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Pain is often undetected in older people with dementia partly due to a deterioration of cognitive functioning. Observational scales enable the measurement of pain by registering physiological changes, facial expressions, or behaviors. Previous research showed that the Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC) is especially useful to measure pain in older people with dementia. PACSLAC was recently translated into Dutch and refined, thus forming PACSLAC-D. The current study uses a different approach to refining PACSLAC by (1) selecting items on the basis of ratings of nursing personnel and (2) applying confirmatory robust maximum likelihood factor analysis and (3) item response theory to investigate the psychometric properties of the selected items. Of the items that nursing personnel frequently registered, 18 valid and reliable items remained. Fourteen of these 18 items were also selected for PACSLAC-D, which confirms that these items are valid and reliable indicators of pain in older people with dementia. Confirmatory factor analysis showed that a 3-factor model is most adequate to describe the data. Differential item functioning analyses indicated that 2 items were biased. Ultimately, a refined version of PACSLAC was created that nursing personnel with different educational backgrounds might use to assess pain in older people with varying degrees of dementia. PERSPECTIVE: This article describes the selection of items of PACSLAC on the basis of ratings of nursing personnel. By comparing this item selection with the items selected for PACSLAC-D, one can confirm that certain items are sound indicators of pain, whereas others need some attention (eg, through the training of raters). [ABSTRACT FROM AUTHOR]

Introduction: Over the last decade, the number of patients receiving home mechanical ventilation (HMV) has increased significantly, which has led to a limited availability of specialist centres, not least due to the scarcity of healthcare professionals. This situation was exacerbated by the COVID-19 pandemic. It is therefore assumed that the repurposing of resources has led to an aggravated change in the healthcare structure in HMV., Methods: This descriptive observational study analysed the Operation and Procedure Classification Codes for patients receiving HMV from 2008 to 2022. The data was provided by the Federal Statistical Office of Germany. Data were additionally analysed with respect to geographical distribution and ventilation status., Results: 737,770 data sets were analysed (mean age 2020 66.5 years). There was a steady increase in HMV initiations (+6%) and controls (+9%) per year before the pandemic (2008-2019). Patient admissions during the pandemic revealed a 28% decrease, with the largest decrease in invasive ventilation (IV) follow-up visits (2019: 3,053; 2020: 2,199; -39%), while the number of IV initiations remained stable. There was a 19% decrease in the number of non-invasive ventilation initiations in 2020 (16,919 vs. 14,227) and a 32% decrease regarding follow-ups (45,812 vs. 34,813) in comparison to 2019., Conclusion: The pandemic has led to a significant decline of inpatient admissions for patients receiving HMV. This decline was most pronounced in the first year of the pandemic. Control visits in particular did not reach the pre-pandemic level. This is an indication of the ongoing change in the healthcare landscape as a result of the pandemic., (S. Karger AG, Basel.)

The treatment of patients with COPD and chronic hypercapnic respiratory failure using noninvasive ventilation (NIV) is well established. A "deventilation syndrome" (DVS) has been described as acute dyspnea after cessation of NIV therapy. A systematic scoping review reporting according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) searching Embase was conducted in September 2021. A final manual search followed in February 2023. Literature synthesis was blinded using Rayyan by three different reviewers. A total of 2,009 studies were screened. Five studies met the eligibility criteria. Four articles presented original data. Three articles examined potential treatment options. Three studies were prospective; none were randomized. A total of 122 patients were included. DVS was defined differently in all studies. Seventy-four patients were identified to suffer from DVS (48 controls). Patients were evaluated by blood gas analysis, transcutaneous TcCO2 measurement, spirometry, whole-body plethysmography, respiratory muscle assessments, diaphragmatic electromyography, ultrasound, 6-min walk test, polysomnography, and questionnaires. Treatment approaches studied were minimization of "patient-ventilator asynchrony" (PVA) and use of pursed- lip breathing ventilation. Pathophysiological mechanisms discussed were PVA, high inspiratory positive airway pressure, hyperinflation, respiratory muscle impairment, and increased respiratory rates. Compared with controls, patients with DVS appeared to suffer from more severe airway obstruction, hyperinflation, and PaCO2 retention; worse exercise test scores; and poorer quality of life. The available evidence does not allow for definite conclusions about pathophysiological mechanisms, ethology, or therapeutic options. Future studies should focus on a consistent definition and possible pathomechanisms., (© 2024 S. Karger AG, Basel.)

Scientifically validated web-based training videos for proper inhalation technique were increasingly used by an international audience during the pandemic. Translations into additional languages would support a larger patient population. https://bit.ly/3lYQwsD., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2023.)

