bluuebunny/crossref_metadata_2025 huggingface dataset:
Hormesis, ethics, and public policy: an overview
Authors: Elliott KC
Published: November 2008

This article synthesizes the major points made in the preceding essays on the topic of “Hormesis and Ethics.” The questions and concerns raised in these essays are organized into three general categories: (1) scientific issues, (2) practical concerns, and (3) “explicitly ethical” considerations. The present article concludes with several suggestions. First, researchers would do well to address scientific concerns about the generalizability of hormesis. Second, it would be helpful to gather further information about the frequency that hormetic effects are beneficial for organisms over the long term. Third, more information is needed about the toxic exposures that the public is already receiving and about the potential synergistic effects of those exposures. Fourth, further reflection is warranted about whether regulations should, on one hand, maximize the ratio of benefits to risks for the population as a whole or, on the other hand, protect individuals from health risks to which they do not consent and for which they cannot easily be compensated.
Science, hormesis and regulation
Authors: Douglas H
Published: November 2008

While hormesis is an intriguing scientific hypothesis, this paper argues that it is not yet an acceptable basis for policy-making. Two reasons are given for this assessment. First, although hormesis has suggestive explanatory power, it does not yet have the predictive successes that indicate a general reliability sufficient for policy-making. Second, the regulatory agenda for chemical exposures is usually focused, for good ethical reasons, on protecting people from involuntary and potentially harmful exposures, rather than focused on maximizing public health benefits.
Ethical principles for hormesis policies
Authors: Hansson SO
Published: November 2008

At least two major choices have to be made in the ethical analysis of hormesis policies. The first is where to put the burden of proof when it is uncertain whether a particular hormesis effect exists or not. It is argued that the burden of proof will have to fall primarily on those who claim the existence of such an effect. The second issue arises when (positive) hormesis effects of a substance are weighed against negative effects of the same substance. A decision must then be made whether negative effects affecting one person can be outweighed by positive effects on another person or only by positive effects on that person herself. It is argued that risk-weighing for hormesis effects should be individualistic. This would mean that benefits for one person do not automatically outweigh negative effects on another person.
Interface dermatitis in skin lesions of Kikuchi–Fujimoto’s disease: a histopathological marker of evolution into systemic lupus erythematosus?
Authors: Paradela S , Lorenzo J , Martínez-Gómez W , Yebra-Pimentel T , Valbuena L , Fonseca E
Published: November 2008

Kikuchi’s disease (KD) is a self-limiting histiocytic necrotizing lymphadenitis (HNL). Cutaneous manifestations are frequent and usually show histopathological findings similar to those observed in the involved lymph nodes. HNL with superposed histological features to KD has been described in patients with lupus erythematosus (LE), and a group of healthy patients previously reported as having HNL may evolve into LE after several months. Up to date, features to predict which HNL patients will have a self-limiting disease and which could develop LE have been not identified. In order to clarify the characteristics of skin lesions associated with KD, we report a case of HNL with evolution into systemic lupus erythematosus (SLE) and a review of previous reports of KD with cutaneous manifestations. A 17-year-old woman presented with a 4-month history of fever and generalised lymphadenopathy. A diagnosis of HNL was established based on a lymph node biopsy. One month later, she developed an erythematoedematous rash on her upper body, with histopathological findings of interface dermatitis. After 8 months, anti-nuclear antibodies (ANA) at titre of 1/320, anti-DNA-ds antibodies and marked decrease of complement levels were detected. During the following 2 years, she developed diagnostic criteria for SLE, with arthralgias, pleuritis, aseptic meningitis, haemolytic anaemia and lupus nephritis. To our knowledge, 27 cases of nodal and cutaneous KD have been reported, 9 of which later developed LE. In all these patients, the skin biopsy revealed interface dermatitis. Skin biopsy revealed a pattern of interface dermatitis in all reviewed KD cases, which evolved into LE. Even this histopathological finding was not previously considered significant; it might be a marker of evolution into LE.
Recurrent urinary tract infections and bladder dysfunction in systemic lupus erythematosus
Authors: Duran-Barragan S , Ruvalcaba-Naranjo H , Rodriguez-Gutierrez L , Solano-Moreno H , Hernandez-Rios G , Sanchez-Ortiz A , Ramos-Remus C
Published: November 2008

