A retrospective study of cholinesterase inhibitors for Alzheimer's disease : the effect of cerebrovascular disease on patient outcomes and the impact of biases on the results.

Introduction: La démence peut être causée par la maladie d’Alzheimer (MA), la maladie cérébrovasculaire (MCEREV), ou une combinaison des deux. Lorsque la maladie cérébrovasculaire est associée à la démence, les chances de survie sont considérées réduites. Il reste à démontrer si le traitement avec des inhibiteurs de la cholinestérase (ChEIs), qui améliore les symptômes cognitifs et la fonction globale chez les patients atteints de la MA, agit aussi sur les formes vasculaires de démence. Objectifs: La présente étude a été conçue pour déterminer si la coexistence d’une MCEREV était associée avec les chances de survie ou la durée de la période jusqu’au placement en hebergement chez les patients atteints de la MA et traités avec des ChEIs. Des études montrant de moins bons résultats chez les patients souffrant de MCEREV que chez ceux n’en souffrant pas pourrait militer contre l’utilisation des ChEIs chez les patients atteints à la fois de la MA et la MCEREV. L'objectif d'une seconde analyse était d'évaluer pour la première fois chez les patients atteints de la MA l'impact potentiel du biais de « temps-immortel » (et de suivi) sur ces résultats (mort ou placement en hebergement). Méthodes: Une étude de cohorte rétrospective a été conduite en utilisant les bases de données de la Régie de l’Assurance Maladie du Québec (RAMQ) pour examiner la durée de la période jusqu’au placement en hebergement ou jusqu’au v décès des patients atteints de la MA, âgés de 66 ans et plus, avec ou sans MCEREV, et traités avec des ChEIs entre le 1er Juillet 2000 et le 30 Juin 2003. Puisque les ChEIs sont uniquement indiquées pour la MA au Canada, chaque prescription de ChEIs a été considérée comme un diagnostic de la MA. La MCEREV concomitante a été identifié sur la base d'un diagnostic à vie d’un accident vasculaire cérébral (AVC) ou d’une endartériectomie, ou d’un diagnostic d'un accident ischémique transitoire au cours des six mois précédant la date d’entrée. Des analyses séparées ont été conduites pour les patients utilisant les ChEIs de façon persistante et pour ceux ayant interrompu la thérapie. Sept modèles de régression à risque proportionnel de Cox qui ont varié par rapport à la définition de la date d’entrée (début du suivi) et à la durée du suivi ont été utilisés pour évaluer l'impact du biais de temps-immortel. Résultats: 4,428 patients ont répondu aux critères d’inclusion pour la MA avec MCEREV; le groupe de patients souffrant seulement de la MA comptait 13,512 individus. Pour le critère d’évaluation composite considérant la durée de la période jusqu’au placement en hebergement ou jusqu’au décès, les taux de survie à 1,000 jours étaient plus faibles parmi les patients atteints de la MA avec MCEREV que parmi ceux atteints seulement de la MA (p<0.01), mais les différences absolues étaient très faibles (84% vs. 86% pour l’utilisation continue de ChEIs ; 77% vs. 78% pour la thérapie avec ChEIs interrompue). Pour les critères d’évaluation secondaires, la période jusqu’au décès était plus courte chez les patients avec la MCEREV que sans la MCEREV, mais la période jusqu’au vi placement en hebergement n’était pas différente entre les deux groupes. Dans l'analyse primaire (non-biaisée), aucune association a été trouvée entre le type de ChEI et la mort ou le placement en maison d'hébergement. Cependant, après l'introduction du biais de temps-immortel, on a observé un fort effet différentiel. Limitations: Les résultats peuvent avoir été affectés par le biais de sélection (classification impropre), par les différences entre les groupes en termes de consommation de tabac et d’indice de masse corporelle (ces informations n’étaient pas disponibles dans les bases de données de la RAMQ) et de durée de la thérapie avec les ChEIs. Conclusions: Les associations entre la coexistence d’une MCEREV et la durée de la période jusqu’au placement en hebergement ou au décès apparaissent peu pertinentes cliniquement parmi les patients atteints de la MA traités avec des ChEIs. L’absence de différence entre les patients atteints de la MA souffrant ou non de la MCEREV suggère que la coexistence d’une MCEREV ne devrait pas être une raison de refuser aux patients atteints de la MA l’accès au traitement avec des ChEIs. Le calcul des « personne-temps » non exposés dans l'analyse élimine les estimations biaisées de l'efficacité des médicaments.

