bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding?
Authors: Fergusson Dean , Glass Kathleen Cranley , Hutton Brian , Shapiro Stan 
Published: June 2005

Background Aprotinin is a serine protease inhibitor used to limit perioperative bleeding and reduce the need for donated blood transfusions during cardiac surgery. Randomized controlled trials of aprotinin evaluating its effect on the outcome of perioperative transfusion have been published since 1987, and systematic reviews were conducted in 1992 and 1997. Methods A systematic search was conducted for all RCTs of aprotinin that used placebo controls or were open-label with no active control treatment. Data collected included the primary outcome, objective of each study, whether a systematic review was cited or conducted as part of the background and/or rationale for the study and the number of previously published RCTs cited. Cumulative meta-analyses were performed. Results Sixty-four randomized, controlled trials of aprotinin were found, conducted between 1987 and 2002, reporting an endpoint of perioperative transfusion. Median trial size was 64 subjects, with a range of 20 to 1784. A cumulative meta-analysis indicated that aprotinin greatly decreased the need for perioperative transfusion, stabilizing at an odds ratio of 0.25 (p, 10 2 6) by the 12th study, published in June of 1992. The upper limit of the confidence interval never exceeded 0.65 and results were similar in all subgroups. Citation of previous RCTs was extremely low, with a median of 20% of prior trials cited. Only 7 of 44 (15%) of subsequent reports referenced the largest trial (N 1/4 1784), which was 28 times larger than the median trial size. Conclusions This study demonstrates that investigators evaluating aprotinin were not adequately citing previous research, resulting in a large number of RCTs being conducted to address efficacy questions that prior trials had already definitively answered. Institutional review boards and journals could reduce the number of redundant trials by requiring investigators to conduct adequate searches for prior evidence and conducting systematic reviews.
Meta-analysis of individual patient data from randomized trials: a review of methods used in practice
Authors: Simmonds Mark C , Higginsa Julian P T , Stewartb Lesley A , Tierneyb Jayne F , Clarke Mike J , Thompson Simon G 
Published: June 2005

Background Meta-analyses based on individual patient data (IPD) are regarded as the gold standard for systematic reviews. However, the methods used for analysing and presenting results from IPD meta-analyses have received little discussion. Methods We review 44 IPD meta-analyses published during the years 1999–2001. We summarize whether they obtained all the data they sought, what types of approaches were used in the analysis, including assumptions of common or random effects, and how they examined the effects of covariates. Results Twenty-four out of 44 analyses focused on time-to-event outcomes, and most analyses (28) estimated treatment effects within each trial and then combined the results assuming a common treatment effect across trials. Three analyses failed to stratify by trial, analysing the data is if they came from a single mega-trial. Only nine analyses used random effects methods. Covariate-treatment interactions were generally investigated by subgrouping patients. Seven of the meta-analyses included data from less than 80% of the randomized patients sought, but did not address the resulting potential biases. Conclusions Although IPD meta-analyses have many advantages in assessing the effects of health care, there are several aspects that could be further developed to make fuller use of the potential of these time-consuming projects. In particular, IPD could be used to more fully investigate the influence of covariates on heterogeneity of treatment effects, both within and between trials. The impact of heterogeneity, or use of random effects, are seldom discussed. There is thus considerable scope for enhancing the methods of analysis and presentation of IPD meta-analysis.
Unblinding of trial participants to their treatment allocation: lessons from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)
Authors: Dinnett Eleanor M , Mungall Moira MB , Kent Jane A , Ronald Elizabeth S , McIntyre Karen E , Anderson Elizabeth , Gaw Allan ,   PROSPER Study Group
Published: June 2005

