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Effective environmental assessment and management requires quantifiable biodiversity targets. Biodiversity benchmarks define these targets by focusing on specific biodiversity metrics, such as species richness. However, setting fixed targets can be challenging because many biodiversity metrics are highly variable, both spatially and temporally. We present a multivariate, hierarchical Bayesian method to estimate biodiversity benchmarks based on the species richness and cover of native terrestrial vegetation growth forms. This approach uses existing data to quantify the empirical distributions of species richness and cover within growth forms, and we use the upper quantiles of these distributions to estimate contemporary, "best-on-offer" biodiversity benchmarks. Importantly, we allow benchmarks to differ among vegetation types, regions, and seasons, and with changes in recent rainfall. We apply our method to data collected over 30 yr at ~35,000 floristic plots in southeastern Australia. Our estimated benchmarks were broadly consistent with existing expert-elicited benchmarks, available for a small subset of vegetation types. However, in comparison with expert-elicited benchmarks, our data-driven approach is transparent, repeatable, and updatable; accommodates important spatial and temporal variation; aligns modeled benchmarks directly with field data and the concept of best-on-offer benchmarks; and, where many benchmarks are required, is likely to be more efficient. Our approach is general and could be used broadly to estimate biodiversity targets from existing data in highly variable environments, which is especially relevant given rapid changes in global environmental conditions., (© 2019 The Authors. Ecological Applications published by Wiley Periodicals, Inc. on behalf of Ecological Society of America.)

Background: Historically, individuals diagnosed with an inherited arrhythmia or cardiomyopathy have been advised to avoid participating in competitive sports. Consequently, these individuals may be more susceptible to weight gain and obesity., Methods: A retrospective longitudinal chart review was performed for a population of children with a genetic or clinical diagnosis of the long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy. We recorded the physical activity recommendation, postdiagnosis sports participation, and body mass index (BMI) over time., Results: A total of 109 charts were reviewed. Some level of physical activity restriction was documented for the majority of phenotype-positive children (80%) but was less common for phenotype-negative children (37%) (P < 0.001). Overall, 38% ( n = 41) of the study population were reportedly participating in a moderate or high dynamic sports following their diagnosis. Nonetheless, the BMI did not differ over time based on physical activity restriction or sports participation, and the proportion of overweight and obese children at follow-up was consistent with that seen in the Canadian pediatric population., Conclusion: Physical activity restriction was recommended for the majority of phenotype-positive children with an inherited arrhythmia or cardiomyopathy. However, many children continue to participate in competitive sports. Children prescribed physical activity restriction appear to face similar concerns relating to obesity as other Canadian children. This study highlights the need to further assess the effectiveness of physical activity recommendations and its impact on the cardiovascular health., (© 2018 Wiley Periodicals, Inc.)

Aims: To synthesize peer-reviewed literature that investigates the dietary intake by food group of individuals with type 2 diabetes mellitus (T2DM) and compare intakes to national and international dietary guidelines., Methods: Four electronic databases (MEDLINE, EMBASE, CINAHL and Web of Sciences) were searched for studies that investigated the dietary intake of adults (≥18 years) with T2DM using the five main food groups (fruit, vegetables, dairy, grains and meat/meat alternatives). Food group intake in serves was compared against national guidelines and fruit and vegetable intake in grams was compared against the World Health Organization (WHO) guidelines., Results: After screening 13,662 publications, 11 studies were included. All reported cross-sectional data. Majority of participants were consuming less than the recommended serves of fruit, vegetables, grains and dairy and were meeting or exceeding the recommended serves for meat/meat alternatives. Two of six studies reported fruit and vegetable recommendations were being met, two reported dairy recommendations were being met and two reported grain recommendations were being met. Of the five studies reporting intake in grams, four met the WHO minimum intake for fruit and vegetables., Conclusions: Individuals with T2DM do not comply with food group recommendations; particularly for fruit, vegetables, dairy and grains. Longitudinal research is required to better understand how food group intake changes over time after diagnosis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Predictive genetic testing in minors should be considered when clinical intervention is available. Children who carry a pathogenic variant for an inherited arrhythmia or cardiomyopathy require regular cardiac screening and may be prescribed medication and/or be told to modify their physical activity. Medical genetics and pediatric cardiology charts were reviewed to identify factors associated with uptake of genetic testing and cardiac evaluation for children at risk for long QT syndrome, hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. The data collected included genetic diagnosis, clinical symptoms in the carrier parent, number of children under 18 years of age, age of children, family history of sudden cardiac arrest/death, uptake of cardiac evaluation and if evaluated, phenotype for each child. We identified 97 at risk children from 58 families found to carry a pathogenic variant for one of these conditions. Sixty six percent of the families pursued genetic testing and 73% underwent cardiac screening when it was recommended. Declining predictive genetic testing was significantly associated with genetic specialist recommendation (p < 0.001) and having an asymptomatic carrier father (p = 0.006). Cardiac evaluation was significantly associated with uptake of genetic testing (p = 0.007). This study provides a greater understanding of factors associated with uptake of genetic testing and cardiac evaluation in children at risk of an inherited arrhythmia or cardiomyopathy. It also identifies a need to educate families about the importance of cardiac evaluation even in the absence of genetic testing.

