Donepezil for the symptomatic treatment of patients with mild to moderate Alzheimer's disease: a meta-analysis of individual patient data from randomised controlled trials

Background: The objective was to evaluate the efficacy and tolerability of donepezil (5 and 10 mg/day) compared with placebo in alleviating manifestations of mild to moderate Alzheimer's disease (AD). Method: A systematic review of individual patient data from Phase II and III double-blind, randomised, placebo-controlled studies of up to 24 weeks and completed by 20 December 1999. The main outcome measures were the ADAS-cog, the CIBIC-plus, and reports of adverse events. Results: A total of 2376 patients from ten trials were randomised to either donepezil 5 mg/day (n = 821), 10 mg/day (n = 662) or placebo (n = 893). Cognitive performance was better in patients receiving donepezil than in patients receiving placebo. At 12 weeks the differences in ADAS-cog scores were 5 mg/day-placebo: - 2.1 [95% confidence interval (CI), - 2.6 to - 1.6; p < 0.001], 10 mg/day-placebo: - 2.5 ( - 3.1 to - 2.0; p < 0.001). The corresponding results at 24 weeks were - 2.0 ( - 2.7 to - 1.3; p < 0.001) and - 3.1 ( - 3.9 to - 2.4; p < 0.001). The difference between the 5 and 10 mg/day doses was significant at 24 weeks (p = 0.005). The odds ratios (OR) of improvement on the CIBIC-plus at 12 weeks were: 5 mg/day-placebo 1.8 (1.5 to 2.1; p < 0.001), 10 mg/day-placebo 1.9 (1.5 to 2.4; p < 0.001). The corresponding values at 24 weeks were 1.9 (1.5 to 2.4; p = 0.001) and 2.1 (1.6 to 2.8; p < 0.001). Donepezil was well tolerated; adverse events were cholinergic in nature and generally of mild severity and brief in duration. Conclusion: Donepezil (5 and 10 mg/day) provides meaningful benefits in alleviating deficits in cognitive and clinician-rated global function in AD patients relative to placebo. Increased improvements in cognition were indicated for the higher dose. Copyright © 2004 John Wiley & Sons, Ltd.

Meta-analysis of individual patient data from randomised trials: a review of methods used in practice

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.

Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies

Objective: To determine the risk of lung cancer associated with exposure at home to the radioactive disintegration products of naturally Occurring radon gas. Design: Collaborative analysis of individual data from 13 case-control studies of residential radon and lung cancer. Setting Nine European countries. Subjects 7148 cases Of lung cancer and 14 208 controls. Main outcome measures: Relative risks of lung cancer and radon gas concentrations in homes inhabited during the previous 5-34 years measured in becquerels (radon disintegrations per second) per cubic incite (Bq/m(3)) Of household air. Results: The mean measured radon concentration in homes of people in tire control group was 97 Bq/m(3), with 11% measuring > 200 and 4% measuring > 400 Bq/m(3). For cases of lung cancer the mean concentration was 104 Bq/m(3). The risk of lung cancer increased by 8.4% (95% confidence interval 3.0% to 15.8%) per 100 Bq/m(3) increase in measured radon (P = 0.0007). This corresponds to an increase of 16% (5% to 31%) per 100 Bq/m(3) increase in usual radon-that is, after correction for the dilution caused by random uncertainties in measuring radon concentrations. The dose-response relation seemed to be linear with no threshold and remained significant (P=0.04) in analyses limited to individuals from homes with measured radon < 200 Bq/m(3). The proportionate excess risk did not differ significantly with study, age, sex, or smoking. In the absence of other causes of death, the absolute risks of lung cancer by age 75 years at usual radon concentrations of 0, 100, and 400 Bq/m(3) would be about 0.4%, 0.5%, and 0.7%, respectively, for lifelong non-smokers, and about 25 times greater (10%, 12%, and 16%) for cigarette smokers. Conclusions: Collectively, though not separately, these studies show appreciable hazards from residential radon, particularly for smokers and recent ex-smokers, and indicate that it is responsible for about 2% of all deaths from cancer in Europe.

