Transdermal Dual-Controlled Delivery of Contraceptive Drugs: Formulation Development,in Vitro and in Vivo Evaluations,and Clinical Performance

Several transdermal contraceptive device (TCD) formulations were developed to provide a dual-controlled transdermal delivery of levonorgestrel (LN), a potent progestin, and 17-estradiol (E₂), a natural estrogen. Using a sensitive HPLC method, the in vitro release and skin permeation profiles of LN and E₂ from various TCD formulations were simultaneously characterized in the hydrodynamically well-calibrated Valia–Chien skin permeation cells and both were found to follow zero-order kinetics. The rates of drug release and skin permeation were observed to vary significantly depending upon some formulation parameters. Six-month stability studies were performed on seven formulations at room and elevated temperatures (37 and 45°C), and two (Formulations 4 and 5) were found to be acceptable, based on drug recovery, release rate, and skin permeation rate data. Judging from the 6-month accelerated stability studies, it is projected these two formulations will have shelf-life of at least 2 years. As a result of development of an efficient manufacturing process, Formulation 4 was selected for further evaluation. One-week primary skin irritation evaluation in 6 rabbits indicated that Formulation 4 is nonirritating, and it was thus selected for Phase I clinical bioavailability/dose proportionality studies in 12 healthy female volunteers of child-bearing age. Results of pharmacokinetic and pharmacodynamic analyses demonstrated that it is capable of achieving and maintaining a steady-state serum level of LN throughout the 3-week treatment period by weekly applications of one or two TCD patches (10 or 20 cm²). A dose proportionality was obtained in the serum drug levels, daily dose delivered, and contraception efficacy. An excellent correlation was obtained for the rates of transdermal delivery determined by the in vitro studies using human cadaver skin, the in vivo studies in rabbits, and the clinical studies in living subjects.     

Signal-dependent wavelets for electromyogram classification

In the study, an efficient method to perform supervised classification of surface electromyogram (EMG) signals is proposed. The method is based on the choice of a relevant representation space and its optimisation with respect to a training set. As EMG signals are the summation of compact-support waveforms (the motor unit action potentials), a natural tool for their representation is the discrete dyadic wavelet transform. The feature space was thus built from the marginals of a discrete wavelet decomposition. The mother wavelet was designed to minimise the probability of classification error estimated on the learning set (supervised classification). As a representative example, the method was applied to simulate surface EMG signals generated by motor units with different degrees of short-term synchronisation. The proposed approach was able to distinguish surface EMG signals with degrees of synchronisation that differed by 10%, with a misclassification rate of 8%. The performance of a spectral-based classification (error rate approximately 33%) and of the classification with Daubechies wavelet (21%) was significantly poorer than with the proposed wavelet optimisation. The method can be used for a number of different application fields of surface EMG classification, as the feature space is adapted to the characteristics of the signal that discriminate between classes. An erratum to this article is available at .     

Enhancing a primary care environment: a case study of effects on patients and staff in a single general practice

BACKGROUND: Few studies have examined the effect on patients and staff of the physical environment in primary care facilities. AIM: To explore changes in patient and staff satisfaction, patient anxiety, and patient-doctor communication when a GP surgery moves from old premises to enhanced purpose-built accommodation. DESIGN OF STUDY: Questionnaire surveys, interviews, and focus groups pre- and post move. SETTING: An urban general practice in Bristol. METHOD: Patient questionnaires assessed anxiety (Spielberger State-Trait Anxiety Inventory; STAI), satisfaction with the environment, and communication during the consultation. Staff questionnaires assessed satisfaction with the environment and job satisfaction. Qualitative methods explored patient and staff views in more depth. RESULTS: A total of 1118 pre-move and 954 post-move patient questionnaires showed significant increases in satisfaction scores for reception/waiting areas (mean 6.46, 95% confidence interval [CI]=5.97 to 6.95) and consulting rooms (mean 3.80, 95% CI=3.44 to 4.15) in the new premises. Patients' satisfaction with patient-doctor communication also increased (mean 0.88, 95% CI=0.30 to 1.46) and anxiety scores were significantly reduced before and after the consultation in the new premises compared with the old (STAI mean difference before consultation 0.72, 95% CI=0.37 to 1.08; mean after consultation 0.37, 95% CI=0.03 to 0.72). Patients highlighted the increased space and light, more modern appearance, greater comfort, and novel works of art in the new surgery. Staff workplace satisfaction increased significantly after moving and remained higher than in the old building. CONCLUSION: This large-scale study examining the effects of a UK primary care environment on patients and staff shows that an enhanced environment is associated with improvements in patients' perception of patient-doctor communication, reduction in anxiety, and increases in patient and staff satisfaction.     

Role of computational fluid mechanics in the analysis of prosthetic heart valve flow

The paper aims to present the strengths and weaknesses of computational fluid mechanics (CFM) compared with existing in vitro haemodynamic techniques such as LDA, hot-wire anemometry and static pressure measurement, and to discuss the application of CFM to the analysis of prosthetic heart valve flow. It presents a brief summary of existing methods used in analysing in vitro heart valve flow (along with CFM), the special problems inherent in each method and the quantities each is capable of giving. The analysis then goes on to present examples of information yielded by CFM. It also contains a brief discussion of the data requirements for the analysis of heart valve performance and the clinical relevance of fluid dynamic occurrences. The conclusion drawn is that CFM has a major role to play in the analysis of prosthetic heart valve flow and design because of the improved availability of data afforded and the increased correlation between CFM and clinical flow regimes, due to the ability to consider realistic models of blood.     