Deficits in behavioral activation, exertion of effort, and other psychomotor/motivational symptoms are frequently seen in people with depression and other disorders. Depressed people show a decision bias towards selection of low effort activities, and animal tests of effort-related decision making are being used as models of motivational dysfunctions seen in psychopathology. The present studies investigated the ability of drugs that block dopamine transport (DAT), norepinephrine transport (NET), and serotonin transport (SERT) to modulate work output in rats responding on a test of effort-related decision making (i.e., a progressive ratio (PROG)/chow feeding choice task). With this task, rats choose between working for a preferred food (high carbohydrate pellets) by lever pressing on a PROG schedule vs. obtaining a less preferred lab chow that is freely available in the chamber. The present studies focused on the effects of the selective DAT inhibitor GBR12909, the selective SERT inhibitor fluoxetine, and the selective NET inhibitors desipramine and atomoxetine. Acute and repeated administration of GBR12909 shifted choice behavior, increasing measures of PROG lever pressing but decreasing chow intake. In contrast, fluoxetine, desipramine and atomoxetine failed to increase lever pressing output, and actually decreased it at higher doses. In the behaviorally effective dose range, GBR12909 elevated extracellular dopamine levels in accumbens core as measured by microdialysis, but fluoxetine, desipramine and atomoxetine decreased extracellular dopamine. Thus, blockade of DAT increases selection of the high effort instrumental activity, while inhibition of SERT or NET does not. These results have implications for the use of monoamine uptake inhibitors for the treatment of effort-related psychiatric symptoms in humans., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Management of individuals with long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy may involve exercise restriction and/or β-blocker therapy., Objective: This study assessed the practices of a group of paediatric electrophysiologists regarding the management of genotype-positive/phenotype-positive and genotype-positive/phenotype-negative individuals with these conditions., Method: An online survey was circulated to members of the Pediatric and Congenital Electrophysiology Society in May, 2014. The survey included questions addressing the respondents' approach regarding exercise recommendations and prescription of β-blocker therapy., Results: A total of 45 cardiologists completed the survey. The majority of respondents restricted symptomatic patients from competitive sports; however, only approximately half restricted phenotype-negative mutation carriers from this level of activity. Recommendations were less consistent regarding other types of activities. A trend was identified regarding physician physical activity and exercise recommendations for phenotype-negative mutation carriers. Less-active physicians were more likely to restrict exercise. β-blocker therapy was discussed by the majority of respondents for symptomatic patients and a significant number of asymptomatic patients., Conclusion: Exercise restriction for patients with long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy varies based on several factors including phenotype, type of exercise, guidelines referred to, and physicians' own level of activity.

In its landmark decision Carter v Canada (Attorney General), the Supreme Court of Canada ruled that the criminal prohibition on physician-assisted suicide and euthanasia for certain persons in certain circumstances violated their rights to life, liberty, and security of the person in sec. 7 of the Canadian Charter of Rights and Freedoms and thus was unconstitutional. The Supreme Court in effect overruled its earlier decision, Rodriguez v British Columbia (Attorney General), which upheld the prohibition as constitutionally valid, on the basis of changes in Charter jurisprudence and in the social facts since Rodriguez was decided. We argue that the Supreme Court's Carter decision shows conceptual disagreements with its Rodriguez decision concerning the nature and scope of the sec. 7-protected interests and the accompanying principles of fundamental justice. Not only do these conceptual differences have little to do with the changes that the Court in Carter invoked for 'revisiting' Rodriguez, the Court's articulation of the sec. 7 interests, particularly the right to life, and the principles of fundamental justice, especially the principle of over breadth, are problematic on their own terms. Furthermore, the way in which the Court dealt with evidence regarding abuses in permissive jurisdictions is also subject to criticism. We recommend that if, as now seems inevitable, legislation is introduced, it should mandate that assisted suicide and euthanasia be performed by specially licensed non-medical personnel and only on the authorization of a Superior Court judge. We also reject the key recommendations recently issued by the Provincial-Territorial Expert Advisory Group on Physician-Assisted Dying., (© The Author 2016. Published by Oxford University Press; all rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In 2013, as part of the Queen's Nursing Institute (QNI) Carers Project, the QNI asked the 4M Learning Network to test the need for a learning resource to enable community nurses to support carers' health and wellbeing needs. In order to measure the learning needs of community nurses, the QNI undertook a literature review (Laing and Sprung, 2013). The 4M team commenced with desk research and extensive consultation using an online survey and workshops across England. The outcomes of this consultation informed the development of an open-access online learning resource for community nurses, with modules covering different aspects of the nurses' role in relation to carers, as well as a comprehensive resource directory and e-workbook. This resource was launched in March 2014. In response to the enthusiasm and positive feedback from the community nurses, two learning resources were launched in March 2015 for practice nurses and school nurses. An accompanying resource directory mobile application is currently being development and is due to be released in summer 2015. It should be noted that throughout the article, the term carers refers to informal carers, i.e. family or friends caring for a person at home; it does not refer to an employed care assistant or helper.

A high-risk patient was informed of a positive HIV antibody/antigen test. However, follow-up samples taken 2-3 months later for HIV RNA and anti-HIV antibodies were negative. Human DNA testing confirmed that all samples were from this patient, excluding a sample mix-up. Laboratory investigations revealed a likely splash-over contamination event., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective. To assess the impact of low-to-moderate risk prostate cancer on patients' quality of life (QoL) at diagnosis and within the first year of treatment. Subjects and Methods. Men (n = 672) aged 50-75 years with prostate cancer (Gleason score ≤7, PSA ≤20 ng/mL and clinical staging T1c-T2b) were enrolled in five European countries. Patients completed five questionnaires, including EORTC Quality of Life Questionnaire-Prostate Cancer 25 (QLQ-PR25) and EORTC Quality of Life Questionnaire-Cancer 30 (QLQ-C30). Questionnaires were completed at baseline, at 3 months and 12 months after starting treatment. The primary endpoint was the change in QLQ-PR25 urinary symptoms subscale score from baseline to the assessment at 3 months. Results. Mean (SD) age was 65.0 (5.7) years and 400 (66%) men had Gleason score ≤6 prostate cancer. The most frequently used initial treatment was radical prostatectomy (71% of patients). QLQ-PR25 urinary symptoms subscale score was significantly increased at 3 months (P < 0.001), indicating that urinary symptoms worsened after treatment. The score was lower at 12 months than at 3 months, but it was still significantly higher than at baseline (P < 0.001). Hormonal treatment-related symptoms, sexual functioning, and sexual activity scores significantly worsened at 3 and 12 months (all P < 0.001). For the QLQ-C30 questionnaire, global health status/QoL score significantly decreased at month 3 but was not different from baseline by month 12. Scales for physical, role, and social functioning, and fatigue, showed significant deterioration at 3 and 12 months. Conclusions. Low-to-moderate risk prostate cancer may have a substantial effect on patients' QoL within one year following treatment.