Background/objective: To assess whether and how the use of scientifically established Web-based training videos for teaching correct inhalation technique in patients with chronic airway diseases has become accepted among the wider population., Methods: The viewing trends of 141 freely available YouTube videos (full playing time, 01:31-04:37 min:s) provided by the German Respiratory League, covering a broad range of internationally prescribed devices, were analyzed over a 10-year period. Specific emphasis was placed both on German and international videos., Results: The total number of views was 3,350,678. Non-German videos (English, Russian, Turkish, Greek, Arabic, Farsi, and Slovakian) accounted for 23.2% of the views. The number of views steadily increased between 2011 and 2020 with a mean annual increase of 54.0% (range 24.5/119.9%) compared to the respective previous year. By 2020, the incidence of views per 100,000 German inhabitants was 725 for German videos only and 1,030 for all videos. In terms of the annual trend, there were two peak viewing periods, namely in spring and late fall, while the lowest amount of views occurred in summer., Conclusion: This study highlights the rising impact of Web-based training videos used for teaching the correct use of inhalation devices, with a steady increase in the number of annual views and a clear seasonal peaking of views in spring and late fall., (© 2022 S. Karger AG, Basel.)

Gene editing following designer nuclease cleavage in the presence of a DNA donor template can revert mutations in disease-causing genes. For optimal benefit, reversion of the point mutation in HBB leading to sickle cell disease (SCD) would permit precise homology-directed repair (HDR) while concurrently limiting on-target non-homologous end joining (NHEJ)-based HBB disruption. In this study, we directly compared the relative efficiency of co-delivery of a novel CRISPR/Cas9 ribonucleoprotein targeting HBB in association with recombinant adeno-associated virus 6 (rAAV6) versus single-stranded oligodeoxynucleotides (ssODNs) to introduce the sickle mutation (GTC or GTG; encoding E6V) or a silent change (GAA; encoding E6optE) in human CD34 + mobilized peripheral blood stem cells (mPBSCs) derived from healthy donors. In vitro, rAAV6 outperformed ssODN donor template delivery and mediated greater HDR correction, leading to both higher HDR rates and a higher HDR:NHEJ ratio. In contrast, at 12-14 weeks post-transplant into recipient, immunodeficient, NOD, B6, SCID Il2rγ -/- Kit(W41/W41) (NBSGW) mice, a ∼6-fold higher proportion of ssODN-modified cells persisted in vivo compared to recipients of rAAV6-modified mPBSCs. Together, our findings highlight that methodology for donor template delivery markedly impacts long-term persistence of HBB gene-modified mPBSCs, and they suggest that the ssODN platform is likely to be most amenable to direct clinical translation., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Typically, clusters and individuals in cluster randomized trials are allocated across treatment conditions in a balanced fashion. This is optimal under homogeneous costs and outcome variances. However, both the costs and the variances may be heterogeneous. Then, an unbalanced allocation is more efficient but impractical as the outcome variance is unknown in the design stage of a study. A practical alternative to the balanced design could be a design optimal for known and possibly heterogeneous costs and homogeneous variances. However, when costs and variances are heterogeneous, both designs suffer from loss of efficiency, compared with the optimal design. Focusing on cluster randomized trials with a 2 × 2 design, the relative efficiency of the balanced design and of the design optimal for heterogeneous costs and homogeneous variances is evaluated, relative to the optimal design. We consider two heterogeneous scenarios (two treatment arms with small, and two with large, costs or variances, or one small, two intermediate, and one large costs or variances) at each design level (cluster, individual, and both). Within these scenarios, we compute the relative efficiency of the two designs as a function of the extents of heterogeneity of the costs and variances, and the congruence (the cheapest treatment has the smallest variance) and incongruence (the cheapest treatment has the largest variance) between costs and variances. We find that the design optimal for heterogeneous costs and homogeneous variances is generally more efficient than the balanced design and we illustrate this theory on a trial that examines methods to reduce radiological referrals from general practices. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

In medicine and health sciences, binary outcomes are often measured repeatedly to study their change over time. A problem for such studies is that designs with an optimal efficiency for some parameter values may not be efficient for other values. To handle this problem, we propose Bayesian designs which formally account for the uncertainty in the parameter values for a mixed logistic model which allows quadratic changes over time. Bayesian D-optimal allocations of time points are computed for different priors, costs, covariance structures and values of the autocorrelation. Our results show that the optimal number of time points increases with the subject-to-measurement cost ratio, and that neither the optimal number of time points nor the optimal allocations of time points appear to depend strongly on the prior, the covariance structure or on the size of the autocorrelation. It also appears that for subject-to-measurement cost ratios up to five, four equidistant time points, and for larger cost ratios, five or six equidistant time points are highly efficient. Our results are compared with the actual design of a respiratory infection study in Indonesia and it is shown that, selection of a Bayesian optimal design will increase efficiency, especially for small cost ratios., (© The Author(s) 2013.)

Cluster randomized and multicenter trials sometimes combine two treatments A and B in a factorial design, with conditions such as A, B, A and B, or none. This results in a two-way nested design. The usual issue of sample size and power now arises for various clinically relevant contrast hypotheses. Assuming a fixed total sample size at each level (number of clusters or centers, number of patients), we derive the optimal proportion of the total sample to be allocated to each treatment arm. We consider treatment assignment first at the highest level (cluster randomized trial) and then at the lowest level (multicenter trial). We derive the optimal allocation ratio for various sets of clinically relevant hypotheses. We then evaluate the efficiency of each allocation and show that the popular balanced design is optimal or highly efficient for a range of research questions except for contrasting one treatment arm with all other treatment arms. We finally present simple equations for the total sample size needed to test each effect of interest in a balanced design, as a function of effect size, power and type I error α. All results are illustrated on a cluster-randomized trial on smoking prevention in primary schools and on a multicenter trial on lifestyle improvement in general practices., (© The Author(s) 2013.)