Cutpoint selection for discretizing a continuous covariate for generalized estimating equations

We consider consider the problem of dichotomizing a continuous covariate when performing a regression analysis based on a generalized estimation approach. The problem involves estimation of the cutpoint for the covariate and testing the hypothesis that the binary covariate constructed from the continuous covariate has a significant impact on the outcome. Due to the multiple testing used to find the optimal cutpoint, we need to make an adjustment to the usual significance test to preserve the type-I error rates. We illustrate the techniques on one data set of patients given unrelated hematopoietic stem cell transplantation. Here the question is whether the CD34 cell dose given to patient affects the outcome of the transplant and what is the smallest cell dose which is needed for good outcomes. (C) 2010 Elsevier BM. All rights reserved.

Cephalometric evaluation of hyoid bone position in a patient with Down syndrome: Case report

The hyoid bone contributes to the maintenance of the airway, chewing and swallowing, given to its anatomical and functional relations to the craniocervical complex. Cephalometric analysis has great importance for orthopedics, orthodontics and oral maxillary surgery. For the treatment of patients with special care needs, the cephalometric evaluation of the position of the hyoid bone should also contribute as a complementary element for dental diagnosis and the selection of the adequate treatment. The aim of this paper is to demonstrate the alteration of the hyoid position after carrying out the functional orthopedic maxillary treatment in a 9 year-old patient with Down Syndrome. Initial cephalometric analysis revealed inadequate position of hyoid bone. The association of speech therapy to dynamic functional rehabilitation of jaws showed a positive effect in occlusal relation and facial expression. After treatment, all dimensions obtained from the hyoid triangle were higher than initial ones, except the anterior-posterior value of C3-H, which suggested function improvement of stomatognathic system. Once considered its anatomical and physiological relationship with the others structures of the stomatognathic system, cephalometric analysis of hyoid bone position was helpful to the comprehension of the craniofacial abnormalities related to chromosomal anomaly, and thus is essential to the interdisciplinary dialogue.

Worldwide genetic variation at the 3 ' untranslated region of the HLA-G gene: balancing selection influencing genetic diversity

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Using Machine Learning Classifiers to Assist Healthcare-Related Decisions: Classification of Electronic Patient Records

Surveillance Levels (SLs) are categories for medical patients (used in Brazil) that represent different types of medical recommendations. SLs are defined according to risk factors and the medical and developmental history of patients. Each SL is associated with specific educational and clinical measures. The objective of the present paper was to verify computer-aided, automatic assignment of SLs. The present paper proposes a computer-aided approach for automatic recommendation of SLs. The approach is based on the classification of information from patient electronic records. For this purpose, a software architecture composed of three layers was developed. The architecture is formed by a classification layer that includes a linguistic module and machine learning classification modules. The classification layer allows for the use of different classification methods, including the use of preprocessed, normalized language data drawn from the linguistic module. We report the verification and validation of the software architecture in a Brazilian pediatric healthcare institution. The results indicate that selection of attributes can have a great effect on the performance of the system. Nonetheless, our automatic recommendation of surveillance level can still benefit from improvements in processing procedures when the linguistic module is applied prior to classification. Results from our efforts can be applied to different types of medical systems. The results of systems supported by the framework presented in this paper may be used by healthcare and governmental institutions to improve healthcare services in terms of establishing preventive measures and alerting authorities about the possibility of an epidemic.