To assess bladder function in systemic lupus erythematosus (SLE) patients with recurrent urinary tract infections (UTIs). A convenience sample of consecutive patients with SLE (American College of Rheumatology criteria), with recurrent UTIs (≥3 events in the preceding 12 months), without history of central nervous system involvement, urolithiasis or preceding tuberculosis were studied. Disease activity (SLEDAI-2K), damage (SDI), lower urinary tract symptoms [Pelvic pain and Urgency/Frequency (PUF) and the Interstitial Cystitis Symptom and Problem Index (ICSPI) scales] and Autonomic Symptom Profile (ASP) were assessed. All patients underwent urological examination and urodynamic assessment with cystometry, uroflow, micturition and urethral pressure profile. Ten patients (nine women) were included. The majority of the patients reported urinary symptoms: urgency ( n = 8), frequency ( n = 8), nocturia ( n = 9) and pain ( n = 10). The patients had a mean (SD) ICSPI score of 18.4 (9.8), PUF score of 17.4 (5.3) and ASP weighted score of 31.7 (16.1). Abnormal urodynamics findings were identified in seven of the 10 patients, including small bladder capacity (two patients), reduced bladder sensation (four patients), subnormal urinary flow rate (one patient) and a significant amount of residual urine (two patients). The urodynamics findings suggest that bladder dysfunction could be one of the mechanisms involved on the occurrence of recurrent UTIs in patients with SLE. These findings have potential implications for the proper assessment and management of SLE patients with recurrent UTIs. Further studies are needed to corroborate our results.
The altered expression of inflammation-related molecules and secretion of IL-6 and IL-8 by HUVEC from newborns with maternal inactive systemic lupus erythematosus is modified by estrogens
Authors: Rodriguez E , Guevara J , Paez A , Zapata E , Collados MT , Fortoul TI , Lopez-Marure R , Masso F , Montaño LF
Published: November 2008

Systemic lupus erythematosus (SLE) predominantly affects women, especially those in reproductive age. Genetic contributions to disease susceptibility as well as immune dysregulation, particularly persistent inflammatory responses, are considered essential features. Our aim was to determine whether human umbilical vein endothelial cells (HUVEC) isolated from healthy newborns to women with inactive SLE show inflammation-related abnormalities that might lead to an early development of SLE in the offsprings. HUVEC isolated from six women with inactive SLE were stimulated with 2.5 ng/mL of TNF-α and/or physiological and pharmacological doses of 17-β estradiol (E2). Then the expression of VCAM-1, ICAM-1, E-selectin, toll-like receptor-9 (TLR-9), heat shock protein 70 (HSP70) and HSP90 were measured. The concentrations of IL-6, IL-8, and IL-10 were also determined in maternal serum and in TNF-α stimulated and non-stimulated HUVEC culture supernatant. HUVEC from children with no family history of autoimmune disease served as controls. Our results showed that in HUVEC from SLE+ mothers, a constitutively low expression of adhesion molecules was enhanced by TNF-α treatment. The E2 (1 ng/mL) increased the expression of adhesion molecules but had no effect upon TNF-α-treated cells. IL-6 was constitutively higher in SLE+ HUVEC, whereas IL-8 was lower; E2 treatment diminished the latter. The E2 had no effect upon IL-6 and IL-8 secretions in TNF-α-treated cells. SLE+ HUVEC showed a disordered cytoskeleton and overexpressed HSP70, HSP90, and TLR-9. Our results indicate that endothelial cells of newborns to SLE+ mothers are in a proinflammatory condition which can be upregulated by estrogens.
High dose cyclophosphamide performs better than monthly dose cyclophosphamide in quality of life measures
Authors: Dussán KB , Magder L , Brodsky RA , Jones RJ , Petri M
Published: November 2008

In spite of current therapies, the overall health status of patients with SLE is poor. High-dose cyclophosphamide (50 mg/kg for 4 days) with or without stem-cell rescue has been introduced as a new therapy for severe SLE, including renal and central nervous system (CNS)-SLE. Long-term durable responses have been found to be 40%. A randomised clinical trial was completed comparing high-dose cyclophosphamide with monthly intravenous cyclophosphamide (750 mg/m squared bovine serum albumin) in patients with SLE who need cyclophosphamide for the first time. The primary outcome of the trial was complete clinical response. In this report, we compare the treatment groups with respect to quality of life. The patients in this study had a mean age of 35.3 ± 10.1 years, were of Caucasian (35%), African-American (51%), Hispanic (8%) and Asian (6%) people, and 88% were women. The organ leading to treatment was renal lupus in 29%, CNS-lupus in 45% and other organs in 26%. Quality of life was measured at each visit using the Medical Outcome Study Short-Form 36 (SF-36). At 6 months, the patients in the high-dose cyclophosphamide trial arm had significantly greater improvement than patients in the monthly intravenous cyclophosphamide arm ( P = 0.026; P = 0.0082, respectively) in the categories of general health and social functioning. At 18 months, the improvement in the role-physical score was significantly greater in the high-dose cyclophosphamide trial arm than in the monthly-dose cyclophosphamide arm ( P = 0.025). At the end of the two and a half-year study, there were no significant differences between the groups with respect to changes in SF-36. By pooling the groups, at 30 months, there was a statistically significant ( P < 0.05) improvement over baseline in 6 of the 8 SF-36 domains. This study shows earlier improvement in SF-36 measures at 6 months in the high-dose cyclophosphamide group but equal improvement in both arms at two and one and a half years. Eventual improvements in quality-of-life with both cyclophosphamide regimens are clinically meaningful to both patients and treating physicians.
Risk and predictors of work disability in Chinese patients with systemic lupus erythematosus
Authors: Mok CC , Cheung MY , Ho LY , Yu KL , To CH
Published: November 2008