An increasing number of genetic counselors are moving into non-clinical roles, where their primary duties do not involve direct patient contact. According to the National Society of Genetic Counselors Professional Status Survey in 2010, 23% of counselors working in non-clinical roles identified laboratory or genetic testing as their primary area of work. Using a survey, we identified 43 genetic counselors who work predominately in laboratory settings. The two primary tasks performed by participants, include acting as a customer liaison (95%) and calling out test results (88%). Nineteen participants (44.2%) also reported spending a considerable amount of time signing reports. The most prevalent areas of job satisfaction were support from laboratory directors (76.8%), autonomy (76.7%), interactions with clinicians (69.7%) and interaction with other genetics counselors (67.5%). This is the first study specifically looking at the roles of laboratory genetic counselors, which is an expanding area of genetic counseling.

Objective: Several matrix metalloproteinases (MMPs) have been implicated in extracellular matrix destruction and other actions that lead to plaque rupture and myocardial infarction. Conversely, other MMPs have been shown to promote vascular smooth muscle cell (VSMC)-driven neointima formation, which contributes to restenosis, fibrous cap formation, and plaque stability. MMP-3 knockout reduced VSMC accumulation in mouse atherosclerotic plaques, implicating MMP-3 in neointima formation. We therefore investigated the effect of MMP-3 knockout on neointima formation after carotid ligation in vivo and VSMC migration in vitro., Methods and Results: Twenty-eight days after left carotid ligation, MMP-3 knockout significantly reduced neointima formation (75%, P<0.01) compared with wild-type (WT) littermates, and also reduced remodeling of ligated and contralateral carotid arteries. Gelatin zymography illustrated that MMP-3 knockout abolished MMP-9 activation in ligated carotids and scratch-wounded VSMC cultures. MMP-3 knockout also attenuated VSMC migration into a scratch wound by 59% compared with WT cells. Addition of exogenous MMP-3 or activated MMP-9 restored migration of MMP-3 knockouts to that of WT VSMCs, but exogenous MMP-3 had no effect on migration in MMP-9 knockout VSMCs. MMP-9 knockout or knockdown with small interfering RNA significantly retarded VSMC migration to the same extent as MMP-3 knockout., Conclusions: These results indicate for the first time that MMP-3 mediated activation of MMP-9 is required for efficient neointima formation after carotid ligation in vivo and for VSMC migration in vitro, whereas MMP-12 plays a redundant role. These findings add to the understanding of MMP action in plaque stability and restenosis.

Background: Standard treatment for high grade glioma (HGG) usually entails surgery (either biopsy or resection) followed by radiotherapy plus or minus temozolomide. Implanting wafers impregnated with chemotherapy agents into the resection cavity represents a novel means of delivering drugs directly to the resection cavity with potentially fewer systemic side effects. It is not clear how effective this modality is or whether it should be recommended as part of standard care for patients with HGG., Objectives: To estimate the clinical effectiveness of chemotherapy wafers for patients with HGG., Search Strategy: The following databases were searched: CENTRAL (issue 4. 2010); MEDLINE and EMBASE. The original search strategy also included: Science Citation Index; Physician Data Query; and the meta-Register of Controlled Trials. Reference lists of all identified studies were searched. The Journal of Neuro-Oncology and Neuro-oncology were hand searched from 1999 to 2010, including all conference abstracts. Neuro-oncologists, trial authors and drug manufacturers were contacted regarding ongoing and unpublished trials., Selection Criteria: Patients included those of all ages with a histologically proven diagnosis of HGG (using intra-operative analysis when undergoing first resection). Therapy could be instigated for either newly diagnosed disease (primary therapy) or at recurrence. Interventions included insertion of chemotherapy wafers to the resection cavity. Included studies had to be randomised controlled trials (RCTs)., Data Collection and Analysis: Two independent review authors assessed the search results for relevance and undertook critical appraisal according to pre-specified guidelines., Main Results: In primary disease two RCTs assessing the effect of carmustine impregnated wafers (Gliadel®) and enrolling a total of 272 participants were identified. Survival was increased with Gliadel® compared to placebo (hazard ratio (HR) 0.65, 95% Confidence Interval (CI) 0.48 to 0.86, P = 0.003). In recurrent disease a single RCT was included comparing Gliadel® with placebo and enrolled 222 participants. It did not demonstrate a significant survival increase (HR 0.83, 95% CI 0.62 to 1.10, P = 0.2). There was no suitable data for any of the secondary outcome measures. Adverse events were not more common in either arm and are presented in a descriptive fashion., Authors' Conclusions: Carmustine impregnated wafers (Gliadel®) result in improved survival without an increased incidence of adverse events over placebo wafers when used for primary disease therapy. There is no evidence of benefit for any other outcome measures. In recurrent disease Gliadel® does not appear to confer any additional benefit.