Sample size calculation for cluster randomized trials (CRTs) with a [Formula: see text] factorial design is complicated due to the combination of nesting (of individuals within clusters) with crossing (of two treatments). Typically, clusters and individuals are allocated across treatment conditions in a balanced fashion, which is optimal under homogeneity of variance. However, the variance is likely to be heterogeneous if there is a treatment effect. An unbalanced allocation is then more efficient, but impractical because the optimal allocation depends on the unknown variances. Focusing on CRTs with a [Formula: see text] design, this paper addresses two questions: How much efficiency is lost by having a balanced design when the outcome variance is heterogeneous? How large must the sample size be for a balanced allocation to have sufficient power under heterogeneity of variance? We consider different scenarios of heterogeneous variance. Within each scenario, we determine the relative efficiency of a balanced design, as a function of the level (cluster, individual, both) and amount of heterogeneity of the variance. We then provide a simple correction of the sample size for the loss of power due to heterogeneity of variance when a balanced allocation is used. The theory is illustrated with an example of a published 2 x2 CRT., (© The Author(s) 2015.)

This paper deals with the optimal sample sizes for a multicentre trial in which the cost-effectiveness of two treatments in terms of net monetary benefit is studied. A bivariate random-effects model, with the treatment-by-centre interaction effect being random and the main effect of centres fixed or random, is assumed to describe both costs and effects. The optimal sample sizes concern the number of centres and the number of individuals per centre in each of the treatment conditions. These numbers maximize the efficiency or power for given research costs or minimize the research costs at a desired level of efficiency or power. Information on model parameters and sampling costs are required to calculate these optimal sample sizes. In case of limited information on relevant model parameters, sample size formulas are derived for so-called maximin sample sizes which guarantee a power level at the lowest study costs. Four different maximin sample sizes are derived based on the signs of the lower bounds of two model parameters, with one case being worst compared to others. We numerically evaluate the efficiency of the worst case instead of using others. Finally, an expression is derived for calculating optimal and maximin sample sizes that yield sufficient power to test the cost-effectiveness of two treatments., (© The Author(s) 2015.)

In this paper, the optimal sample sizes at the cluster and person levels for each of two treatment arms are obtained for cluster randomized trials where the cost-effectiveness of treatments on a continuous scale is studied. The optimal sample sizes maximize the efficiency or power for a given budget or minimize the budget for a given efficiency or power. Optimal sample sizes require information on the intra-cluster correlations (ICCs) for effects and costs, the correlations between costs and effects at individual and cluster levels, the ratio of the variance of effects translated into costs to the variance of the costs (the variance ratio), sampling and measuring costs, and the budget. When planning, a study information on the model parameters usually is not available. To overcome this local optimality problem, the current paper also presents maximin sample sizes. The maximin sample sizes turn out to be rather robust against misspecifying the correlation between costs and effects at the cluster and individual levels but may lose much efficiency when misspecifying the variance ratio. The robustness of the maximin sample sizes against misspecifying the ICCs depends on the variance ratio. The maximin sample sizes are robust under misspecification of the ICC for costs for realistic values of the variance ratio greater than one but not robust under misspecification of the ICC for effects. Finally, we show how to calculate optimal or maximin sample sizes that yield sufficient power for a test on the cost-effectiveness of an intervention.

Items pertaining to hearing and hearing aids from the Hearing Aid Rehabilitation Questionnaire were applied to a heterogeneous sample of Dutch patients aged 55 years and more to evaluate their potential use in hearing screening. Subjects aged 55+ were recruited from a large general practitioners practice to participate. Three groups were formed: a group of 63 persons with a hearing aid, a group of 64 without a hearing aid but with sufficient hearing impairment to qualify for hearing aid reimbursement, and a group of 85 non-hearing impaired persons. Factor and reliability analyses revealed a structure with two scales regarding hearing, namely functionality and social hearing and three scales pertaining to hearing aids, namely hearing aid stigma, pressure to be assessed and not wanting a hearing aid. Scale validity was assessed with pure tone averages over the frequencies 1, 2 and 4 kHz and with a visual analogue scale for subjective hearing. The derived scales can be applied reliably in audiological assessment in an adult hearing screen setting to detect experienced hearing problems as well as attitudes related to hearing and hearing aids.