The aim of this study is to determine the risk and predictive factors for work disability in patients with SLE. A cross-sectional questionnaire study was performed to evaluate the employment status of a sample of consecutive Chinese patients with SLE. Demographic, socioeconomic data (age, gender, marital status, years of education and household income), employment status, self-reported fatigue score and disease characteristics (SLE duration, organ damage and disease activity) were collected. Work disability was defined by the failure to work due to SLE. The cumulative incidence of work disability since the time of SLE diagnosis was studied by a Kaplan Meier’s plot, and factors predictive of work disability were studied by Cox regression. A total of 147 patients with SLE were studied (mean age = 39.4 ± 11.3 years; 95% women). Among 105 patients who were working at the time of SLE diagnosis, 39 (37%) lost their ability to work as a result of SLE after a mean disease duration of 10.0 ± 6.1 years. Twenty-two (56%) patients lost their work ability within 2 years of diagnosis of SLE. The self-reported reasons for job loss were musculoskeletal pain (87%), skin disease (26%), renal problem (21%), fatigue (85%), memory deterioration (51%), anxiety or depressive symptoms (74%), too frequent sick leave (10%) and long-term hospitalisation (10%). The cumulative risk of work disability was 36% at 5 years after SLE diagnosis. In a Cox regression model, age (HR = 1.06 [1.02–1.11] per year; P = 0.008), self-reported fatigue score (HR = 1.06 [1.01–1.10] per point; P = 0.01) and mean disease activity score in the preceding two years (HR = 1.20 [1.02–1.42] per point; P = 0.03) were independently associated with working disability. In all, 37% of this group of patients with SLE lost their work ability after having the disease for 10 years. More than 50% of these patients developed work disability within the first 2 years of SLE diagnosis. Older age, fatigue and more active disease were independent predictors of work disability.
Peripheral B cell abnormalities and disease activity in systemic lupus erythematosus
Authors: Hostmann A , Jacobi AM , Mei H , Hiepe F , Dörner T
Published: November 2008

Autoreactive B cells and plasma cells appear to be of central importance in the pathogenesis of systemic lupus erythematosus (SLE) characterized by a plethora of autoantibodies. Recent insights into abnormalities of B cell and plasma cell compartments in human SLE have identified a number of cellular disturbances within these compartments that in part correlate with the disease activity. This review discusses these findings and the potential underlying extrinsic and/or intrinsic influences apparently driving general B cell activation in this entity.
The Politics of Sport Diplomacy and Reunification in Divided Korea
Authors: Merkel Udo
Published: November 2008

This article examines the use of sport as a foreign policy and diplomatic tool on the politically divided Korean peninsula. The recent increase in sport exchanges between the Republic of Korea (ROK) in the south and the Democratic People's Republic of Korea (DPRK) in the north offer a unique opportunity to analyse the changing role and efficacy of contemporary sport diplomacy. The research investigates and critically evaluates the political agenda of these events on the divided peninsula. The theoretical framework of this study derives from the pluralist paradigm of International Relations. Therefore this article does not only deal with state initiatives and governmental policies but also with non-state and non-governmental organizations. The article focuses on sport's contribution to the improvement of inter-Korean relations and the reunification of the Korean nation, a key policy objective of both countries, in one of the very few remaining politically divided societies. Due to sport's versatile symbolic potency sport diplomacy goes far beyond the promotion of détente between the two Korean states and makes a significant contribution to the foreign policy agenda.
Athletic Career Termination Model in the Czech Republic
Authors: Kadlcik Jiri , Flemr Libor
Published: November 2008

This study was designed to explore the process of sport career termination in the Czech Republic, and was based on the theoretical-conceptual background of sport career transition models (Stambulova, 1997, 2003; Taylor and Ogilvie, 1994, 2001). Participants were six male and five female former elite athletes, averaging 14.6 years of athletic career experience. Qualitative data were collected using semi-structured interviews. Eleven general dimensions emerged from the hierarchical content analysis. Manifold reasons for sport career termination and various planning strategies to retire from sport activities were identified. Several factors contributing to the positive adaptation to athletic retirement as well as factors constraining the transitional process are described. Significant others and coping strategies played important roles during the transition process. Athletes experienced significant changes in their lives after retirement in social, psychosocial, health and economic spheres of their lives.
The Use of Anabolic Steroids and Other Prohibited Substances By Gym Enthusiasts in Cyprus
Authors: Kartakoullis Nicos L. , Phellas Constantinos , Pouloukas Stavros , Petrou Michael , Loizou Christina
Published: November 2008

