with a constructive and open dialogue, if clinical trials are to be successfully undertaken in a practice environment.

The views of dentists on their participation in a primary care-based research trial.

AIMS: To determine the attitudes and opinions of dentists undertaking research in primary care dental practices, about the value of research in primary care. METHOD: The data were collected during a face-to-face interview utilising a schedule of open and closed questions, which were used to guide the interview. RESULTS: Twenty-seven of the 40 primary care dentists (67.5%) who had participated in a five-year primary care clinical trial completed the interview. All the respondents believed that primary care research was important and should be of relevance to their practice, but only 12 (44%) thought it was important they carried out this research. The majority (96%) of respondents felt it did not pay financially to do research as a primary care practitioner and 12 (44%) thought research in primary care was too time consuming, but 25 (92%) were prepared to get involved in a primary care research group. Five (56%) salaried service (SS) practitioners and 14 (78%) general dental services (GDS) dentists felt they did not have enough experience, skills or knowledge to conduct their own research. Significantly more salaried dentists compared with GDS dentists felt adequately supported to do primary care research. CONCLUSION: Future research in primary care should be focused on topics primary care practitioners feel of use to their clinical practice. A method of funding practitioners and providing time for them to complete research away from their clinical duties is necessary. There is a need for collaborative working with an academic institution, which can provide training and academic support for practitioners.

Chemical risk assessment: a review.

People are exposed to a staggering assortment of chemicals and foreign substances. Potential health risks accompany these exposures. Intelligent, informed decisions are needed on which risks can and should be reduced, eliminated, or simply ignored. Therefore, a method of determining the attendant human health risks involved in chemical exposure is necessary. This need has resulted in the evolution of the risk assessment process which was developed to aid in identifying, characterizing and quantifying risks. Risk assessment today is an essential component of regulatory decision-making. In the context of chemical exposure, risk assessment is an evaluation of the risk in human exposure to chemicals in the environment. Quantitative risk assessment (QRA) is the use of experimental laboratory data and/or human epidemiological data in a process to derive a quantitative value for the estimate of the probability of harm occurring to exposed human populations. It is a sophisticated process involving an array of techniques that can be used to identify potential risks to human health. There are 4 components involved in the formalized risk assessment process--hazard identification, toxicity assessment, exposure assessment and risk characterization. These 4 steps collectively address each of 6 key areas identified as essential in characterizing a risk situation involving a chemical exposure. The process of risk estimation involves uncertainties because there are always gaps in knowledge or a lack in understanding mechanisms. These crucial gaps in knowledge are filled when extrapolations, models or assumptions are used. The uncertainties inherent in the risk assessment process are the basis of arguments against the use of the process. Many of these sources of uncertainty inherent in the risk assessment process are examined herein. These include, but are not limited to, modeling methods, understanding mechanisms and pharmacodynamics, exposure data, assumptions and extrapolations. Some new techniques and approaches being applied to the risk assessment process are examined. These include improved models for extrapolating data and quantifying risks, improved laboratory techniques for investigating pharmacodynamic and mechanistic pathways and advancements in quality and application of epidemiological data. The actual concept of uncertainty is being examined and attempts are being made to directly address, quantify and manage uncertainty.

Influence of smoking habits on change in carbon monoxide transfer factor over 10 years in middle aged men.

BACKGROUND: Emphysema is associated with a reduction in carbon monoxide transfer coefficient (TLCO/VA), but little is known about the evolution of changes in TLCO/VA in middle aged smokers at risk of developing chronic airflow obstruction. METHODS: TLCO/VA (single breath method) was measured on two occasions 10 years apart in 122 middle aged men. RESULTS: Initially TLCO/VA averaged 97% predicted in never smokers (n = 42, mean age 37.2 years), 99% predicted in ex-smokers (n = 21, mean age 41.9 years), and 85% predicted in those who smoked over 15 cigarettes a day (n = 42, mean age 42.0 years). Mean rates of decrease in TLCO/VA over 10 years, however, were similar in the three groups, so that differences between smokers and non-smokers did not increase during the 10 years. Seventeen men (mean age 40.9 years) who initially were smokers became sustained ex-smokers within two years of the first measurement; in these men mean absolute values of TLCO/VA rose, averaging 89% predicted at the first assessment but 102% predicted 10 years later. CONCLUSION: By the age of about 40 years TLCO/VA was lower in smokers than in never smokers but this difference did not increase over the following 10 years. Sustained ex-smokers had values similar to those of never smokers even when TLCO/VA was known to have been reduced while they were smoking. Changes in TLCO/VA associated with stopping smoking were considerably larger than could be explained by carbon monoxide back pressure, indicating that mechanisms other than irreversible increase in the size of terminal air spaces underlie the lower values in smokers. To detect emphysema in smokers it is necessary to use reference equations that take account of current smoking.