Subject-specific hemodynamic response functions (HRFs) have been recommended to capture variation in the form of the hemodynamic response between subjects (Aguirre et al., [ 1998]: Neuroimage 8:360-369). The purpose of this article is to find optimal designs for estimation of subject-specific parameters for the double gamma HRF. As the double gamma function is a nonlinear function of its parameters, optimal design theory for nonlinear models is employed in this article. The double gamma function is linearized by a Taylor approximation and the maximin criterion is used to handle dependency of the D-optimal design on the expansion point of the Taylor approximation. A realistic range of double gamma HRF parameters is used for the expansion point of the Taylor approximation. Furthermore, a genetic algorithm (GA) (Kao et al., [ 2009]: Neuroimage 44:849-856) is applied to find locally optimal designs for the different expansion points and the maximin design chosen from the locally optimal designs is compared to maximin designs obtained by m-sequences, blocked designs, designs with constant interstimulus interval (ISI) and random event-related designs. The maximin design obtained by the GA is most efficient. Random event-related designs chosen from several generated designs and m-sequences have a high efficiency, while blocked designs and designs with a constant ISI have a low efficiency compared to the maximin GA design., (Copyright © 2011 Wiley-Liss, Inc.)

Background: In this study, the effect of guidance on students' performance was investigated. This effect was hypothesized to be manifested through a reduction of cognitive load and enhancement of self-explanations., Aim: The goal of this study was to investigate the effect of guiding questions on students' understanding of statistics., Sample and Method: In an experimental setting, two randomly selected groups of students (N= 49) answered achievement and transfer questions on statistics as a measure of performance. Students in the intervention condition were given guiding questions to direct their way of reasoning before they answered the achievement questions. The students in the control condition were asked to write down their way of thinking before they answered the same achievement questions. In this way, both groups were stimulated to self-explain, but only the reasoning processes of the students in the intervention condition were guided., Results and Conclusion: It was found that students in the intervention condition performed significantly better on achievement and transfer questions and that this effect of guidance was mediated by self-explanations. Attitude towards statistics was positively related to performance., (©2011 The British Psychological Society.)

Objective: Researchers in Health Sciences and Medicine often use cohort designs to study treatment effects and changes of outcome variables over time period. The costs of these studies can be reduced by choosing an optimal number of repeated measurements over time and by selecting cohorts of subjects more efficiently with optimal design procedures. The objective of this study is to provide evidence on how to design large-scale cohort studies with budget constraints as efficiently as possible., Study Design and Setting: A linear cost function for repeated measurements is proposed, and this cost function is used in the optimization procedure. For a given budget/cost, different designs for linear mixed-effects models are compared by means of their efficiency., Results: We found that adding more repeated measures is only beneficiary if the costs of selecting and measuring a new subject are much higher than the costs of obtaining an additional measurement for an already recruited subject. However, this gain in efficiency and power is not very large., Conclusion: Adding more cohorts or repeated measurements do not necessarily lead to a gain in efficiency of the estimated model parameters. A general guideline for the optimal choice of a cohort design in practice is required and we offer this guideline., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Education is aimed at students reaching conceptual understanding of the subject matter, because this leads to better performance and application of knowledge. Conceptual understanding depends on coherent and error-free knowledge structures. The construction of such knowledge structures can only be accomplished through active learning and when new knowledge can be integrated into prior knowledge., Aims: The intervention in this study was directed at both the activation of students as well as the integration of knowledge., Sample: Undergraduate university students from an introductory statistics course, in an authentic problem-based learning (PBL) environment, were randomly assigned to conditions and measurement time points., Method: In the PBL tutorial meetings, half of the tutors guided the discussions of the students in a traditional way. The other half guided the discussions more actively by asking directive and activating questions. To gauge conceptual understanding, the students answered open-ended questions asking them to explain and relate important statistical concepts., Results and Conclusions: Results of the quantitative analysis show that providing directive tutor guidance improved understanding. Qualitative data of students' misconceptions seem to support this finding. Long-term retention of the subject matter seemed to be inadequate., (©2010 The British Psychological Society.)

The design of a multi-subject fMRI experiment needs specification of the number of subjects and scanning time per subject. For example, for a blocked design with conditions A or B, fixed block length and block order ABN, where N denotes a null block, the optimal number of cycles of ABN and the optimal number of subjects have to be determined. This paper presents a method to determine the optimal number of subjects and optimal number of cycles for a blocked design based on the A-optimality criterion and a linear cost function by which the number of cycles and the number of subjects are restricted. Estimation of individual stimulus effects and estimation of contrasts between stimulus effects are both considered. The mixed-effects model is applied and analytical results for the A-optimal number of subjects and A-optimal number of cycles are obtained under the assumption of uncorrelated errors. For correlated errors with a first-order autoregressive (AR1) error structure, numerical results are presented. Our results show how the optimal number of cycles and subjects depend on the within- to between-subject variance ratio. Our method is a new approach to determine the optimal scanning time and optimal number of subjects for a multi-subject fMRI experiment. In contrast to previous results based on power analyses, the optimal number of cycles and subjects can be described analytically and costs are considered., (Copyright © 2011 Elsevier Inc. All rights reserved.)

ODMixed is a computer program to obtain optimal designs for linear mixed models of longitudinal studies. These designs account for heterogeneous correlated errors and for data with dropout. Designs are compared by using relative efficiencies, e.g., between a D-optimal design for homogeneous data and another for heterogeneous data or between a D-optimal design for complete data against another that optimizes designs when data is missing at random. Two examples are worked out to illustrate how researchers could use this computer program to profit of optimal design theory at the planning stage of longitudinal studies., (2011 Elsevier Ireland Ltd. All rights reserved.)