Impact of drug-eluting stent selection on long-term clinical outcomes in patients treated for unprotected left main coronary artery disease: the sirolimus vs paclitaxel drug-eluting stent for left main registry (SP-DELFT)

AIM: To compare the long-term relative efficacy and safety of SES and PES in patients undergoing percutaneous coronary intervention (PCI) for unprotected left main coronary artery (ULMCA) disease and to evaluate the role of lesion location and stenting technique in determining outcomes. METHODS AND RESULTS: From April 2002 to April 2004, 288 consecutive patients who underwent elective PCI with DES implantation for de novo lesions on ULMCA have been retrospectively selected and analyzed in seven European and US tertiary care centers. All patients had a minimum follow-up of 3 years. SES was used in 152 patients while 136 received PES. Isolated ostial-shaft disease was present in 27% of patients. Distal LM disease (73%) was treated with single and double stent approach in 29.5% and 43.4% of patients respectively. After 3 years, rates of survival free from any of the events investigated, were independent from lesion location and stenting approach and did not differ significantly between SES and PES groups. Freedom from MACE (SES vs. PES) was 76.3% vs. 83.1% in the ostial/shaft group, 80.3% vs. 72.8% in the distal-single stent group and 67.1% vs. 66.2% in the distal-double stent group. Definite stent thrombosis occurred only in 1(0.3%) patient at 439 days. CONCLUSIONS: In elective patients who underwent PCI for de novo lesions in the ostium, shaft or distal ULMCA, long-term clinical outcomes with SES and PES use were similar independently of lesion location and stenting technique.

The exchange of radiotherapy data as part of an electronic patient-referral system

PURPOSE: To describe the implementation and use of an electronic patient-referral system as an aid to the efficient referral of patients to a remote and specialized treatment center. METHODS AND MATERIALS: A system for the exchange of radiotherapy data between different commercial planning systems and a specially developed planning system for proton therapy has been developed through the use of the PAPYRUS diagnostic image standard as an intermediate format. To ensure the cooperation of the different TPS manufacturers, the number of data sets defined for transfer has been restricted to the three core data sets of CT, VOIs, and three-dimensional dose distributions. As a complement to the exchange of data, network-wide application-sharing (video-conferencing) technologies have been adopted to provide methods for the interactive discussion and assessment of treatments plans with one or more partner clinics. RESULTS: Through the use of evaluation plans based on the exchanged data, referring clinics can accurately assess the advantages offered by proton therapy on a patient-by-patient basis, while the practicality or otherwise of the proposed treatments can simultaneously be assessed by the proton therapy center. Such a system, along with the interactive capabilities provided by video-conferencing methods, has been found to be an efficient solution to the problem of patient assessment and selection at a specialized treatment center, and is a necessary first step toward the full electronic integration of such centers with their remotely situated referral centers.

Erythropoietin or Darbepoetin for patients with cancer--meta-analysis based on individual patient data