Influence of environmental stress on distributions of times to first division in Escherichia coli populations, as determined by digital-image analysis of individual cells

The distributions of times to first cell division were determined for populations of Escherichia coli stationary-phase cells inoculated onto agar media. This was accomplished by using automated analysis of digital images of individual cells growing on agar and calculation of the "box area ratio." Using approximately 300 cells per experiment, the mean time to first division and standard deviation for cells grown in liquid medium at 37 degrees C and inoculated on agar and incubated at 20 degrees C were determined as 3.0 h and 0.7 h, respectively. Distributions were observed to tail toward the higher values, but no definitive model distribution was identified. Both preinoculation stress by heating cultures at 50 degrees C and postinoculation stress by growth in the presence of higher concentrations of NaCl increased mean times to first division. Both stresses also resulted in an increase in the spread of the distributions that was proportional to the mean division time, the coefficient of variation being constant at approximately 0.2 in all cases. The "relative division time," which is the time to first division for individual cells expressed in terms of the cell size doubling time, was used as measure of the "work to be done" to prepare for cell division. Relative division times were greater for heat-stressed cells than for those growing under osmotic stress.

A novel method for measuring lag times in division of individual bacterial cells using image analysis

A method is presented for determining the time to first division of individual bacterial cells growing on agar media. Bacteria were inoculated onto agar-coated slides and viewed by phase-contrast microscopy. Digital images of the growing bacteria were captured at intervals and the time to first division estimated by calculating the "box area ratio". This is the area of the smallest rectangle that can be drawn around an object, divided by the area of the object itself. The box area ratios of cells were found to increase suddenly during growth at a time that correlated with cell division as estimated by visual inspection of the digital images. This was caused by a change in the orientation of the two daughter cells that occurred when sufficient flexibility arose at their point of attachment. This method was used successfully to generate lag time distributions for populations of Escherichia coli, Listeria monocytogenes and Pseudomonas aeruginosa, but did not work with the coccoid organism Staphylococcus aureus. This method provides an objective measure of the time to first cell division, whilst automation of the data processing allows a large number of cells to be examined per experiment. (c) 2005 Elsevier B.V. All rights reserved.

Construction management research at the individual-level of analysis: current status, gaps and future directions

Individual-level constructs are seldom taken into consideration in construction management research relating to project performance. This is antithetical to the objectives of properly conceptualizing and contextualizing the research we do because many project performance outcomes, such as the extent of cooperation and level of communication or teamwork are influenced and moderated by individuals’ perceptions, values and behaviour. A brief review of the literature in organizational studies centred on culture, identity, empowerment and trust is offered. These constructs are then explored in relation to project performance issues and outcomes, and it is noted that they are predominantly studied at the project and industry levels. We argue that focusing these constructs at the individual unit of analysis has significant implications for project performance and therefore their effects need to be systematically accounted for in explanations of the success and failure of projects. Far from being prescriptive, the aim is to generate interest and awareness for more focused research at the individual level of analysis in order to add new insights and perspectives to critical performance questions in construction management. To this end, a research agenda is outlined, arguing that construction management research integrating individual-level constructs and broader, macro-contextual issues will help define and enhance the legitimacy of the field.

Analysis of plant LTR-retrotransposons at the fine-scale family level reveals individual molecular patterns

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Spontaneous eye blink analysis in the normal individual

Purpose: Spontaneous eye blink activity in the primary eye position and its relationship to age and gender were assessed using digital image processing techniques to quantify blink opening and closing time. Methods: One hundred-and-eighty healthy volunteers (90 males and 90 females), divided into the age groups 0-3, 4-12, 13-20, 21-40, 41-60 and ≥60 years old, were evaluated prospectively. They were videotaped digitally in a standard setting and the images were transferred to a personal computer (Macintosh 400) and processed with the iMovie software. Blink opening and closing time were measured at 30 frames/second. The data were then subjected to statistical analysis. Results: The closing time was significantly longer than the opening time for all ages and both genders. Elderly individuals (≥41 years old) and women had significantly longer closing times. Conclusion: Image processing techniques made possible the observation of differences in spontaneous eye blink opening and closing time in relation to age and gender. Copyright © 2005 Taylor & Francis LLC.

In search of the autonomous and critical individual: a philosophical and pedagogical analysis of the physical education curriculum of São Paulo (Brazil)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Analysis of plant LTR-retrotransposons at the fine-scale family level reveals individual molecular patterns