In this paper we apply the genetic algorithm developed by Kao et al. (2009) to find designs which are robust against misspecification of the error autocorrelation. Two common optimality criteria, the A-optimality criterion and the D-optimality criterion, based upon a general linear model are employed to obtain locally optimal designs for a given value of the autocorrelation. The maximin criterion is then used to obtain designs which are robust against misspecification of the autocorrelation. Furthermore, robustness depending on the choice of optimality criterion is evaluated. We show analytically and empirically that the A- and D-optimality criterion will result in different optimal designs, e.g. with different stimulus frequencies. Optimal stimulus frequency for the A-optimality criterion has been derived by Liu et al. (2004) whereas we derive here the optimal stimulus frequency for the D-optimality criterion. Conclusions about the robustness of an optimal design against misspecification of model parameters and choice of optimality criterion are drawn based upon our results., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Objectives: To investigate the effects of an educational intervention on the use of physical restraints with psychogeriatric nursing home residents., Design: Cluster-randomized trial., Setting: Fifteen psychogeriatric nursing home wards in the Netherlands., Participants: In total, 432 psychogeriatric nursing home residents from 15 psychogeriatric nursing home wards in seven nursing homes were selected for participation; 404 consented, and 371 of these were available at baseline. Two hundred forty-one from 14 wards had complete data and were included in the data analyses., Intervention: The nursing home wards were assigned at random to educational intervention or control status. The educational intervention consisted of an educational program for nursing staff combined with consultation with a nurse specialist (registered nurse (RN) level)., Measurements: Data were collected at baseline and 1, 4, and 8 months postintervention. At each measurement, the use of physical restraints was measured using observations of blinded, trained observers on four separate occasions over a 24-hour period. Other resident characteristics, such as cognitive status, were determined using the Minimum Data Set., Results: Logistic and linear regression analyses showed no treatment effect on restraint status, restraint intensity, or multiple restraint use in any of the three postintervention measurements. Furthermore, only small changes occurred in the types of restraints used with residents in the experimental group., Conclusion: An educational program for nursing staff combined with consultation with a nurse specialist (RN level) had no effect on the use of physical restraints with psychogeriatric nursing home residents. In addition to restraint education and consultation, new measures to reduce the use of physical restraints with psychogeriatric nursing home residents should be developed.

Many large scale longitudinal cohort studies have been carried out or are ongoing in different fields of science. Such studies need a careful planning to obtain the desired quality of results with the available resources. In the past, a number of researches have been performed on optimal designs for longitudinal studies. However, there was no computer program yet available to help researchers to plan their longitudinal cohort design in an optimal way. A new interactive computer program for the optimization of designs of longitudinal cohort studies is therefore presented. The computer program helps users to identify the optimal cohort design with an optimal number of repeated measurements per subject and an optimal allocations of time points within a given study period. Further, users can compute the loss in relative efficiencies of any other alternative design compared to the optimal one. The computer program is described and illustrated using a practical example.

Background: Although there is an urgent need for restraint-free care, the number of randomized clinical trials on preventing or reducing physical restraints has been limited., Objectives: To investigate the effectiveness of an educational intervention to prevent the use of physical restraints on residents newly admitted to psycho-geriatric nursing home wards., Design: Cluster-randomized trial., Setting: Fourteen Dutch psycho-geriatric nursing home wards., Participants: 138 residents admitted to 14 psycho-geriatric nursing home wards after baseline measurement of the trial were selected, out of which 33 residents died or informed consent had not been obtained. A total of 105 residents were included in the analyses., Methods: The nursing home wards were randomly assigned to either educational intervention or control status. The educational intervention consisted of an educational programme for nurses combined with a nurse specialist's consultation. The data were collected at 1, 4 and 8 months post-intervention. The use of physical restraints was measured by blinded, trained observers on four separate occasions over a 24-h period. The Minimum Data Set was used to determine residents' characteristics, such as their cognitive status., Results: During the study period, no statistically significant differences between the experimental group and the control group regarding restraint status, restraint intensity, multiple restraints and types of restraints were found. One month post-intervention, 38% of the residents newly admitted to the experimental wards were restrained. Bilateral bedrails were the most frequently used restraints at Post-test 1 (24%), Post-test 2 (23%) and Post-test 3 (28%), followed by the use of infrared systems at Post-tests 2 and 3., Conclusion: An educational programme combined with the consultation of a nurse specialist does not prevent the use of physical restraints on residents newly admitted to psycho-geriatric nursing home wards. Although other studies have shown promising results with the effectiveness of these types of intervention on restraint reduction, the development of additional interventions to prevent restraint usage is recommended.

Comparative studies between the one- and two-color microarrays provide supportive evidence for similarities of results on differential gene expression. So far, no design comparisons between the two platforms have been undertaken. With the objective of comparing optimal designs of one- and two-color microarrays in their statistical efficiencies, techniques of design optimization were applied within a mixed model framework. A- and D-optimal designs for the one- and two-color platforms were sought for a 3 x 3 factorial experiment. The results suggest that the choice of the platform will not affect the "subjects to groups" allocation, being concordant in the two designs. However, under financial constraints, the two-color arrays are expected to have a slight upper hand in terms of efficiency of model parameters estimates, once the price of arrays is more expensive than that of subjects. This statement is especially valid for microarray studies envisaging class comparisons.