Background The gold standard clinical trial design is the double-blind, randomized, controlled trial. No standard practice exists for the “unblinding” of trial participants and no legal obligation is placed on investigators to inform participants of their treatment allocation or study results at the end of a trial. Here we document our experiences of unblinding the 2520 Scottish participants in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Methods The objectives of the PROSPER unblinding process were to provide all study participants with their study medication status and on-trial cholesterol levels and to respect the rights of participants not to be unblinded. It was considered imperative by the study executive that the blind was maintained until the presentation and publication of the results. Staff therefore remained “blinded” throughout the unblinding process. Inappropriate contact with the PROSPER participants was avoided by confirming their current vital status and health status. Results To coincide with the presentation of the PROSPER results, all participants, for whom it was deemed appropriate, were sent a summary of the results and were offered the opportunity to be advised of their treatment allocation and on-trial lipid profiles. The majority of participants opted for telephone unblinding. All primary care physicians who had patients randomised to the study were also sent a summary of the study results and sealed documents detailing the treatment allocation and lipid profiles for each patient. Relocated patients were traced and the information forwarded to their new primary care physicians. Conclusion The dissemination of study results and treatment allocation to study participants is an integral part of the research process and should be included in the design of any clinical trial.
Abstracts presented at the American Society of Clinical Oncology conference: how completely are trials reported?
Authors: Hopewell Sally , Clarke Mike 
Published: June 2005

Purpose To assess how completely trials published in conference proceedings are reported and whether this has changed over time. Methods Conference abstracts published at the American Society of Clinical Oncology (ASCO) conference (1992 and 2002) were read to identify reports of randomized trials. A checklist was devised (based on CONSORT) to assess the completeness of reporting. Results Four-hundred and ninety-four abstracts reporting randomized trials were identified; 209 in 1992 and 285 in 2002. More trials included “randomized” in the title in 2002 compared to 1992 (54% versus 36%). Almost no trials stated the method of allocation concealment, 12% stated the method of blinding, 95% described eligible participants and 98% described the interventions. Ninety-five per cent reported the number of participants in each trial. The median number of participants per trial increased over time; 120 in 1992 and 209 in 2002 (P, 0.01). In 1992, 67% of trials reported the number of participants analysed, compared to only 49% in 2002 (P, 0.01), 28% reported or suggested intention to treat analysis dropping to 15% in 2002. Twenty-nine abstracts in 2002 and five in 1992 reported no results, with a promise of presentation at the meeting. Conclusions The reporting of conference abstracts for trials should be improved to further facilitate understanding of their conduct and validity.
Reduction of Insulin-Stimulated Glucose Uptake in L6 Myotubes by the Protein Kinase Inhibitor SB203580 Is Independent of p38MAPK Activity
Authors: Antonescu C. N. , Huang C. , Niu W. , Liu Z. , Eyers P. A. , Heidenreich K. A. , Bilan P. J. , Klip A. 
Published: June 2005

AbstractInsulin increases glucose uptake through translocation of the glucose transporter GLUT4 to the plasma membrane. We previously showed that insulin activates p38MAPK, and inhibitors of p38MAPKα and p38MAPKβ (e.g. SB203580) reduce insulin-stimulated glucose uptake without affecting GLUT4 translocation. This observation suggested that insulin may increase GLUT4 activity via p38α and/or p38β. Here we further explore the possible participation of p38MAPK through a combination of molecular strategies. SB203580 reduced insulin stimulation of glucose uptake in L6 myotubes overexpressing an SB203580-resistant p38α (drug-resistant p38α) but barely affected phosphorylation of the p38 substrate MAPK-activated protein kinase-2. Expression of dominant-negative p38α or p38β reduced p38MAPK phosphorylation by 70% but had no effect on insulin-stimulated glucose uptake. Gene silencing via isoform-specific small interfering RNAs reduced expression of p38α or p38β by 60–70% without diminishing insulin-stimulated glucose uptake. SB203580 reduced photoaffinity labeling of GLUT4 by bio-LC-ATB-BMPA only in the insulin-stimulated state. Unless low levels of p38MAPK suffice to regulate glucose uptake, these results suggest that the inhibition of insulin-stimulated glucose transport by SB203580 is likely not mediated by p38MAPK. Instead, changes experienced by insulin-stimulated GLUT4 make it susceptible to inhibition by SB203580.
Evidence that the Cells Responsible for Marrow Fibrosis in a Rat Model for Hyperparathyroidism Are Preosteoblasts
Authors: Lotinun Sutada , Sibonga Jean D. , Turner Russell T. 
Published: June 2005

