bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.
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.
Classification of lymphoid neoplasms: the microscope as a tool for disease discovery
Authors: Jaffe Elaine S. , Harris Nancy Lee , Stein Harald , Isaacson Peter G. 
Published: November 2008

AbstractIn the past 50 years, we have witnessed explosive growth in the understanding of normal and neoplastic lymphoid cells. B-cell, T-cell, and natural killer (NK)–cell neoplasms in many respects recapitulate normal stages of lymphoid cell differentiation and function, so that they can be to some extent classified according to the corresponding normal stage. Likewise, the molecular mechanisms involved the pathogenesis of lymphomas and lymphoid leukemias are often based on the physiology of the lymphoid cells, capitalizing on deregulated normal physiology by harnessing the promoters of genes essential for lymphocyte function. The clinical manifestations of lymphomas likewise reflect the normal function of lymphoid cells in vivo. The multiparameter approach to classification adopted by the World Health Organization (WHO) classification has been validated in international studies as being highly reproducible, and enhancing the interpretation of clinical and translational studies. In addition, accurate and precise classification of disease entities facilitates the discovery of the molecular basis of lymphoid neoplasms in the basic science laboratory.
A qualitative assessment of stakeholder perceptions and socio-cultural influences on the acceptability of harm reduction programs in Tijuana, Mexico
Authors: Philbin Morgan M , Lozada Remedios , Zúñiga María Luisa , Mantsios Andrea , Case Patricia , Magis-Rodriguez Carlos , Latkin Carl A , Strathdee Steffanie A 
Published: November 2008

Abstract

Background
The Mexico-U.S. border region is experiencing rising rates of blood-borne infections among injection drug users (IDUs), emphasizing the need for harm reduction interventions.

Methods
We assessed the religious and cultural factors affecting the acceptability and feasibility of three harm reduction interventions – Needle exchange programs (NEPs), syringe vending machines, and safer injection facilities (SIFs) – in Tijuana, Mexico. In-depth qualitative interviews were conducted with 40 community stakeholders to explore cultural and societal-related themes.

Results
Themes that emerged included Tijuana's location as a border city, family values, and culture as a mediator of social stigma and empathy towards IDUs. Perception of low levels of both awareness and socio-cultural readiness for harm reduction interventions was noted. Religious culture emerged as a theme, highlighting the important role religious leaders play in determining community responses to harm reduction and rehabilitation strategies for IDUs. The influence of religious culture on stakeholders' opinions concerning harm reduction interventions was evidenced by discussions of family and social values, stigma, and resulting policies.

Conclusion
Religion and politics were described as both a perceived benefit and deterrent, highlighting the need to further explore the overall influences of culture on the acceptability and implementation of harm reduction programs for drug users.