The use of prohibited substances in sport does not solely concern athletes, but it is also quite common among other categories of the population: people who do not engage in competitive sports but use doping substances for a number of other reasons. This article is based on a survey that was administered to 532 people of both sexes, aged 14 years and above, in 22 gyms around Cyprus. The respondents engaged in one or more sports with a very small percentage (6%) participating in competitive sports. The results showed that 11.6 percent of the respondents had used or were using prohibited substances in order to improve their performance. The use of prohibited substances seemed to be higher among certain interviewees sharing common characteristics, that is, gender, age, education and socio-economic status. Doping was common among body-builders. The research also examined the reasons for the use of prohibited substances in relation to: the reasons for exercising; the nature of the sport; smoking and drinking habits; and the level of use within the wider environment.
A Reconnaissance Study of a Potential Emerging Mexican Mesothelioma Epidemic due to Fibrous Zeolite Exposure
Authors: Ilgren E.B. , Ortega Breña Mariana , Castro Larragoitia Javier , Loustaunau Navarrete Gustavo , Fuentes Breña Alvar , Krauss Edgar , Fehér Guillermina
Published: November 2008

A mesothelioma cluster has been found in a remote part of central Mexico. The region is primarily agricultural with no clear source of industrial asbestos exposure. This investigation has revealed that the mesothelioma cluster was situated on an area heavily laden with zeolites. Fibrous erionite was not found. However, the geological conditions and mineralogical characteristics of the affected area very closely resemble those parts of Turkey where mesotheliomas are epidemic and those parts of the western United States where erionite was taken for biological testing. Those biological tests abundantly confirmed the extreme carcinogenicity of erionite for mesothelioma production. This preliminary study should prompt additional investigation to confirm definitively the cause of the elevated mesothelioma risk.
Longitudinal Study of Indoor Particulate Matter and its Relationship to Outdoor Concentrations in New Delhi, India
Authors: Saksena Sumeet , Uma R.
Published: November 2008

Current models used to estimate the health effects and burden of outdoor urban air pollution assume a strong day-to-day correlation between outdoor and indoor concentration of the pollutant(s) of interest. Studies of indoor—outdoor relationships, based on a day-to-day longitudinal design, in developing countries have been rare. Our study is a comparatively long longitudinal study conducted over three and a half years. Indoor levels of Total Suspended Particulates (TSP) and Respirable Suspended Particulates (RSP), d50 = 10 μm, were measured in an office building and also just outside the building. The mean values of indoor TSP and RSP concentrations, though much higher than those observed in similar micro-environments in developed countries, were less than the outdoor concentrations but higher than the Indian ambient standards. However, while studies in developed countries (and in some developing countries) have observed strong longitudinal correlations between indoor and outdoor concentrations, the results of our study were contrary. The variation in outdoor concentration of RSP could explain only 25% of the variation in indoor concentration. Our results strongly support the belief that indoor— outdoor relationships cannot be generalized, but are strongly dependent on factors such as type of building, ventilation, climate among others.
Thermal Comfort Levels in a Room with Solar Radiation
Authors: Chan MY , Mak CW
Published: November 2008

Thermal comfort in occupied spaces is important for building occupants. The thermal sensation they experience is highly correlated to the intensity of solar radiation, orientation of windows, and surface reflectance from the walls. The objective of this study is to predict the changes in thermal comfort levels in a space due to solar radiation during summer time and at different locations inside a room. A box model was used for predicting the mean radiant temperature. The model was based on basic radiant heat transfer theories and shape factors. A measurement was carried out to validate the data derived from the model. The mean radiant temperature was then applied to the Predicted Mean Vote (PMV) and Predicted Percentage of Dissatisfaction (PPD). This study should be useful for optimizing thermal comfort, windows areas, and use of daylight.
Development of Analytical Tool for Indoor VOC Concentration Using Enthalpy Changes in New Apartments in Korea
Authors: Pang S.K. , Lee J.S. , Cho H. , Sohn J.Y. , Cho S.
Published: November 2008

This study evaluated the indoor air quality in 36 new apartment houses in six big cities in Korea from July 2005 to January 2006. Most of the indoor finishing materials in the new houses were environment-friendly and designated by the Korea Air Cleaning & Researching Association. In the new apartments, which were all built with the same finishing materials, air levels of toluene averaged 1475 μg · m-3 in summer, when there were relatively high temperatures and humidity, and averaged 2711 μg· m-3 in winter. In addition, benzene, ethylbenzene, styrene, xylene, and formaldehyde measured 9.99, 628, 232, 2392 and 951μg·m-3 in summer and 9.99, 628, 232, 2392, and 951μg·m-3 in winter, respectively. Concentrations of volatile organic compounds (VOCs) and formaldehyde were increased as indoor temperature and humidity increased. This study evaluated concentrations of VOCs compounds in a room according to season using enthalpy, which considers two indexes, temperature and humidity. Concentrations of benzene, ethylbenzene, styrene, xylene, and formaldehyde increased with increased enthalpy.
Management of the Indoor Environment: from a Component Related to an Interactive Top-down Approach
Authors: Bluyssen Philomena M.
Published: November 2008