AbstractWe examined proliferation of cells associated with PTH-induced peritrabecular bone marrow fibrosis in rats as well as the fate of those cells after withdrawal of PTH. Time-course studies established that severe fibrosis was present 7 d after initiation of a continuous sc PTH infusion (40 μg/kg·d). To ascertain cell proliferation, rats were coinfused for 1 wk with PTH (treated) or vehicle (control) and [3H]thymidine (1.5 mCi/rat). Groups of control and treated rats were killed immediately (d 0) and 1 wk (d 7) later. Few osteoblasts (Obs) and osteocytes in treated and control groups were radiolabeled on d 0. Peritrabecular cells expressing a fibroblastic (Fb) phenotype and surrounded by an extracellular matrix were not present in controls on either d 0 or d 7. Multiple cell layers of Fbs lined most (70%) of the bone surface on d 0 in treated rats and nearly all (85%) of the Fbs were radiolabeled. Fbs had entirely disappeared from bone surfaces on d 7. Eighty-five percent of the Obs on and 73% of the osteocytes within the active remodeling sites were radiolabeled. Immunohistochemistry revealed that Fbs induced by PTH treatment produced osteocalcin, osteonectin, and core binding factor-α1. These data provide compelling evidence that Fbs recruited to bone surfaces in response to a continuous PTH infusion undergo extensive proliferation, express osteoblast-specific proteins, and produce an extracellular matrix that is similar to osteoid. After restoration of normal PTH levels, Fbs differentiated to Obs, providing further evidence that Fbs are preosteoblasts.
Knockout of Luteinizing Hormone Receptor Abolishes the Effects of Follicle-Stimulating Hormone on Preovulatory Maturation and Ovulation of Mouse Graafian Follicles
Authors: Pakarainen Tomi , Zhang Fu-Ping , Nurmi Laura , Poutanen Matti , Huhtaniemi Ilpo 
Published: June 2005

Abstract
It is considered a dogma that a secretory peak of LH is indispensable as the trigger of ovulation. However, earlier studies on hypophysectomized rodents have shown that stimulation with recombinant FSH, devoid of any LH activity, is able to boost the final stages of follicular maturation and trigger ovulation. As the expression of ovarian LH receptors (LHRs) still persists after hypophysectomy, such studies cannot totally exclude the possibility that LHR activation is involved in the apparently pure FSH effects. To revisit this question, we analyzed in LHR knockout (LuRKO) mice the progression of folliculogenesis and induction of ovulation by human chorionic gonadotropin and human recombinant FSH treatments. The results provide clear evidence that follicular development and ovulation could not be induced by high doses of FSH in the absence of LHR expression. Ovarian histology and oocyte analyses indicated that follicular maturation did not advance in LuRKO mice beyond the antral follicle stage. Neither were ovulations detected in LuRKO ovaries after any of the gonadotropin treatments. The ovarian resistance to FSH treatment in the absence of LHR was confirmed by real-time RT-PCR and immunohistochemical analyses of a number of gonadotropin-dependent genes, which only responded to the treatments in wild-type control mice. Negative findings were not altered by estradiol priming preceding the gonadotropin stimulations. Hence, the present study shows that, in addition to ovulation, the expression of LHR is essential for follicular maturation in the progression from antral to preovulatory stage.
Selective Serotonin-Reuptake Inhibitors in the Treatment of Premature Ejaculation
Authors: Moreland Amanda J , Makela Eugene H 
Published: June 2005