Background: Sugarcane is an important crop worldwide for sugar production and increasingly, as a renewable energy source. Modern cultivars have polyploid, large complex genomes, with highly unequal contributions from ancestral genomes. Long Terminal Repeat retrotransposons (LTR-RTs) are the single largest components of most plant genomes and can substantially impact the genome in many ways. It is therefore crucial to understand their contribution to the genome and transcriptome, however a detailed study of LTR-RTs in sugarcane has not been previously carried out. Results: Sixty complete LTR-RT elements were classified into 35 families within four Copia and three Gypsy lineages. Structurally, within lineages elements were similar, between lineages there were large size differences. FISH analysis resulted in the expected pattern of Gypsy/heterochromatin, Copia/euchromatin, but in two lineages there was localized clustering on some chromosomes. Analysis of related ESTs and RT-PCR showed transcriptional variation between tissues and families. Four distinct patterns were observed in sRNA mapping, the most unusual of which was that of Ale1, with very large numbers of 24nt sRNAs in the coding region. The results presented support the conclusion that distinct small RNA-regulated pathways in sugarcane target the lineages of LTR-RT elements. Conclusions: Individual LTR-RT sugarcane families have distinct structures, and transcriptional and regulatory signatures. Our results indicate that in sugarcane individual LTR-RT families have distinct behaviors and can potentially impact the genome in diverse ways. For instance, these transposable elements may affect nearby genes by generating a diverse set of small RNA's that trigger gene silencing mechanisms. There is also some evidence that ancestral genomes contribute significantly different element numbers from particular LTR-RT lineages to the modern sugarcane cultivar genome.

In Vitro Macroscopic and Endoscopic Analysis of Three-Rooted Maxillary Premolars and Two-Rooted Mandibular Premolars in the Same Individual: a Case Report

The recent addition of endoscopy in dental practice has enabled clinicians to have an excellent view of the operative field, yielding highly successful visualization of anatomical structures that are difficult to access, both in oral surgery and endodontics. The purpose of this report is to provide an in vitro macroscopic, radiographic, and endoscopic description of the anatomic variation of the roots of maxillary and mandibular first premolars in the same patient. A 22-year-old patient was referred by an orthodontist for the extraction of all the first premolars. Once extracted, the premolars were examined macroscopically and then analyzed radiographically after trepanation and filled root canal systems. Subsequently, a diaphanization process was carried out and the samples were sectioned at the middle and apical third for observation by endoscope. It was found that both the maxillary first premolars had three roots, and mandibular first premolars had two roots, all with complete root formation. Apical deltas or accessory canals were not identified in the radiographic images; however, through endoscope at the middle third, it was possible to observe an accessory canal to the first maxillary and mandibular right premolars. Thus, it can be concluded that the view through the endoscope allows better identification of accessory canals than X-rays.

Safety and Functional Outcome of Thrombolysis in Dissection-Related Ischemic Stroke: A Meta-Analysis of Individual Patient Data

The safety and efficacy of thrombolysis in cervical artery dissection (CAD) are controversial. The aim of this meta-analysis was to pool all individual patient data and provide a valid estimate of safety and outcome of thrombolysis in CAD.

Intravaginal practices, bacterial vaginosis, and HIV infection in women: individual participant data meta-analysis

Background Identifying modifiable factors that increase women's vulnerability to HIV is a critical step in developing effective female-initiated prevention interventions. The primary objective of this study was to pool individual participant data from prospective longitudinal studies to investigate the association between intravaginal practices and acquisition of HIV infection among women in sub-Saharan Africa. Secondary objectives were to investigate associations between intravaginal practices and disrupted vaginal flora; and between disrupted vaginal flora and HIV acquisition. Methods and Findings We conducted a meta-analysis of individual participant data from 13 prospective cohort studies involving 14,874 women, of whom 791 acquired HIV infection during 21,218 woman years of follow-up. Data were pooled using random-effects meta-analysis. The level of between-study heterogeneity was low in all analyses (I2 values 0.0%–16.1%). Intravaginal use of cloth or paper (pooled adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.18–1.83), insertion of products to dry or tighten the vagina (aHR 1.31, 95% CI 1.00–1.71), and intravaginal cleaning with soap (aHR 1.24, 95% CI 1.01–1.53) remained associated with HIV acquisition after controlling for age, marital status, and number of sex partners in the past 3 months. Intravaginal cleaning with soap was also associated with the development of intermediate vaginal flora and bacterial vaginosis in women with normal vaginal flora at baseline (pooled adjusted odds ratio [OR] 1.24, 95% CI 1.04–1.47). Use of cloth or paper was not associated with the development of disrupted vaginal flora. Intermediate vaginal flora and bacterial vaginosis were each associated with HIV acquisition in multivariable models when measured at baseline (aHR 1.54 and 1.69, p<0.001) or at the visit before the estimated date of HIV infection (aHR 1.41 and 1.53, p<0.001), respectively. Conclusions This study provides evidence to suggest that some intravaginal practices increase the risk of HIV acquisition but a direct causal pathway linking intravaginal cleaning with soap, disruption of vaginal flora, and HIV acquisition has not yet been demonstrated. More consistency in the definition and measurement of specific intravaginal practices is warranted so that the effects of specific intravaginal practices and products can be further elucidated.