Designs for Instruction, Designs for Change: Distributing Knowledge of Evidence-Based Practice

We comment on the target article by Weingardt (this issue), which discusses recent advances in instructional design and technology (IDT) and their implications for dissemination of evidence-based practices. These arguments are extended to the topic of psychological intervention design, and possibilities for new intervention structures are briefly explored. Finally, comments are offered on maintaining a careful balance between technological and social processes in the effort to promote the dissemination of innovative and evidence-based psychological procedures.     

Publication Guidelines for Heart Rate Studies in Man

Publication guidelines are provided for the collection, quantification, and analysis of heart rate data.     

A LISREL 8 model with constrained parameters for twin and adoptive families

Constrained optimization recently has been implemented in the LISREL software package, allowing formulation of parent-offspring transmission models in a simple and efficient manner. A reverse path model of parental transmission is described within the LISREL framework for application to twin and/or adoptive family data. The model incorporates genetic and environmental parameter constraints arising from assortative mating and cultural transmission. An illustration of the LISREL model is given using measures obtained from twins and parents involving fear of social criticism.     

利用CT扫描及CAD技术建立腰椎活动节段的有限元模型

目的 :探讨腰椎活动节段有限元模型的建立。方法 :选取一正常自愿者L4～L5节段为研究对象 ,通过CT扫描、图像数字化处理及计算机辅助设计建立了腰椎活动节段的有限元模型 ,通过Super SAP有限元分析软件包对模型进行了应力分析。结果 :建立了L4～L5活动节段的有限元模型 ,并分析了生理载荷下腰椎活动节段不同组成部分的应力分布。结论 :为腰椎活动节段有限元模型的建立提供了一种简便、准确的方法 ,为分析和研究该模型在各种情况下的生物力学表现创造了条件     

Perceptual Speed and IQ Are Associated Through Common Genetic Factors

Individual differences in inspection time explain about 20% of IQ test variance. To determine whether the association between inspection time and IQ is mediated by common genes or by a common environmental factor, inspection time and IQ were assessed in an extended twin design. Data from 688 participants from 271 families were collected as part of a large ongoing project on the genetics of adult brain function and cognition. The sample consisted of a young adult cohort (mean age 26.2 years) and an older adult cohort (mean age 50.4 years). IQ was assessed with the Dutch version of the WAIS-3R. Inspection time was measured in the so-called -paradigm, in which a subject is asked to decide which leg of the -figure is longest at varying display times of the -figure. The number of correct inspections per second (i.e., the reciprocal of inspection time) was used to index perceptual speed. For Verbal IQ and Performance IQ, heritabilities were 85% and 69%, respectively. For perceptual speed, 46% of the total variance was explained by genetic variance. No differences in heritability estimates across age cohorts or sexes were found. Across the whole sample, a significant phenotypic correlation was found between perceptual speed and Verbal IQ (0.19) and between perceptual speed and Performance IQ (0.27). These correlations were entirely due to a common genetic factor that accounted for 10% of the genetic variance in verbal IQ and for 22% of the genetic variance in performance IQ. This factor is hypothesized to reflect the influence of genetic factors that determine axonal myelination in the central nervous system.     

Long-term mortality study of oil refinery workers: V. Comparison of workers hired before, during, and after World War II (1940-1945) with a discussion of the impact of study designs on cohort results

The mortality experience of a large refinery cohort (1937-1978) was examined by dividing it into three subcohorts according to hire dates: those hired before 1940, those hired during the period 1940-1945, and those hired after 1945. These three periods are approximately equivalent to before, during, and after World War II and span a total hiring period of more than 75 years. The results showed that a substantial portion of the cohort (3,330 or 27%) had been recruited during 1940-1945, and they contributed 980 or 28% of the total deaths. However, their mortality experience was quite different from the rest. A series of significant increases were seen among the external causes for accidents, suicide, and homicide. In terms of overall mortality and in contrast to the rest of the cohort, no "healthy worker effect" was seen (SMR = 1.00). They also showed increases in several types of cancer including cancers of the pancreas and prostate and leukemia. These unusual experiences cannot be explained either on the basis of their war-related deaths or on their period of employment (one-half were terminated within 1 year from date of hire), and data is insufficient to separate the role of hiring practices or their socioeconomic status. However, their life-styles were probably quite different judged from the fact that alcoholism-related deaths were increased as much as fivefold. Almost two-thirds of the total deaths occurred among 4,080 workers in the before 1940 subcohort. Further, the 5,117 workers of the after-1945 subcohort contributed only 5% of the total deaths. Thus, the results of the original refinery cohort (1937-1978) primarily reflect the experience of those employees hired before 1940. Given the same cohort method (historical prospective), cohort results vary widely according to different study designs, and this has implications for "generalizable" risk assessment or risk projections. A prospective study of new hires with 30 years of follow-up is rather inefficient because it would yield only a small number of deaths, with a strong healthy worker effect. The same is true for studies based on active workers with a short period of follow-up. Studies based on time of hire, however, provide a means for controlling time-related occupational exposures.