The Schwann cells are the myelinating glia of the peripheral nervous system that originated during development from the highly motile neural crest. However, we do not know what the guidance signals for the Schwann cell precursors are. Therefore, we set to test some of the known neurotrophins that are expressed early in developing embryos and have been shown to be critical for the survival and patterning of developing glia and neurons. The goal of this study was to determine more specifically if GDNF, NRG1 and NGF are chemoattractants and/or chemokinetic molecules for a Schwann cell precursor line, the Spl201. We performed live chemoattraction assays, with imaging and also presented these molecules as part of their growing substrate. Our results show for the first time that GDNF and NRG1 are potent chemoattractive and chemokinetic molecules for these cells while NGF is a chemokinetic molecule stimulating their motility.

Aim: This study aimed to identify actual and potential peristomal skin problems in relation to the use of different types of stoma appliances and accessories. It also compared ostomists' perceptions of their peristomal skin condition with those of stoma care nurse specialists., Background: Maintaining skin integrity is a basic skill that ensures good stoma management. It is widely accepted that from time to time a patient with a stoma will seek clinical advice about a peristomal skin problem. Little is known about how often patients present with these problems, the clinical course of peristomal skin problems, and how patients manage them., Method: A multi-centred descriptive study was conducted among 80 ostomists. Fieldwork took place over 13 months. The sample was drawn from a UK home care delivery database. Using structured questionnaires, ostomists were interviewed by a stoma care nurse specialist. A digital photograph was taken of their peristomal skin and their answers compared with nurse assessment using the Stoma Care Ostomy Research index scoring system., Findings: Of the interviewees 32% had healthy peristomal skin both via questionnaire and at observation. At observation, 68% were observed to have peristomal skin problems, of whom 44% had irritated skin, 12% had ulcerated skin, 9% had an apparent allergy and 3% had macerated/eroded skin. In addition, 21% had an ill-fitting appliance at observation. Half (50%) were observed to have a parastomal hernia, although only 24% reported having one. These findings demonstrate significant differences between the perception of skin problems among ostomists and actual skin problems observed by stoma care nurse specialists., Conclusions: Peristomal skin problems are common among ostomists. The difference between ostomists' and nurses' perceptions of peristomal skin condition led to the identification of educational needs for the new ostomist. Education and regular follow-up by the stoma care nurse specialist is imperative.

Autoantibodies to islet antigen 2 (IA-2A) are important markers for predicting diabetes in children and young adults. Harmonization of IA-2A assay measurement is essential if results from different laboratories are to be compared. We investigated whether sodium azide, a bacteriostatic agent added to some assays, could affect IA-2A binding and thereby contribute to differences in IA-2A measurement between laboratories. Addition of 0.1% azide to assay buffer was found to reduce median IA-2A binding of 18 selected sera from IA-2A positive patients with type 1 diabetes and their relatives by 41% (range, 78 to -33%, p<0.001). The effect on binding was epitope specific; median IA-2A binding by 14 sera with antibodies to the protein tyrosine phosphatase region of IA-2 was reduced by 48% (range, 11 to 78%, p<0.001), while binding by 4 sera with antibodies specific to only the juxtamembrane region of IA-2 showed no change (median increase 16% (range 6 to 33%, p=0.125). When the Tween-20 concentration was reduced from 1% to 0.15% the median reduction in IA-2A binding with azide by the 18 sera was only 10% (range, -12 to 41%, p<0.001). Tween-20 also exerted an independent effect, since median IA-2A binding increased by 23% (range 3% to 86%, p<0.001) when Tween-20 concentration was reduced from 1% to 0.15% in the absence of azide. We conclude that common assay reagents such as azide and Tween-20 can strongly influence IA-2A binding in an epitope-related manner, and their use may explain some of the differences between laboratories in IA-2A measurement.

Background: High grade glioma (HGG) is an aggressive form of brain tumour the treatment of which usually entails biopsy or resection where possible followed by radiotherapy. Temozolomide is a novel oral chemotherapeutic drug that penetrates into the brain and has a low incidence of adverse effects., Objectives: To assess whether temozolomide holds any advantage over conventional therapy for HGG in either primary or recurrent disease settings., Search Strategy: The following databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2007. Medline, EMBASE, Science Citation Index, Physician Data Query and the Meta-Register of Controlled Trials. Reference lists of identified studies were searched. The Journal of Neuro-Oncology was hand searched from 1999 to 2007 including conference abstracts. Neuro-oncologists were contacted regarding ongoing and unpublished trials., Selection Criteria: Randomised controlled trials (RCTs). Interventions included the use of temozolomide during primary therapy or for recurrent disease. Patients included those of all ages with a proven pathological diagnosis of HGG., Data Collection and Analysis: Quality assessment and data extraction were undertaken by two review authors. Outcome measures included survival, time to progression, quality of life (QOL) and adverse events., Main Results: In primary disease two RCTs were identified, enrolling a total of 703 patients, that investigated concomitant and adjuvant temozolomide in Glioblastoma Multiforme (GBM). Temozolomide increased survival (hazard ratio (HR) 0.84, confidence interval (CI) 0.50 to 0.68, p < 0.001) and an increase in time to progression (HR 0.52 CI 0.42 to 0.64 p < 0.0001). This was without having a statistically significant negative effect on QOL and with a low incidence of early adverse events. Grade 3/4 haematological toxicity was found in 5 to14%. The long term effects of temozolomide are still to be assessed. In recurrent GBM a single trial enrolling 225 patients in total found that temozolomide did not increase overall survival but it did increase time to progression (HR 0.68 CI 0.51 to 0.90 p0.008). Severe adverse events were low in this setting., Authors' Conclusions: Temozolomide is an effective therapy in GBM for prolonging survival and delaying progression as part of primary therapy without impacting on QoL and with a low incidence of early adverse events. The frequency and severity of late adverse events is unknown. In recurrent GBM it improves time to progression but not overall survival. These findings are from three good quality but non-blinded RCTs of over 900 patients in total.