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients and may improve quality of life, but there are concerns that ESAs might increase mortality. OBJECTIVES: Our objectives were to examine the effect of ESAs and identify factors that modify the effects of ESAs on overall survival, progression free survival, thromboembolic and cardiovascular events as well as need for transfusions and other important safety and efficacy outcomes in cancer patients. SEARCH STRATEGY: We searched the Cochrane Library, Medline, Embase and conference proceedings for eligible trials. Manufacturers of ESAs were contacted to identify additional trials. SELECTION CRITERIA: We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusions (as necessary) versus red blood cell transfusions (as necessary) alone, to prevent or treat anemia in adult or pediatric cancer patients with or without concurrent antineoplastic therapy. DATA COLLECTION AND ANALYSIS: We performed a meta-analysis of randomized controlled trials comparing epoetin alpha, epoetin beta or darbepoetin alpha plus red blood cell transfusions versus transfusion alone, for prophylaxis or therapy of anemia while or after receiving anti-cancer treatment. Patient-level data were obtained and analyzed by independent statisticians at two academic departments, using fixed-effects and random-effects meta-analysis. Analyses were according to the intention-to-treat principle. Primary endpoints were on study mortality and overall survival during the longest available follow-up, regardless of anticancer treatment, and in patients receiving chemotherapy. Tests for interactions were used to identify differences in effects of ESAs on mortality across pre-specified subgroups. The present review reports only the results for the primary endpoint. MAIN RESULTS: A total of 13933 cancer patients from 53 trials were analyzed, 1530 patients died on-study and 4993 overall. ESAs increased on study mortality (combined hazard ratio [cHR] 1.17; 95% CI 1.06-1.30) and worsened overall survival (cHR 1.06; 95% CI 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 and I(2) 7.1%, p=0.33, respectively). Thirty-eight trials enrolled 10441 patients receiving chemotherapy. The cHR for on study mortality was 1.10 (95% CI 0.98-1.24) and 1.04; 95% CI 0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients receiving different cancer treatments (P for interaction=0.42). AUTHORS' CONCLUSIONS: ESA treatment in cancer patients increased on study mortality and worsened overall survival. For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded.

The importance of allocation concealment and patient blinding in osteoarthritis trials: a meta-epidemiologic study

OBJECTIVE: To evaluate the association of adequate allocation concealment and patient blinding with estimates of treatment benefits in osteoarthritis trials. METHODS: We performed a meta-epidemiologic study of 16 meta-analyses with 175 trials that compared therapeutic interventions with placebo or nonintervention control in patients with hip or knee osteoarthritis. We calculated effect sizes from the differences in means of pain intensity between groups at the end of followup divided by the pooled SD and compared effect sizes between trials with and trials without adequate methodology. RESULTS: Effect sizes tended to be less beneficial in 46 trials with adequate allocation concealment compared with 112 trials with inadequate or unclear concealment of allocation (difference -0.15; 95% confidence interval [95% CI] -0.31, 0.02). Selection bias associated with inadequate or unclear concealment of allocation was most pronounced in meta-analyses with large estimated treatment benefits (P for interaction < 0.001), meta-analyses with high between-trial heterogeneity (P = 0.009), and meta-analyses of complementary medicine (P = 0.019). Effect sizes tended to be less beneficial in 64 trials with adequate blinding of patients compared with 58 trials without (difference -0.15; 95% CI -0.39, 0.09), but differences were less consistent and disappeared after accounting for allocation concealment. Detection bias associated with a lack of adequate patient blinding was most pronounced for nonpharmacologic interventions (P for interaction < 0.001). CONCLUSION: Results of osteoarthritis trials may be affected by selection and detection bias. Adequate concealment of allocation and attempts to blind patients will minimize these biases.

Consensus on the Need for a Hierarchical List of Patient-reported Pain Outcomes for Metaanalyses of Knee Osteoarthritis Trials: An OMERACT Objective.

OBJECTIVE Although protocol registration for systematic reviews is still not mandatory, reviewers should be strongly encouraged to register the protocol to identify the methodological approach, including all outcomes of interest. This will minimize the likelihood of biased decisions in reviews, such as selective outcome reporting. A group of international experts convened to address issues regarding the need to develop hierarchical lists of outcome measurement instruments for a particular outcome for metaanalyses. METHODS Multiple outcome measurement instruments exist to measure the same outcome. Metaanalysis of knee osteoarthritis (OA) trials, and the assessment of pain as an outcome, was used as an exemplar to assess how Outcome Measures in Rheumatology (OMERACT), the Cochrane Collaboration, and other international initiatives might contribute in this area. The meeting began with formal presentations of background topics, empirical evidence from the literature, and a brief introduction to 2 existing hierarchical lists of pain outcome measurement instruments recommended for metaanalyses of knee OA trials. RESULTS After discussions, most participants agreed that there is a need to develop a methodology for generation of hierarchical lists of outcome measurement instruments to guide metaanalyses. Tools that could be used to steer development of such a prioritized list are the COSMIN checklist (Consensus-based Standards for the selection of health status Measurement Instruments) and the OMERACT Filter 2.0. CONCLUSION We list meta-epidemiological research agenda items that address the frequency of reported outcomes in trials, as well as methodologies to assess the best measurement properties (i.e., truth, discrimination, and feasibility).