Evaluation of radiologist performance using telemedicine services.

Observer performance of radiologists using a telemedicine service was evaluated. Diagnoses between the rural and consulting radiologists agreed 84% of the time. The main reason for disagreement was extent of lesion rather than type or absence/presence. Consulting times and image quality were considered adequate.

Acute cardiotoxicity of nucleoside analogs FddA and FddI in rats.

The acute cardiotoxic potential of single dosages of FddA (2'-fluoro-2',3'-dideoxyadenosine) and FddI (2'-fluoro-2',3'-dideoxyinosine) was investigated in 6- to 9-week-old rats. Both nucleoside analogs were administered orally at 1000 and 2000 mg/kg and intravenously at 500 or 1000 mg/kg. For comparative purposes, additional groups of rats received 2'-deoxyadenosine or the 2-fluororibose moiety common to both the FddA and FddI molecules. The effects of two adenosine receptor antagonists, caffeine and theophylline, on the cardiotoxicity induced by FddA were also investigated. Deaths occurred within a few hours to a few days in FddA-treated rats given 2000 mg/kg orally or 500 mg/kg intravenously and in FddI-treated rats given 1000 mg/kg intravenously. Microscopic examination of the hearts revealed myocardial degeneration and necrosis for all rats that died and myocardial fibrosis for many survivors. No deaths or cardiac lesions were observed after administration of 2'-deoxyadenosine or the 2-fluororibose moiety. FddA was more cardiotoxic than FddI in rats at equivalent dosages administered either orally or intravenously. Based on the anatomic findings, all deaths were attributed to cardiac lesions. The administration of high, oral dosages of caffeine and theophylline accentuated the acute cardiotoxicity of FddA in rats.

Pulmonary function after bone marrow transplantation for chronic myeloid leukaemia.

Pulmonary function was measured before and at intervals after treatment in 44 patients who received a bone marrow transplant for chronic myeloid leukaemia in the chronic phase. All patients were treated with cytotoxic drugs, total body irradiation, and post-graft immunosuppression. Thirty four patients surviving for 12 months were followed at three monthly intervals and 16 patients for 24 months. Fifteen patients received unmanipulated donor marrow cells and 29 patients received donor marrow cells depleted of lymphocytes ex vivo with the monoclonal antibody Campath-1. The 21 patients treated early in this study received 10 Gy of total body irradiation whereas the 23 patients treated more recently, who were all T lymphocyte depleted, received 12 Gy. Pretransplant lung function for the group was normal and was similar in survivors (n = 34) and nonsurvivors (n = 10), and in smokers (n = 8) and non-smokers (n = 36). (Carbon monoxide transfer factor--TLCO) was under 75% of predicted normal in nine patients before transplantation. TLCO, carbon monoxide transfer coefficient (KCO), FEV1, and vital capacity (VC) values were lower 6 and 12 months after bone marrow transplant than initially. The greatest decline was in TLCO, from an initial value of 89% to 66% at 6 and 70% at 12 months. The 16 longer term survivors showed significant recovery of function between 6 and 24 months after bone marrow transplant for TLCO, KCO, and VC, the increase ranging from 6.3% to 7.3% predicted. Airflow obstruction (FEV1/VC ratio less than 70%) developed in one patient. The major factors associated with deterioration in pulmonary function at 6 and 12 months after transplantation in the 34 survivors (stepwise multiple regression analysis) were (a) transplantation with T cell depleted donor marrow (p less than 0.005) and higher total body irradiation dose (p less than 0.02) with a fall in KCO and an increase in the FEV1/VC ratio; (b) chronic graft versus host disease with a fall in VC (p less than 0.01); and less fall in KCO (p less than 0.01); and (c) acute graft versus host disease with a fall in FEV1 (p less than 0.01). It is considered that most patients who survive the short term risks of bone marrow transplant have only minor long term impairment of pulmonary function.