Background: Standard treatment for high grade glioma (HGG) usually entails biopsy or surgical resection where possible followed by radiotherapy. Systemic chemotherapy is usually only given in selected cases and its use is often limited by side effects. Implanting wafers impregnated with chemotherapy agents into the resection cavity represents a novel means of delivering drugs to the central nervous system (CNS) with fewer side effects. It is not clear how effective this modality is or whether it should be recommended as part of standard care for HGG., Objectives: To assess whether chemotherapeutic wafers have any advantage over conventional therapy for HGG., Search Strategy: The following databases were searched: The Cochrane Central Register of Controlled Trials (CENTRAL), Issue 2, 2007, MEDLINE, EMBASE, SCIENCE CITATION INDEX, Physician Data Query and the meta-Register of Controlled Trials. Reference lists of all identified studies were searched. The Journal of Neuro-Oncology was hand searched from 1999 to 2007, including all conference abstracts. Neuro-oncologists were contacted regarding ongoing and unpublished trials., Selection Criteria: Patients included those of all ages with a presumed diagnosis of malignant glioma from clinical examination and radiology. Interventions included insertion of chemotherapeutic wafers to the resection cavity at either primary surgery or for recurrent disease. Included studies had to be randomised controlled trials (RCTs)., Data Collection and Analysis: Quality assessment and data extraction were undertaken by two review authors. Outcome measures included survival, time to progression, quality of life (QOL) and adverse events., Main Results: In primary disease two RCTs assessing the effect of carmustine impregnated wafers (Gliadel(R)) and enrolling a total of 272 participants were identified. Survival was increased (hazard ratio (HR) 0.65 confidence interval (CI) 0.48 to 0.86 p = 0.003). In recurrent disease a single RCT was included assessing the effect of Gliadel(R) and enrolling 222 participants. It did not demonstrate a significant survival increase (HR 0.83 CI 0.62 to 1.10 p = 0.2). There was no suitable data for time to progression or QOL. Adverse events were not more common in either arm, and were presented in a descriptive fashion., Authors' Conclusions: Gliadel(R) results in a prolongation of survival without an increased incidence of adverse events when used as primary therapy. There is no evidence of enhanced progression free survival (PFS) or QOL. In recurrent disease, Gliadel(R) does not appear to confer any added benefit. These findings are based on the results of three RCTs with approximately 500 patients in total.

Background: High-grade gliomas are aggressive brain tumours that are extremely challenging to treat effectively. The intracranial implantation of carmustine wafers (BCNU-W), which delivers chemotherapy directly to the affected area, may prolong survival in this population. However, no attention has yet been paid to the economic implications of BCNU-W in this setting., Objective: To investigate the cost effectiveness of BCNU-W as an adjunct to surgery followed by radiotherapy, compared with surgery plus radiotherapy alone. Newly diagnosed, operable grade III and IV gliomas in a population with a mean age of 55 years were considered., Methods: A Markov cost-utility model was developed in Microsoft Excel, adopting a UK NHS perspective. Transition probabilities and cost data (year 2004 values) were obtained from published literature or expert opinion. The model incorporated utility values, obtained from members of the public, reflecting the quality of life associated with high-grade glioma. The effects of uncertainty were explored through extensive one-way and probabilistic sensitivity analysis., Results: Surgery with the implantation of BCNU-W followed by radiotherapy costs pound sterling 54 500 per additional QALY gained when compared with surgery plus radiotherapy alone. Probabilistic sensitivity analysis shows a <10% probability that BCNU-W would be considered cost effective at a willingness-to-pay threshold of pound sterling 30 000 per QALY. Although model outputs were sensitive to alterations in several key parameters, the incremental cost effectiveness of the intervention remained above pound sterling 30 000 per QALY in all analyses., Conclusion: Compared with usual care for the treatment of newly diagnosed high-grade gliomas, BCNU-W is unlikely to be considered a cost-effective use of healthcare resources when judged by the standards commonly adopted in England and Wales. However, the dreadful prognosis of the condition and the paucity of alternative therapies are additional issues that healthcare commissioners may choose to take into account when considering an adoption decision.

Objective: To assess the short term health effects of improving housing., Design: Randomised to waiting list., Setting: 119 council owned houses in south Devon, UK., Participants: About 480 residents of these houses., Intervention: Upgrading houses (including central heating, ventilation, rewiring, insulation, and re-roofing) in two phases a year apart., Main Outcome Measures: All residents completed an annual health questionnaire: SF36 and GHQ12 (adults). Residents reporting respiratory illness or arthritis were interviewed using condition-specific questionnaires, the former also completing peak flow and symptom diaries (children) or spirometry (adults). Data on health service use and time lost from school were collected., Results: Interventions improved energy efficiency. For those living in intervention houses, non-asthma-related chest problems (Mann-Whitney test, p = 0.005) and the combined asthma symptom score for adults (Mann-Whitney test, z = 2.7, p = 0.007) diminished significantly compared with control houses. No difference between intervention and control houses was seen for SF36 or GHQ12., Conclusions: Rigorous study designs for the evaluation of complex public health and community based interventions are possible. Quantitatively measured health benefits are small, but as health benefits were measured over a short time scale, there may have been insufficient time for measurable improvements in general and disease-specific health to become apparent.