A qualitative analysis of leadership styles and the selection of quality improvement in primary care practice

In the Practice Change Model, physicians act as key stakeholders, people who have both an investment in the practice and the capacity to influence how the practice performs. This leadership role is critical to the development and change of the practice. Leadership roles and effectiveness are an important factor in quality improvement in primary care practices.^ The study conducted involved a comparative case study analysis to identify leadership roles and the relationship between leadership roles and the number and type of quality improvement strategies adopted during a Practice Change Model-based intervention study. The research utilized secondary data from four primary care practices with various leadership styles. The practices are located in the San Antonio region and serve a large Hispanic population. The data was collected by two ABC Project Facilitators from each practice during a 12-month period including Key Informant Interviews (all staff members), MAP (Multi-method Assessment Process), and Practice Facilitation field notes. This data was used to evaluate leadership styles, management within the practice, and intervention tools that were implemented. The chief steps will be (1) to analyze if the leader-member relations contribute to the type of quality improvement strategy or strategies selected (2) to investigate if leader-position power contributes to the number of strategies selected and the type of strategy selected (3) and to explore whether the task structure varies across the four primary care practices.^ The research found that involving more members of the clinic staff in decision-making, building bridges between organizational staff and clinical staff, and task structure are all associated with the direct influence on the number and type of quality improvement strategies implemented in primary care practice.^ Although this research only investigated leadership styles of four different practices, it will offer future guidance on how to establish the priorities and implementation of quality improvement strategies that will have the greatest impact on patient care improvement. ^

How Escherichia coli can bias the results of molecular cloning: Preferential selection of defective genomes of hepatitis C virus during the cloning procedure

Cloned PCR products containing hepatitis C virus (HCV) genomic fragments have been used for analyses of HCV genomic heterogeneity and protein expression. These studies assume that the clones derived are representative of the entire virus population and that subsets are not inadvertently selected. The aim of the present study was to express HCV structural proteins. However, we found that there was a strong cloning selection for defective genomes and that most clones generated initially were incapable of expressing the HCV proteins. The HCV structural region (C-E1-E2-p7) was directly amplified by long reverse transcription–PCR from the plasma of an HCV-infected patient or from a control plasmid containing a viable full-length cDNA of HCV derived from the same patient but cloned in a different vector. The PCR products were cloned into a mammalian expression vector, amplified in Escherichia coli, and tested for their ability to produce HCV structural proteins. Twenty randomly picked clones derived from the HCV-infected patient all contained nucleotide mutations leading to absence or truncation of the expected HCV products. Of 25 clones derived from the control plasmid, only 8% were fully functional for polyprotein synthesis. The insertion of extra nucleotides in the region just upstream of the start codon of the HCV insert led to a statistically significant increase in the number of fully functional clones derived from the patient (42%) and from the control plasmid (72–92%). Nonrandom selection of clones during the cloning procedure has enormous implications for the study of viral heterogeneity, because it can produce a false spectrum of genomic diversity. It can also be an impediment to the construction of infectious viral clones.

Anti-melanoma antibodies from melanoma patients immunized with genetically modified autologous tumor cells: selection of specific antibodies from single-chain Fv fusion phage libraries.