Over the last century, management of the indoor environment was focused only on its single components (thermal comfort, noise, light, air quality) and to a lesser extent on interrelations between these components in the so-called bottom-up approach. Although standards and guidelines are met, the quality of the indoor environment, as experienced by the occupants, is not acceptable and could be unhealthy, causing health and comfort problems. Inappropriate communication between stakeholders of the indoor environment, during the life-cycle of a building, also causes problems. Internal and external drivers can influence the wishes and demands of the end-users, which consequently change over time and are now very different from 100 years ago. The indoor environments need to be able to anticipate those changes. An interactive top-down approach, next to the traditional bottom-up approach, is presented as a possible solution.
Study on the Cooling Performance and Thermal Comfort of a Thermoelectric Ceiling Cooling Panel System
Authors: Lertsatitthanakorn C. , Tipsaenprom W. , Srisuwan W. , Atthajariyakul S.
Published: November 2008

The cooling performance and thermal comfort of a thermoelectric ceiling cooling panel (TE-CCP) was investigated for this paper. The TE-CCP was composed of 36 TE modules. The cold side of the TE modules was fixed to an aluminum-ceiling panel to cool a test chamber of 4.5m3 volume, while a copper heat exchanger with circulating cooling water at the hot side of the TE modules was used for heat release. Tests were conducted using various system parameters. It was found that the cooling performance of the system depended on the electrical supply, cooling water temperature, and flow rate through the heat exchanger. Thermal acceptability assessment was performed to find out whether the resultant indoor environment met the ASHRAE Standard-55's 80% acceptability criteria. A suitable condition was measured at 1 A of current flow with a corresponding cooling capacity of 201.6 W, which gives a Coefficient of Performance of 0.82 for an average indoor temperature of 27°C and 0.8 m·s -1 indoor air velocity.
Modeling and Detection of Joint Loosening using Output-Only Broad-Band Vibration Data
Authors: Milanese A. , Marzocca P. , Nichols J.M. , Seaver M. , Trickey S.T.
Published: November 2008

Damage detection and structural health monitoring techniques based on vibration data have seen increased attention in recent years. Among the different vibration-based methods, the ones based on random vibrations are of particularly interest, especially when they do not require measurement of the input(s). In this work, several frequency and time domain signal processing techniques are explored in their respective abilities to detect damage in a bolted composite structure. First, a joint loosening model is developed and used to simulate the dynamic response to a stationary Gaussian excitation. Informed by the model, two signal processing techniques are used to assess the connection strength. The first method relies on basic statistical properties of the measured strains and their time derivatives, while the second is based on the signal power in different frequency bands. Both approaches are then used to assess progressive bolt loosening on an experimental composite-to-metal joint. All strain response data were obtained using a fiber optic strain sensing system. Results are presented in the form of Receiver Operating Characteristic (ROC) curves, showing both Type-I and Type-II errors associated with the proposed detection schemes.
Acoustic Emission Testing of Beams to Simulate SHM of Vintage Reinforced Concrete Deck Girder Highway Bridges
Authors: Lovejoy Steven C.
Published: November 2008

The practical application of Acoustic emission (AE) testing in the Structural Health Monitoring (SHM) of vintage steel reinforced concrete highway bridges has been recently investigated by the Oregon Department of Transportation (ODOT) and Oregon State University (OSU). A large number of full scale laboratory test beams designed to simulate a particular class of highway bridge structure and a particular type of structural damage were tested with AE. The results of the AE test data analyzed using the Felicity and Calm ratios are presented and related to physically observed structural damage. New thresholds on the Felicity and Calm ratios specific to this class of structure and loading are suggested (based on the test results) to be used in both the damage assessment diagrams developed in the Japanese Non-destructive Inspection Standard NDIS-2421 and implementation into a SHM program currently under development at ODOT.
Action research, practical challenges and the formation of theory
Authors: Gustavsen Bjørn
Published: November 2008

It is a common assumption that action research exists in a number of varieties. In efforts to explain these varieties, the point of departure is sometimes sought in differences in practical challenges, sometimes in differences in theoretical outlook. Taken separately, these perspectives can, however, both be too limited. Drawing upon an action research tradition that has been in existence for four decades, it will be seen that one and the same tradition has passed through a series of different ways of combining theory and practice. The prime moving force has been success and failure in meeting specific practical challenges; the role of theory has been to deepen the understanding of these challenges and indicate what courses of action are open in each specific situation.
An existential approach to engaging adult learners in the process of legitimizing and constructing meanings from their narrative knowledge
Authors: Hussein Jeylan Wolyie
Published: November 2008

The aim of this study is two-fold. One is evaluating the action research process and how the existential situations of the inquiry influence the process of intervention. The second is generating and analysing the thematic structure of the learners' reconstructions of their lived experiences. The study highlighted that through challenging, one can convince learners to legitimate their narrative knowledge through sharing their personal narratives and to understand how to reach their existential reality. It is evident from the steps that action research can help a practitioner make learners see and believe that their narrative knowledge is valuable and can serve as input for critical reflection. The other finding is that learners may not need advanced language to give expressions to their lived experience. Finally, the article concludes with the researcher's emotional dissonance regarding where an inquirer into the lived experiences of his/her research participants should stand.
The influence of obesity on pulmonary rehabilitation outcomes in patients with COPD
Authors: Ramachandran K , McCusker C , Connors M , ZuWallack R , Lahiri B
Published: November 2008