Concentrations of serum testosterone, cortisol, thyroxine (free and total T4), triiodothyronine (free and total T3) and thyroid stimulating hormone (TSH) were measured to assess adrenal and thyroid function as they relate to testicular activity and musth in captive elephants. Blood samples were collected approximately weekly from Asian (n=8) and African (n=12) bulls at seven facilities for periods of 4 months to 9.5 years. Age ranges at study onset were 8-50 years for Asian and 10-21 years for African elephants. Based on keeper logs, seven Asian and three African bulls exhibited behavioral and/or physical (temporal gland secretion, TGS, or urine dribbling, UD) signs of musth, which lasted 2.8+/-2.5 months in duration. Serum testosterone was elevated during musth, with concentrations often exceeding 100 ng/ml. Patterns of testosterone secretion and musth varied among bulls with no evidence of seasonality (P>0.05). Only three bulls at one facility exhibited classic, well-defined yearly musth cycles. Others exhibited more irregular cycles, with musth symptoms often occurring more than once a year. A number of bulls (1 Asian, 9 African) had consistently low testosterone (<10 ng/ml) and never exhibited significant TGS or UD. At facilities with multiple bulls (n=3), testosterone concentrations were highest in the oldest, most dominant male. There were positive correlations between testosterone and cortisol for six of seven Asian and all three African males that exhibited musth (range, r=0.23-0.52; P<0.05), but no significant correlations for bulls that did not (P>0.05). For the three bulls that exhibited yearly musth cycles, TSH was positively correlated (range, r=0.22-0.28; P<0.05) and thyroid hormones (T3, T4) were negatively correlated (range, r=-0.25 to -0.47; P<0.05) to testosterone secretion. In the remaining bulls, there were no clear relationships between thyroid activity and musth status. Overall mean testosterone and cortisol concentrations increased with age for all bulls combined, whereas thyroid activity declined. In summary, a number of bulls did not exhibit musth despite being of adequate physical maturity. Cortisol and testosterone were correlated in most bulls exhibiting musth, indicating a possible role for the adrenal gland in modulating or facilitating downstream responses. Data were generally inconclusive as to a role for thyroid hormones in male reproduction, but the finding of discrete patterns in bulls showing clear testosterone cycles suggests they may facilitate expression or control of musth in some individuals.

Colobomata represent visually impairing ocular closure defects that are associated with a diverse range of developmental anomalies. Characterization of a chromosome 8q21.2-q22.1 segmental deletion in a patient with chorioretinal coloboma revealed elements of nonallelic homologous recombination and nonhomologous end joining. This genomic architecture extends the range of chromosomal rearrangements associated with human disease and indicates that a broader spectrum of human chromosomal rearrangements may use coupled homologous and nonhomologous mechanisms. We also demonstrate that the segmental deletion encompasses GDF6, encoding a member of the bone-morphogenetic protein family, and that inhibition of gdf6a in a model organism accurately recapitulates the proband's phenotype. The spectrum of disorders generated by morpholino inhibition and the more severe defects (microphthalmia and anophthalmia) observed at higher doses illustrate the key role of GDF6 in ocular development. These results underscore the value of integrated clinical and molecular investigation of patients with chromosomal anomalies.

A three-year study (1999-2001) was initiated in the UK to assess the effect of improving housing conditions in 3-4 bedroom, single-family unit, social rented sector houses on the health of the occupants. The houses were randomised into two groups. Phase I houses received extensive upgrading including wet central heating, on demand ventilation, double-glazed doors, cavity wall and roof/loft insulation. An identical intervention for Phase II houses was delayed for one year. As part of this randomised waiting list study, discrete measurements were made of indoor environmental variables in each house, to assess the short-term effects of improving housing conditions on the indoor environment. Variables representative of indoor environmental conditions were measured in the living room, bedroom and outdoors in each of the three years of the study. In 2000, there was a significant difference between the changes from 1999 to 2000 between Phase I (upgraded) and II (not then upgraded) houses for bedroom temperatures (p=0.002). Changes in wall surface dampness and wall dampness in Phase I houses were also significantly different to the change in Phase II houses in 2000 (p=0.001), but by 2001 the Phase I houses had reverted to the same dampness levels they had before upgrading. The housing upgrades increased bedroom temperatures in all houses. Other indoor environmental variables were not affected.

Purpose: Chemoprevention may significantly impact the natural history of prostate cancer. The most potent intraprostatic androgen, dihydrotestosterone, has a significant role in the pathophysiology of prostate cancer. It represents a biologically plausible target for chemoprevention through the inhibition of 5alpha-reductase isoenzymes., Materials and Methods: The Reduction by Dutasteride of Prostate Cancer Events clinical trial is an international, multicenter, double-blind, placebo controlled chemoprevention study designed to determine if dutasteride 0.5 mg daily decreases the risk of biopsy detectable prostate cancer. A total of 8,000 men will be randomized to receive dutasteride or placebo for 4 years. Eligible men must be 50 to 75 years old, have a serum prostate specific antigen of 2.5 to 10 ng/ml (ages 50 to 60 years) or 3.0 to 10 ng/ml (older than 60 years). Men must have a negative 6 to 12 core biopsy within 6 months prior to enrollment. Repeat biopsies will be taken at 2 and 4 years. The rates of prostate cancer for each treatment group will be compared. Genetic and protein biomarkers of prostate cancer, and the effect of dutasteride on benign prostatic hyperplasia and prostatitis symptomatology and histopathology will also be assessed., Results: Results remain to be determined., Conclusions: The study will examine the effects of the dual 5alpha-reductase inhibitor dutasteride on the natural history of prostate cancer in men at increased risk for this malignancy. It affords a unique opportunity to examine biomarkers and genetic linkage for prostate cancer, and assess a range of prostate health outcome measures.