OBJECTIVE To review the use of selective serotonin-reuptake inhibitors (SSRIs) in the treatment of premature ejaculation. DATA SOURCES Articles were retrieved through a MEDLINE search (1966–January 2004). Search terms used to identify articles included serotonin uptake inhibitors, premature ejaculation, rapid ejaculation, and sexual behavior, as well as the generic names of currently available SSRIs: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, and escitalopram. The literature search was limited to articles published in the English language containing human subjects. STUDY SELECTION AND DATA EXTRACTION Articles obtained through the literature search were evaluated, and randomized controlled trials were included in this review. Information from noncontrolled trials or case reports was considered for inclusion if it contributed to the completeness of this review and if it was the highest level of evidence available. DATA SYNTHESIS Premature ejaculation is a commonly reported sexual difficulty. Delayed ejaculation is a widely reported sexual adverse effect of SSRIs. In some men exhibiting premature ejaculation, the ability of the SSRIs to delay ejaculation has been therapeutic. Trials evaluating the ejaculation-delaying ability of SSRIs demonstrated that paroxetine, fluoxetine, sertraline, and citalopram produce a statistically significant increase in the ejaculation latency time compared with placebo. CONCLUSIONS Taking advantage of the ejaculation-delaying effects of SSRIs increases the treatment options available to prescribers and patients. Convenience and minimal adverse effect profile make these agents an alternative to previously used behavior modalities and older pharmacologic agents. Although some questions still surround the details of their use, SSRIs have the potential to improve the quality of life for men with premature ejaculation and their partners.
Phosphodiesterase 5 Inhibitors for Erectile Dysfunction
Authors: Setter Stephen M , Iltz Jason L , Fincham Jack E , Campbell R Keith , Baker Danial E 
Published: June 2005

OBJECTIVETo review the pharmacologic and clinical trial data of the Food and Drug Administration–approved phosphodiesterase 5 (PDE5) inhibitors for the treatment of erectile dysfunction (ED).DATA SOURCESPrimary research and review articles were identified through a search of ScienceDirect, PubMed/MEDLINE, and International Pharmaceutical Abstracts (1990–August 2004). The following search terms were used in the Medicine Dentistry and Pharmacology, Toxicology, and Pharmaceutical Sciences subcategories: phosphodiesterase 5 inhibitor, PDE5 inhibitor, erectile dysfunction, sildenafil, vardenafil, tadalafil, prostatectomy, and diabetes. Web of Science (1990–August 2004) was used to search for additional abstracts using the same search terms as above. The package inserts for sildenafil, vardenafil, and tadalafil were also consulted.STUDY SELECTION AND DATA EXTRACTIONAll identified research, review articles, and abstracts were assessed for relevance, and all relevant information was included. Priority was given to the primary medical literature and clinical trial reports.DATA SYNTHESISED is a common disorder in males with increased prevalence associated with age and presence of cardiovascular disease, prostatectomy, or diabetes mellitus. Sildenafil, vardenafil, and tadalafil are selective PDE5 inhibitors currently available for treatment of ED. Their pharmacology and pharmacokinetics vary slightly, but with potentially important clinical differences in duration of activity; all have similar clinical efficacy and adverse effect profiles in patients with ED of various causes.CONCLUSIONSSildenafil, vardenafil, and tadalafil are safe and effective PDE5 inhibitors for the treatment of ED.
Quality Assurance Instrument Focusing on Patient Counseling
Authors: Puumalainen Inka I , Kause Johanna M , Airaksinen Marja S 
Published: June 2005

BACKGROUND Patient counseling is a professional service provided by community pharmacists. To assess the quality of these services, specific quality assurance instruments are needed. OBJECTIVE To develop a validated, easy-to-use patient counseling quality assurance instrument for community pharmacists. The development process was part of a national project to enhance patient counseling in community pharmacies (TIPPA 2000–2003). METHODS A modified Delphi method was used with 2 expert panels: Panel 1, consisting of experienced pharmacy practitioners (n = 10), and Panel 2, consisting of academic and professional experts (n = 10). The final consensus was assessed by a Delphi questionnaire round involving both panels, the employers of Panel 1 members (n = 5), and the members of the executive board of the TIPPA project (n = 10), comprising 35 people (response rate 74%; n = 26). RESULTS The first Delphi round yielded a high consensus, with the level of agreement varying between 69% and 100%. All but one item met the predefined criteria for approval. A total of 16 indicators were identified in 3 quality dimensions: patient (4 indicators), process (6), and learning and innovations (6). Strategy and vision of the pharmacy in patient counseling formed the core of the instrument. CONCLUSIONS The modified Delphi method proved to be applicable in the development process of an instrument assessing patient counseling services. The instrument comprehensively takes into account factors related to quality assurance of counseling practices.
From Practice Research to Public Policy—The Ministerial Summit on Health Research
Authors: Bell Simon 
Published: June 2005