Fusion phage libraries expressing single-chain Fv antibodies were constructed from the peripheral blood lymphocytes of two melanoma patients who had been immunized with autologous melanoma cells transduced the gamma-interferon gene to enhance immunogenicity, in a trial conducted at another institution. Anti-melanoma antibodies were selected from each library by panning the phage against live cultures of the autologous tumor. After two or three rounds of panning, clones of the phage were tested by ELISA for binding to the autologous tumor cells; > 90% of the clones tested showed a strong ELISA reaction, demonstrating the effectiveness of the panning procedure for selecting antimelanoma antibodies. The panned phage population was extensively absorbed against normal melanocytes to enrich for antibodies that react with melanoma cells but not with melanocytes. The unabsorbed phage were cloned, and the specificities of the expressed antibodies were individually tested by ELISA with a panel of cultured human cells. The first tests were done with normal endothelial and fibroblast cells to identify antibodies that do not react, or react weakly, with two normal cell types, indicating some degree of specificity for melanoma cells. The proportion of phage clones expressing such antibodies was approximately 1%. Those phage were further tested by ELISA with melanocytes, several melanoma lines, and eight other tumor lines, including a glioma line derived from glial cells that share a common lineage with melanocytes. The ELISA tests identified three classes of anti-melanoma antibodies, as follows: (i) a melanoma-specific class that reacts almost exclusively with the melanoma lines; (ii) a tumor-specific class that reacts with melanoma and other tumor lines but does not react with the normal melanocyte, endothelial and fibroblast cells; and (iii) a lineage-specific class that reacts with the melanoma lines, melanocytes, and the glioma line but does not react with the other lines. These are rare classes from the immunized patients' repertoires of anti-melanoma antibodies, most of which are relatively nonspecific anti-self antibodies. The melanoma-specific class was isolated from one patient, and the lineage-specific class was isolated from the other patient, indicating that different patients can have markedly different responses to the same immunization protocol. The procedures described here can be used to screen the antibody repertoire of any person with cancer, providing access to an enormous untapped pool of human monoclonal anti-tumor antibodies with clinical and research potential.

Meaning selection and the subcortex: Evidence of reduced lexical ambiguity repetition effects following subcortical lesions

Recent research indicates that individuals with nonthalamic subcortical (NS) lesions call experience difficulties processing lexical ambiguities in a variety of contexts. This study examined how prior processing of a lexical ambiguity influences subsequent meaning activation in 10 individuals with NS lesions and 10 matched healthy controls. Subjects made speeded lexical decisions oil related or unrelated targets following homophone primes. Homophones were repealed with different targets biasing the same or different meanings oil the second presentation. The effects of prime-target relatedness, interstimulus interval (200 or 1250 ms), and same vs different meaning repetition were examined Both the patient and control groups showed printing when the same homophone meaning was biased oil repetition. When a different meaning was biased on the second presentation. no priming was evident in the controls, while facilitation remained present for the NS group, consistent with aberrant meaning selection and deactivation processes. These findings are discussed in terms of age and task-related repetition effects and current conceptions of frontal-subcortical involvement in cognition.

On the interaction between perceptual and response selection: neuropsychological evidence

We examined the relations between selection for perception and selection for action in a patient FK, with bilateral damage to his temporal and medial frontal cortices. The task required a simple grasp response to a common object (a cup) in the presence of a distractor (another cup). The target was cued by colour or location, and FK made manual responses. We examined the effects on performance of cued and uncued dimensions of both the target and the distractor. FK was impaired at perceptually selecting the target when cued by colour, when the target colour but not its location changed on successive trials. The effect was sensitive to the relative orientations of targets and distractors, indicating an effect of action selection on perceptual selection, when perceptual selection was weakly instantiated. The dimension-specific carry-over effect on reaching was enhanced when there was a temporal delay between a cue and the response, and it disappeared when there was a between-trial delay. The results indicate that perceptual and action selection systems interact to determine the efficiency with which actions are selected to particular objects.