Objectives: To examine the rate of prostate cancer detection in three large randomized placebo-controlled benign prostatic hyperplasia trials of dutasteride. Dutasteride, which lowers serum dihydrotestosterone more than 93% by inhibiting type 1 and type 2 5-alpha-reductase, is effective in the treatment of benign prostatic hyperplasia. However, its effect on the development of prostate cancer is unknown., Methods: A total of 4325 men with benign prostatic hyperplasia but without a history, or evidence, of prostate cancer, and a serum prostate-specific antigen level of 1.5 to 10 ng/mL, were randomized to 0.5 mg/day dutasteride or placebo for 24 months. The prostate cancer detection rates for subjects were determined by non-protocol-mandated biopsies, either during the double-blind phase of the study or during the first 3 months of the open-label extension. A follow-up questionnaire was administered to a subset of consenting subjects to ascertain the number, outcomes, and reasons for the prostate biopsies., Results: The cumulative incidence of prostate cancer as an adverse event was significantly lower in the dutasteride versus placebo group at 24 months (1.1% versus 1.9%, P = 0.025) and 27 months (1.2% versus 2.5%, P = 0.002). There were no differences in the diagnosis rates of prostate cancer during the first 15 months, after which time the detection rate of prostate cancer increased in the placebo group and remained low in the dutasteride group., Conclusions: Prostate cancer detection was significantly lower in subjects randomized to dutasteride compared with the placebo group. These results have prompted the initiation of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, which was designed and powered to test the hypothesis that treatment with dutasteride decreases the incidence and progression of prostate cancer.

Tumour necrosis factor alpha (TNFalpha) has been identified in the pathogenesis of synovitis and joint destruction in rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Therefore selected targeting of pathogenic elements of disease is possible (Chu et al., 1991). TNFalpha is a pro-inflammatory cytokine (mediator) and the over-expression of mediators is considered to be responsible for the damage to articular cartilage in bones. Elevated levels of TNFalpha, correlating with disease activity, have been measured in the serum and synovial fluid of patients with rheumatic diseases and are therefore an ideal target for therapy (Mangge et al., 1995; Cope et al., 1992). The National Institute for Clinical Excellence (NICE) approved the use of two therapies; entanercept (Enbrel) and infliximab (Remicade) for use in patients with active RA in 2002 (NICE, 2002). Other biologic treatments including adalimumab (D2E7) and anakinra (Kineret) will also be available for use in the future. This paper explores the development of a service to provide these therapies to patients.

Background: A randomized study of the effect on people's health of improving their housing is underway in Torbay. The link between poor health, particularly respiratory health, and poor housing conditions has been recognized for a long time, but there have been few intervention studies to demonstrate that improving housing can improve health. In 1994, South and West Devon Health Authority set up a community development project in a deprived area of Torbay, in response to the concerns of local primary health-care workers. A community development worker helped local residents survey their homes for dampness and record their respiratory symptoms. The survey reported high levels of condensation/dampness and respiratory illness and the Council agreed to direct the majority of their housing improvement funds to the estate over the next 3 years. The Health Authority, University of Plymouth and Torbay Council were successful in obtaining funding to evaluate the housing improvements from the NHS R & D programme., Participants and Methods: Of 119 houses eligible for the study, 50 were chosen at random and improved in the first year. The rest were improved the following year. Questionnaires screening for health problems were sent to all 580 residents and baseline surveys of the indoor environment were also carried out. More detailed health surveys were completed by community nurses visiting residents in their homes. All adults were asked to complete SF-36 and GHQ 12 questionnaires, as well as disease-specific questionnaires if appropriate., Progress: All houses in the study have now been improved, including insulation, double-glazing, re-roofing, heating, ventilation and electrical rewiring. Follow-up surveys are underway.

Purpose: Eniluracil (776C85), a potent inactivator of dihydropyrimidine dehydrogenase, allows fluorouracil (5-FU) to be administered orally on a schedule that simulates continuous-infusion 5-FU. The primary objective of this study was to estimate the objective tumor response rate of orally administered eniluracil and 5-FU in the treatment of anthracycline- and taxane-resistant advanced breast cancer., Patients and Methods: Patients with anthracycline- and taxane-resistant advanced breast cancer were enrolled onto this open-label, phase II, multicenter study. Patients received orally administered 5-FU 1.0 mg/m(2) with eniluracil given in a 10:1 ratio (eniluracil:5-FU) twice daily for the first 28 days of each 35-day cycle., Results: Eighty-four patients were enrolled. Eight partial responses were observed in 84 patients (10%; 95% confidence interval [CI], 4.2% to 17.9%), and 20 patients (24%) had stable disease. The median duration of partial response was 20.1 weeks (95% CI, 12 to 26.7 weeks). The median duration of progression-free survival and overall survival for all patients was 9.9 weeks and 40.4 weeks, respectively. Most adverse events were grade 1 or 2 in intensity. Diarrhea, nausea, malaise/fatigue, vomiting, and mucositis were the most common treatment-related nonhematologic adverse events. The most frequently occurring grade 3 or 4 treatment-related adverse events were malaise/fatigue and diarrhea, occurring in 17% and 7% of patients, respectively. The incidence of grade 3 or 4 hematologic toxicity was low. Grade 3 or 4 hyperbilirubinemia occurred in 17% of patients., Conclusion: Eniluracil-5-FU has modest antitumor activity and an acceptable safety profile in anthracycline- and taxane-resistant breast cancer. Treatment was convenient, and patient compliance was high.