OBJECTIVE To report on the outcomes of discussions on the role of research in the improvement of population health that took place at the Ministerial Summit on Health Research. DATA SOURCES Information was gathered from presentations and discussions at the Ministerial Summit on Health Research conducted in Mexico City November 16–20, 2004. DATA SYNTHESIS Strategies to strengthen health systems through closer collaboration between researchers and policy makers were debated. Consideration was given to persisting inequalities in health research, including the 10/90 gap (10% of health research expenditure is devoted to diseases responsible for 90% of the world's disease burden), the “know-do” gap (the gap between research knowledge and professional practice), and the divide in access to health information. Adopting measures to address human resource shortages was seen as critical. Participants at the Summit issued “The Mexico Statement on Health Research.” CONCLUSIONS All stakeholders must develop the political will to share information, resources, and experiences to ensure that practice research and public policy develop in accordance with patients' needs.
Multicomponent protein adsorption in supported cationic polyacrylamide hydrogels
Authors: Russell Shawn M. , Carta Giorgio 
Published: June 2005

AbstractPartitioning and transport of proteins in charged polyacrylamide gels were studied for single and two‐component protein mixtures. The gels were synthesized within fused‐silica capillaries allowing a direct microscopic determination of concentration profiles in the gel during adsorption and desorption of fluorescently labeled proteins. α‐lactalbumin, ovalbumin, and BSA were used as model proteins spanning molecular masses between 15 and 65 kDa. The proteins were conjugated to green and red rhodamine fluorescent labels, allowing simultaneous and independent determinations of two proteins during binary adsorption. The proteins were found to be favorably but reversibly partitioned into the gel and could be eluted at high salt concentrations. The transient concentration profiles were found to be consistent with a Fickian diffusion model with a driving force based on the adsorbed phase concentration gradient. The diffusivity and adsorption capacity of the proteins determined from the microscopic data compared favorably to results previously obtained from macroscopic studies of Q‐HyperD, a gel‐filled particle chemically similar to the gels synthesized in this work. Coadsorption and sequential adsorption experiments also resulted in diffuse concentration profiles indicating that the underlying transport mechanism is the same as for single component transport. The diffusion model was extended to predict the two‐component cases. Predictions were reasonably accurate for co‐adsorption, but gave rates higher than seen experimentally for sequential adsorption, probably as a result of diffusion flux coupling or other nonidealities. © 2005 American Institute of Chemical Engineers AIChE J, 2005
Nonlinear adaptive model predictive control based on self‐correcting neural network models
Authors: Alexandridis Alex , Sarimveis Haralambos 
Published: June 2005

AbstractTwo major issues in process control are the nonlinearities and variations with time that are observed in the dynamics of the processes. In most cases these problems are confronted by robust linear controllers, which are frequently retuned to take into account changes in the operating region or the system dynamics. Obviously, the performance of these controllers is limited by the degree of nonlinearities and the frequency of process variations. In this paper we present a new model predictive control (MPC) framework that can deal with both these issues. The proposed methodology is based on a nonlinear dynamic radial basis function (RBF) model of the process that is able to correct itself as new information about the process dynamics becomes available. The adaptive training algorithm that is used is able to update both the structure and the parameters of the RBF model. The typical formulation of the on‐line optimization problem is augmented by a persistent excitation condition that guarantees that enough perturbation is introduced to the system by the control moves. The proposed MPC framework is applied on the digester control problem and proves to be superior to other MPC configurations. © 2005 American Institute of Chemical Engineers AIChE J, 2005