Although obesity is increasing in prevalence, relatively little attention has been given to its impact on outcomes in patients with chronic obstructive pulmonary disease (COPD) completing pulmonary rehabilitation. We conducted a retrospective chart review of 114 patients with COPD who completed outpatient pulmonary rehabilitation at our center. Body habitus categories were determined based on body mass index (BMI). Underweight patients (BMI < 21 kg/m2) were excluded from the analysis. Normal weight and overweight patients were classified as non-obese. Obese patients (BMI >30 kg/m2) were compared with non-obese patients in the following areas: forced expiratory volume in 1 s (FEV1) percent predicted, the 6-min walk distance (6MWD), health status, the number of unsupported arm lifts per minute, and functional performance. Health status was determined using the Self-Reported Chronic Respiratory Questionnaire (CRQ-SR), which has dimensions of dyspnea, fatigue, emotion, and mastery. Functional performance was determined using the Pulmonary Functional Status Scale Daily Activities subscore. Compared with non-obese patients, obese patients had a higher FEV1 percent-predicted (44 ± 15% vs 52 ± 16%; P = 0.01), yet had lower 6MWD (269 ± 11 vs 203 ± 13; P = 0.0002), lower functional status, and greater fatigue at initial evaluation. However, the two groups had similar walk-work, which adjusts for differences in weight. Despite the baseline differences, both groups improved similarly following pulmonary rehabilitation (change in 6MWD was 52 ± 7 m in the non-obese patients versus 47 ± 9 in the obese patients; P = 0.65). Our study suggests that obese COPD patients are referred to pulmonary rehabilitation at an earlier spirometric stage of their disease, but have a poorer exercise performance, a greater degree of functional impairment and greater fatigue levels. This is probably, largely because of the effect of an increased weight burden. However, obesity did not seem to adversely affect the pulmonary rehabilitation outcomes.
Obesity and respiratory diseases
Authors: Murugan AT , Sharma G
Published: November 2008

Obesity is a worldwide epidemic and is known to increase the risk of cardiovascular disease, type 2 diabetes, and certain forms of cancer. In addition, obesity is now recognized as an important risk factor in the development of several respiratory diseases. Of these respiratory diseases, it has already been well established that obesity can lead to obstructive sleep apnea (OSA) and obesity-hypoventilation syndrome (OHS). More recent data suggest that the prevalence of wheezing and bronchial hyper-responsiveness, two symptoms often associated with asthma, are increased in overweight and obese individual. Indeed, epidemiological studies have reported that obesity is a risk factor for the development of asthma. Furthermore, a number of studies indicate that obesity is also associated with a higher risk of developing deep vein thrombi, pulmonary emboli, pulmonary hypertension, and pneumonia. Finally, weight reduction has been shown to be effective in improving the symptoms and severity of several respiratory diseases, including OSA and asthma. Thus, overweight and obese patients should be encouraged to lose weight to reduce their risk of developing respiratory diseases or improve the course of pre-existing conditions.
What have we learned from prospective cohort studies of asthma in children?
Authors: Henderson AJ
Published: November 2008

Prospective cohort studies have provided a useful tool for the study of the natural history of asthma and lung function and for the development of concepts of asthma phenotypes during childhood. However, although observational epidemiology has indicated a large number of credible associations between environmental variables and asthma onset in childhood, it can be argued that it has yet to fulfill the promise of identifying modifiable, causal risk factors that are amenable to intervention for the primary or secondary prevention of disease. The development of efficient, high-throughput genotyping that can be applied to large, longitudinal cohorts with detailed data on exposures and phenotypic outcomes, opens the way for studies of genetic effects and gene–environment interactions that may come closer to identifying causal pathways between exposure and disease. Therefore, there continues to be an important role for large-scale, observational studies with careful attention to definition and evaluation of outcomes and plausible risk factors.
Benefit in phase 1 oncology trials: therapeutic misconception or reasonable treatment option?
Authors: Miller Franklin G , Joffe Steven
Published: November 2008

Novel treatments for cancer are tested initially in phase 1 trials enrolling patients with advanced disease who have exhausted standard treatment options. Although these trials are designed to evaluate safety and to define dosing for future efficacy trials, most patients volunteer with the hope of obtaining medical benefit. Do phase 1 oncology trials promote a `therapeutic misconception' among eligible patients about the personal meaning of trial participation, or do they offer them a reasonable prospect of direct medical benefit as compared with available alternatives? Recent evidence on outcomes of phase 1 oncology trials is examined systematically, with the aim of accurately assessing the prospect of direct medical benefit for participants and drawing implications for informed consent. We argue that, in view of important uncertainties, aggregate data from phase 1 trials relating to the surrogate outcomes of tumor shrinkage and stable disease do not permit any definitive estimate of a `clinical benefit rate.' Nevertheless, these trials do offer participants a prospect of direct medical benefit. As a result, accurately informed patients may reasonably decide to enroll in phase 1 oncology trials in hopes of obtaining benefit, after considering the anticipated risks and available clinical alternatives. Motivation to enroll in these studies to receive personal benefit does not, in itself, compromise informed consent.
Use of biological assignment in hematopoietic stem cell transplantation clinical trials
Authors: Logan Brent , Leifer Eric , Bredeson Chris , Horowitz Mary , Ewell Marian , Carter Shelly , Geller Nancy
Published: November 2008