Background: Studies on pain and pain prevalence in older people with dementia are limited compared to those on cognitively intact older people. Pain prevalence rates in older people with dementia are estimated to be between 28% and 83%., Aims: This study aimed to explore pain prevalence in nursing home residents with dementia using observational scale PACSLAC-D, and to identify the association between pain prevalence and (dementia) demographic parameters such as cognitive status, gender, analgesic use and co-morbidity., Methods: Using an observational study design, 117 residents were observed and assessed for pain during personal morning care. Prevalence data were calculated and regression analyses applied., Results: This study showed that almost half of the participants (47%) experienced pain to some extent. However, overall pain intensity scores were relatively mild. Among the independent variables, co-morbidities, analgesic use and the adjusted interaction term 'co-morbidities+analgesic use' had the strongest associations with pain and were thus shown to be valid significant predictors., Conclusion: With its relatively new approach of measuring pain using an observational scale, this study confirms the expectation gleaned from other studies on less impaired older populations: namely, that pain prevalence in older residents with dementia in Dutch nursing homes is high.

Cluster randomized and multicentre trials evaluate the effect of a treatment on persons nested within clusters, for instance patients within clinics or pupils within schools. Although equal sample sizes per cluster are generally optimal for parameter estimation, they are rarely feasible. This paper addresses the relative efficiency (RE) of unequal versus equal cluster sizes for estimating variance components in cluster randomized trials and in multicentre trials with person randomization within centres, assuming a quantitative outcome. Starting from maximum likelihood estimation, the RE is investigated numerically for a range of cluster size distributions. An approximate formula is presented for computing the RE as a function of the mean and variance of cluster sizes and the intraclass correlation. The accuracy of this approximation is checked and found to be good. It is concluded that the loss of efficiency for variance component estimation due to variation of cluster sizes rarely exceeds 20% and can be compensated by sampling 25% more clusters.

Dropout is often encountered in longitudinal data. Optimal designs will usually not remain optimal in the presence of dropout. In this paper, we study D-optimal designs for linear mixed models where dropout is encountered. Moreover, we estimate the efficiency loss in cases where a D-optimal design for complete data is chosen instead of that for data with dropout. Two types of monotonically decreasing response probability functions are investigated to describe dropout. Our results show that the location of D-optimal design points for the dropout case will shift with respect to that for the complete and uncorrelated data case. Owing to this shift, the information collected at the D-optimal design points for the complete data case does not correspond to the smallest variance. We show that the size of the displacement of the time points depends on the linear mixed model and that the efficiency loss is moderate.

The D-optimality criterion is used to construct optimal designs for different numbers of independent cohorts, which constitute a number of repeated measurements per subject over time. A cost function for longitudinal data is proposed, and the optimality criterion is optimized taking into account the cost of the study. First, an optimal number of design points for a given number of cohorts and cost was identified. Then, an optimal number of cohorts is identified by comparing the relative efficiencies (REs). A numerical study shows that for models describing the trend of a continuous outcome over time by polynomials, the most efficient number of repeated measurements is equal to the sum of the total number of cohorts and the degree of the polynomial in the model. REs of a purely longitudinal cohort design with only one cohort, and mixed longitudinal and cross-sectional cohort designs with more cohorts are compared. The results show that a purely longitudinal cohort design with only one cohort of subjects measured at the optimal time points is the most efficient design. The findings in this paper show that one can obtain a highly efficient design for parameter estimation with only a few repeated measurements. The results of this study will reduce the cost of data collection and ease the logistical burdens in cohort studies.

The effect of adding intermediate measures on the efficiency of treatment effect estimation is considered for a second-order polynomial treatment effect, equidistant time-points, different covariance structures and two optimality criteria, assuming either a fixed sample size or a fixed budget. The benefit of adding intermediate measures (at the expense of subjects) depends strongly on the assumed covariance structure and is hardly affected by the two used optimality criteria (Ds or c). For a fixed sample size, the increase in efficiency by adding intermediate measures is large for a compound symmetric structure and small for a first-order auto-regressive structure. For a first-order auto-regressive structure with measurement error, the results depend on the covariance parameter values. For a fixed budget and linear cost function, the design with only three measures per subject is often highly efficient. If the structure resembles compound symmetry and the cost per subject is eight or more times larger than the cost per repeated measure, however, more than three measures are required to obtain highly efficient treatment effect estimators. If the covariance structure is unknown, the optimal design based on a first-order auto-regressive structure with measurement error is preferable in terms of robustness against misspecification of the covariance structure. Given a design with three repeated measures and a second-order polynomial treatment effect, equidistant time-points are either optimal (Ds-) or highly efficient (c-optimality criterion). The results are illustrated by a practical example.