Sixty-four dogs with histories and clinical signs consistent with cervical intervertebral disk disease were presented for evaluation. Survey spinal radiographs were obtained, followed by myelography. In 61% of the survey radiographs, evaluators identified sites of disk extrusion or protrusion based on radiographic findings. Of those radiographs where a site was identified, ability to accurately identify the correct site of disk extrusion ranged from 53% to 67%, with an average of 58%. Therefore, the overall accuracy rate for correct identification of the site(s) of disk extrusion for all survey radiographs was 35%. Twelve cases had more than one site of disk extrusion or protrusion evident myelographically. In cases where multiple sites of extrusion were confirmed myelographically, the ability to localize at least one of the sites on the corresponding survey radiographs ranged from 63% to 80%, with an average of 70%. The major site of disk extrusion or protrusion was incorrectly identified in 16% to 31% of the survey radiographs, with an average of 26%. The use of survey radiographs alone is an inaccurate means for localization of cervical intervertebral disk extrusion or protrusion.

A year-long assessment of cross-border air pollution was conducted in the eastmost section of the US-Mexico border region, known as the Lower Rio Grande Valley, in South Texas. Measurements were conducted on the US side and included fine particle mass (PM2.5) and elemental composition, volatile organic compounds (VOCs) and meteorology. Wind sector analyses of chemical tracers and diagnostic ratios, in addition to principal component analysis (PCA), were initially applied to assess cross-border and overall air shed influences. Linear-angular correlation statistics [Biometrika, 63, (1976), 403-405] and nonparametric multiple comparisons between wind sectors were computed with the particle element data using principal component scores from PCA to determine the direction of source classes. Findings suggest crustal particles and salts carried or stirred by sea breeze winds from a southerly and southeasterly direction from the Gulf of Mexico heavily influenced the elemental composition of the particulate samples. Pair-wise comparisons of wind directions for the principal component scores suggest possible oil combustion influences from utilities or boilers coming from the south and possible coal combustion influences from the north and northwest. The techniques discussed can provide a methodology to assess future ambient levels and cross-border influences in the Valley as conditions change.

Three dogs with recurrent paraphimosis were surgically treated by creation of a phallopexy between the dorsal surface of the penis and the corresponding surface of the prepuce. Follow-up evaluation was performed 4 to 31 months postoperatively. Treatment was successful in each case, and no dog had any adverse sequelae.

In keeping with our transdisciplinary orientation, in this article we try to do several things at once. We address research on preventing mental illness and its relation to existing conceptions of public health, a topic to which insufficient attention has been paid in the era of the biological brain, while using this case study to illustrate the limits of conventional approaches in bioethics. After identifying the crucial need for methodological self-consciousness in prevention research and policy, we explore the implications as they relate to (i) the values embedded in the choice of research designs and strategies, and (ii) contrasting intellectual starting points regarding the biological plausibility of preventing mental illness. We then draw attention to the need for more thoughtful analysis of the appropriate role and limits of economics in making choices about prevention of mental illness.

The objective of this study was to evaluate the use of NHS money to improve health by improving housing conditions. A pilot study assessing health outcomes before and after improving housing conditions was conducted, studying 72 children with previously diagnosed asthma living in 59 damp houses in Cornwall. The intervention was the installation of central heating. This improved the energy efficiency of the housing. The children's health was a symptom-based outcome measure for asthma and time lost from school. Improvements comprised installation of gas central heating in 28/59 (47%) houses, electric storage heaters in 22/59 (37%), solid fuel central heating in 7/59 (12%) and oil-fired central heating in 2/59 (4%) houses. Energy efficiency improved by a mean of 2.1 on the National Home Energy Rating scale (95% CI 1.68-2.47, P<0.001) in the 37/59 (62%) houses for which two readings were available. Initially, 69/72 (92%) children's bedrooms were unheated and 44/72 (61%) were damp; following improvements, the proportions were 10/72 (14%) and 15/72 (21%) respectively. All respiratory symptoms were significantly reduced after intervention; the greatest reduction was seen in nocturnal cough from a median score of 3 (most nights) to 1 (on one or several nights) (P<0.001) in the previous month. School-age children lost significantly less time from school for asthma in the previous 3 months (9.3 days per 100 school days before intervention and 2.1 days afterwards, P<0.01) but not for other reasons (1.4 days per 100 school days before and 3.2 after, P>0.05). In conclusion, this study provides the first evaluation of health outcomes following housing improvements. Lack of a comparison group means that effects of age, season and biased reporting cannot be eliminated. More work is needed to substantiate these results.

The Fragile X syndrome is a common form of X-linked mental retardation, affecting approximately 1 in 4,000 males. Since the discovery of the FMR1 gene responsible for the syndrome, molecular, rather than cytogenetic, diagnosis of Fragile X syndrome has become the gold standard. Numerous molecular diagnostic centers worldwide use PCR and Southern blotting to characterize the size of the CGG repeats within the gene, expansion of which has been shown to be associated with the vast majority of cases of Fragile X syndrome. Instability of this repeat through successive generations has been demonstrated in many patients and has been associated with numerous factors, including repeat length and molecular structure of the repeat. Nine males with normal-size alleles that exhibit repeat length instability by the presence of a second normal length distinct band by repeated PCR analysis from peripheral lymphocytes are reported. Many hypotheses addressing the reason for this apparent instability were tested without elucidating the underlying molecular causes, including cytogenetic analysis, sequence analysis of the repeat locus, and analysis of flanking dinucleotide repeat loci. All patients exhibited a normal complement of sex chromosomes by cytogenetic and molecular analysis. These results from the widely used PCR analysis illustrate an interesting molecular phenomenon and raise many questions relating to the factors and mechanisms involved in trinucleotide instability as well as having implications for the diagnostic testing of the Fragile X syndrome.