Background: When comparing treatments for a specific illness, it is sometimes impractical or impossible to conduct a randomized clinical trial (RCT). Biological assignment trials are one alternative design. In hematopoietic stem cell transplantation (HCT) trials, a human leukocyte antigen (HLA)-matched sibling donor is considered optimal, but such donors are available for only 20—30% of otherwise eligible patients. Rather than randomizing only those with a matched sibling donor, in a recent multiple myeloma trial, the type of HCT each patient received was biologically based, i.e., chosen according to whether or not the patient had a matched sibling donor.

Purpose: This article describes the design and implementation of biological assignment trials as well as their advantages and disadvantages.

Methods: We focus on several aspects of such trials, including efficiency of trial duration, ethical issues, and potential sources of bias. Statistical issues are considered including sample size calculations, monitoring for biased enrollment, and adjustments for imbalances in patient characteristics. A multiple myeloma trial is used as an illustration.

Results: Although they often require a larger sample size, biological assignment trials can provide substantial efficiency in terms of study duration over randomized trials when accrual to a randomized trial would be slow. Determination of sample size requires consideration of the anticipated proportion of patients with a biologically favored (HLA-matched sibling) donor. An add-on randomization of patients without a matched sibling donor may alleviate ethical concerns about applicability of study results to all patients regardless of whether the biological assignment groups differ with respect to outcome.

Limitations: Prognostic factor imbalance and enrollment bias can occur in a biological assignment trial. Statistical adjustment for potential imbalance in prognostic factors is important, as is monitoring center accrual for enrollment bias and performing an appropriate intention-to-treat analysis.

Conclusions: A biological assignment trial can be a reasonable way to compare treatments which are biologically based, such as HLA-matched sibling transplants, when the gold-standard randomized trial design is impractical or impossible. Implementing such a trial requires careful consideration of the ethical issues and potential biases.
Optimal sample size determinations from an industry perspective based on the expected value of information
Authors: Willan Andrew R
Published: November 2008

Background Traditional sample size calculations for randomized clinical trials depend on somewhat arbitrarily chosen factors, such as type I and II errors. As an alternative, taking a societal perspective, and using the expected value of information based on Bayesian decision theory, a number of authors have recently shown how to determine the sample size that maximizes the expected net gain, i.e., the difference between the cost of the trial and the value of the information gained from the results. Other authors have proposed Bayesian methods to determine sample sizes from an industry perspective.

Purpose The purpose of this article is to propose a Bayesian approach to sample size calculations from an industry perspective that attempts to determine the sample size that maximizes expected profit.

Methods A model is proposed for expected total profit that includes consideration of per-patient profit, disease incidence, time horizon, trial duration, market share, discount rate, and the relationship between the results and the probability of regulatory approval. The expected value of information provided by trial data is related to the increase in expected profit from increasing the probability of regulatory approval. The methods are applied to an example, including an examination of robustness. The model is extended to consider market share as a function of observed treatment effect.

Results The use of methods based on the expected value of information can provide, from an industry perspective, robust sample size solutions that maximize the difference between the expected cost of the trial and the expected value of information gained from the results.

Limitations The method is only as good as the model for expected total profit. Although the model probably has all the right elements, it assumes that market share, per-patient profit, and incidence are insensitive to trial results. The method relies on the central limit theorem which assumes that the sample sizes involved ensure that the relevant test statistics are normally distributed.

Conclusions Industry officials should consider the use of expected value of information methods for determining sample sizes for proposed trials. The method also can be used to select, from a number of proposed trials, those which maximize return from a fixed research budget.
Using item banks to construct measures of patient reported outcomes in clinical trials: investigator perceptions
Authors: Flynn Kathryn E , Dombeck Carrie B , DeWitt Esi Morgan , Schulman Kevin A , Weinfurt Kevin P
Published: November 2008

Background Item response theory (IRT) promises more sensitive and efficient measurement of patient-reported outcomes (PROs) than traditional approaches; however, the selection and use of PRO measures from IRT-based item banks differ from current methods of using PRO measures.

Purpose To anticipate barriers to the adoption of IRT item banks into clinical trials. Methods We conducted semistructured telephone or in-person interviews with 42 clinical researchers who published results from clinical trials in the Journal of the American Medical Association, the New England Journal of Medicine, or other leading clinical journals from July 2005 through May 2006. Interviews included a brief tutorial on IRT item banks.