Repeated measures (RM) and ANCOVA models are compared with respect to treatment effect estimation in randomized clinical trials with a pre- and a post-treatment measure. The covariance matrices of repeated measures are assumed to be I) homogeneous or II) heterogeneous across groups. In situation I, ANCOVA is preferred to RM, because the estimated variance of the treatment effect estimator is unbiased for ANCOVA and biased downwards for RM. In situation II, RM with Kenward and Roger's adjustment is preferred to ANCOVA, because the ANCOVA variance estimator does not correct for unknown pre-treatment expectation. The results are illustrated with an example.

Background: Aging is known to be associated with a high prevalence (up to 80%) of persistent pain among residents of nursing homes. However, even with high pain prevalence rates, nursing home residents are at risk for undertreatment. Knowledge deficits and beliefs among nurses influence staff behaviour in pain assessment and management., Objectives: To develop a psychometrically sound questionnaire and to gather information about knowledge and beliefs of nursing staff regarding various aspects of pain in elderly patients with dementia. In addition, the differences among several categories of nurses (based on educational level and work experience) with respect to beliefs about pain were investigated., Methods: Participants were 123 staff members of psychogeriatric wards in two nursing homes in the Netherlands (mean of 11.4 years of experience). Their results were compared with those of two groups of nurses, one consisting of 25 registered nurse PhD students in nursing science and the other consisting of 20 trainee pain nurse specialists., Results: The main findings indicate that nursing home staff respondents showed knowledge deficits about several aspects of pain, even though they were satisfied about the way pain was assessed and treated at their wards. Specific knowledge deficits were found regarding pain treatment and medication in elderly nursing home residents. Staff educational level seemed to influence their beliefs and knowledge about pain in elderly nursing home patients.

This paper reports a study of the relationship between the use of physical restraints with psycho-geriatric nursing home residents and the characteristics of organisations and residents. It is hypothesised that impairment in residents and organisational characteristics, such as a high workload of nursing staff and a low full-time equivalent (FTE) ratio on the wards, are associated with increased restraint use. In a cross-sectional study involving 15 Dutch psycho-geriatric nursing home wards, 432 residents were selected for participation, of which 371 actually participated. Restraint status was measured using observations. Other resident characteristics, such as cognitive status, were determined using the Minimum Data Set (MDS). Job characteristics, such as workload, were determined by different self-reported measures. Characteristics of the wards, such as the FTE ratio, were derived from the registration system of the wards. Physical restraints were used with 56% of the psycho-geriatric nursing home residents. Bivariate analysis showed that job and ward characteristics were not associated with restraint use. Bivariate and multilevel analysis showed that residents' characteristics, such as mobility and cognitive status were significantly associated with restraint use. Furthermore, multilevel analysis showed that higher job autonomy experienced by nursing staff and a higher FTE ratio on the wards were also associated with increased restraint use. In conclusion, job and ward characteristics were not as strongly associated as residents' characteristics with restraint use. Impairments in residents, such as immobility, were strongly related to the use of restraints. Therefore, education and support of nursing staff in caring for psycho-geriatric nursing home residents with poor mobility is recommended to reduce the use of physical restraints in nursing homes.

Cluster randomized and multicentre trials evaluate the effect of a treatment on persons nested within clusters, for instance, patients within clinics or pupils within schools. Optimal sample sizes at the cluster (centre) and person level have been derived under the restrictive assumption of equal sample sizes per cluster. This paper addresses the relative efficiency of unequal versus equal cluster sizes in case of cluster randomization and person randomization within clusters. Starting from maximum likelihood parameter estimation, the relative efficiency is investigated numerically for a range of cluster size distributions. An approximate formula is presented for computing the relative efficiency as a function of the mean and variance of cluster size and the intraclass correlation, which can be used for adjusting the sample size. The accuracy of this formula is checked against the numerical results and found to be quite good. It is concluded that the loss of efficiency due to variation of cluster sizes rarely exceeds 10 per cent and can be compensated by sampling 11 per cent more clusters., ((c) 2006 John Wiley & Sons, Ltd.)

Aim: This paper is a description of the process of item reduction as part of the construction of the Pain Assessment Checklist for Seniors with Limited Ability to Communicate to assess pain in Dutch older nursing home residents with dementia., Background: A valid and reliable clinically useful tool is important for assessing pain in people with dementia. The Pain Assessment Checklist for Seniors with Limited Ability to Communicate has demonstrated good inter- and intra-rater reliability and evidence of construct validity. However, nurses found the scale too long for clinical use., Methods: In an observational study in 2005, nursing home patients (n = 128) were observed while receiving an influenza injection, and a selection of patients were also assessed at a patient-specific pain moment. Internal consistency and Principal Component Analysis were used to refine the scale, to examine the psychometric quality and underlying factor structure of the scale., Results: A brief and manageable version of the Pain Assessment Checklist for Seniors with Limited Ability to Communicate in Dutch was developed, with a three-component solution including 24 items. This version had high levels of internal consistency for the complete scale (Cronbach's alpha range 0.82-0.86) and for all subscales (alpha range 0.72-0.82). Social-emotional items played a significant role in detecting pain., Conclusion: It is important to have a valid, reliable, brief and manageable pain scale available for the nursing home setting. Further research is needed to examine the adequacy and effectiveness of the scale in daily clinical practice.