Results After the tutorial, 39 of 42 participants understood the novel products available from an IRT item bank, namely customized short forms and computerized adaptive testing. Most participants (38/42) thought that item banks could be useful in their clinical trials, but they mentioned several potential barriers to adoption, including economic and logistical constraints, concerns about whether item banks are better than current PRO measures, concerns about how to convince study personnel or statisticians to use item banks, concerns about FDA or sponsor acceptance, and the lack of availability of item banks validated in specific disease populations. Limitations Selection bias might have led to more positive responses to the concept of item banks in clinical trials.

Conclusions Clinical investigators are open to a new method of PRO measurement offered in IRT item banks, but bank developers must address investigator and stakeholder concerns before widespread adoption can be expected.
Parametric conditional frailty models for recurrent cardiovascular events in the lipid study
Authors: Jisheng Cui  , Forbes Andrew , Kirby Adrienne , Marschner Ian , Simes John , West Malcolm , Tonkin Andrew
Published: November 2008

Background Analysis of recurrent event data is frequently needed in clinical and epidemiological studies. An important issue in such analysis is how to account for the dependence of the events in an individual and any unobserved heterogeneity of the event propensity across individuals.

Methods We applied a number of conditional frailty and nonfrailty models in an analysis involving recurrent myocardial infarction events in the Long-Term Intervention with Pravastatin in Ischaemic Disease study. A multiple variable risk prediction model was developed for both males and females.

Results A Weibull model with a gamma frailty term fitted the data better than other frailty models for each gender. Among nonfrailty models the stratified survival model fitted the data best for each gender. The relative risk estimated by the elapsed time model was close to that estimated by the gap time model. We found that a cholesterol-lowering drug, pravastatin (the intervention being tested in the trial) had significant protective effect against the occurrence of myocardial infarction in men (HR = 0.71, 95% CI 0.60—0.83). However, the treatment effect was not significant in women due to smaller sample size (HR = 0.75, 95% CI 0.51—1.10). There were no significant interactions between the treatment effect and each recurrent MI event (p = 0.24 for men and p = 0.55 for women). The risk of developing an MI event for a male who had an MI event during follow-up was about 3.4 (95% CI 2.6—4.4) times the risk compared with those who did not have an MI event. The corresponding relative risk for a female was about 7.8 (95% CI 4.4—13.6).

Limitations The number of female patients was relatively small compared with their male counterparts, which may result in low statistical power to find real differences in the effect of treatment and other potential risk factors.

Conclusions The conditional frailty model suggested that after accounting for all the risk factors in the model, there was still unmeasured heterogeneity of the risk for myocardial infarction, indicating the effect of subject-specific risk factors. These risk prediction models can be used to classify cardiovascular disease patients into different risk categories and may be useful for the most effective targeting of preventive therapies for cardiovascular disease.
Adaptive designs for dose-finding in non-cancer phase II trials: influence of early unexpected outcomes
Authors: Resche-Rigon Matthieu , Zohar Sarah , Chevret Sylvie
Published: November 2008

Background In non-cancer phase II trials, dose-finding trials are usually carried out using fixed designs, in which several doses including a placebo are randomly distributed to patients. However, in certain vulnerable populations, such as neonates or infants, there is an heightened requirement for safety, precluding randomization.

Purpose To estimate the minimum effective dose of a new drug from a non-cancer phase II trial, we propose the use of adaptive designs like the Continual Reassessment Method (CRM). This approach estimates the dose closest to some target response, and has been shown to be unbiased and efficient in cancer phase I trials.

Methods Based on a motivating example, we point out the individual influence of first outliers in this setting. A weighted version of the CRM is proposed as a theoretical benchmark to control for these outliers. Using simulations, we illustrate how this approach provides further insight into the behavior of the CRM.

Results When dealing with low targets like a 10% failure rate, the CRM appears unable to rapidly overcome an early unexpected outcome. This behavior persisted despite changing the inference (Bayesian or likelihood), underlying dose—response model (though slightly improved using the power model), and the number of patients enrolled at each dose level.

Limitations The choices for initial guesses of failure rates, the vague prior for the model parameter, and the log-log shape of weights can appear somewhat arbitrary.

Conclusions In phase II dose-finding studies in which failure targets are below 20%, the CRM appears quite sensitive to first unexpected outcomes. Using a power model for dose—response improves some behavior if the trial is started at the first dose level and includes at least three to five patients at the starting dose before applying the CRM allocation rule.
Satellite cultures in Europe
Authors: Volkmer Ingrid
Published: November 2008

Satellites operate in a transnational communication sphere, independent of conceptual frames of national public territories. As satellites become major global industries and advance technologically, providing a variety of services, including broadcasting, telecommunication, internet applications, meteorological data and military intelligence, they contribute, this article suggests, to structurally multilayered forms of satellite cultures within an emerging European public sphere. The advances in the technology of satellite communication has, the article argues, created a platform for new, interesting flows of trans-European communication. The article considers the evidence for a new trans-European television sphere, while examples from the realities of European broadcast culture demonstrate the limitations of conventional terminologies of national, regional and local `broadcasting'.