In view of the need for valid, reliable, and clinically useful scales to assess pain in elderly people with dementia, this study evaluated the psychometric properties of translated versions of the PAINAD, PACSLAC, and DOLOPLUS-2 scales. In an observational study design, two raters simultaneously assessed the nursing home residents (n=128) for pain during influenza vaccination and care situations. The PACSLAC was valued as the most useful scale by nurses. Cronbach's alpha was high (>.80) for the total scale at T2 and T3 and adequate for the 'Facial expression' and 'Social/personality/mood' subscales. IC scores for the 'Activity/body movement' and 'Physiological indicators/eating/sleeping changes/vocal behaviors' subscales were low. It demonstrated good validity and reliability, although the scale should be further refined. This refinement should increase homogeneity. The PAINAD showed good psychometric qualities in terms of reliability, validity, and homogeneity (alpha ranged .69-.74 at T2 and T3) (except for the 'Breathing' item). The PAINAD scale had lower scores for clinical usefulness in this sample. The Dutch version of the DOLOPLUS-2 was considered more difficult to use but showed acceptable psychometric qualities in terms of the issues assessed, except for the 'psychosocial reactions' subscale. IC of the DOLOPLUS were adequate for the total scale (alpha ranged .74-.75) and almost all subscales (alpha ranged .58-.80). Findings of this study provide evidence of validity and reliability of the three pain assessment scales. Now that a pain scale is available, future studies also need to focus on its implementation in nursing practice.

Background: Physical restraints are still frequently used in nursing home residents despite growing evidence for the ineffectiveness and negative consequences of these methods. Therefore, reduction in the use of physical restraints in psycho-geriatric nursing home residents is very important. The aim of this study was to investigate the short-term effects of an educational intervention on the use of physical restraints in psycho-geriatric nursing home residents., Methods: A cluster randomized trial was applied to 5 psycho-geriatric nursing home wards (n = 167 residents with dementia). The wards were assigned at random to either educational intervention (3 wards) or control status (2 wards). The restraint status was observed and residents' characteristics, such as cognitive status, were determined by using the Minimum Data Set (MDS) at baseline and 1 month after intervention., Results: Restraint use did not change significantly over time in the experimental group (55%-56%), compared to a significant increased use (P < 0.05) in the control group (56%-70%). The mean restraint intensity and mean multiple restraint use in residents increased in the control group but no changes were shown in the experimental group. Logistic regression analysis showed that residents in the control group were more likely to experience increased restraint use than residents in the experimental group., Conclusion: An educational programme for nurses combined with consultation with a nurse specialist did not decrease the use of physical restraints in psycho-geriatric nursing home residents in the short term. However, the residents in the control group experienced more restraint use during the study period compared to the residents in the experimental group. Whether the intervention will reduce restraint use in the long term could not be inferred from these results. Further research is necessary to gain insight into the long-term effects of this educational intervention.

Background: Pressure ulcers are a major problem in all areas of health care in the Netherlands. National guidelines for the prevention and treatment of pressure ulcers were originally developed in 1985 and revised in 1991 and 2002. The value of these guidelines can be questioned because it seems they are not in line with the beliefs and practice of the caregivers and only 5% of them are evidence-based., Aims and Objectives: To get a better insight into nurses' current knowledge, beliefs and performed practices relating to massage, a study was designed to assess changes in these three aspects after the publication of the 2002 Dutch national guidelines. The outcome was compared with the situation in 1991, the year in which the previous guidelines were published., Design and Method: A cross-sectional comparative study was designed using written questionnaires. Questions were formulated regarding knowledge and beliefs about prevention methods and the actual use of these methods in the prevention of pressure ulcers. The 2003-survey population consisted of nurses working in the Netherlands and was approached at random via subscriptions to Nursing News (i.e. Verpleegkunde Nieuws), a Dutch professional journal or via affiliations to an institution participating in the 2003 National Prevalence Survey of Pressure Ulcers., Results and Conclusions: Compared with the 1991 findings, the 2003 results show an improvement for the topic of pressure ulcers, but a deterioration regarding dehydration. It is obvious that the knowledge of the current CBO-guidelines on massage is still not widely distributed as it should be. Our overall conclusion is that the differences in responses between 1991 and 2003 are significant and suggest that the nurses were better informed in 2003., Relevance to Clinical Practice: For the improvement of health care in the domain of pressure ulcer preventions, we need more than an accurate implementation of new or existing guidelines. Guidelines should also be based on qualitative, methodological well-designed studies to be evidence-based.

The effect of number of repeated measures on the variance of the generalized least squares (GLS) treatment effect estimator is considered assuming a linearly divergent treatment effect, equidistant time-points and either a fixed number of subjects or a fixed study budget. The optimal combination of group sizes and number of repeated measures is calculated by minimizing this variance subject to a linear cost function. For a fixed number of subjects, the variance of the GLS treatment effect estimator can be decreased by adding intermediate measures per subject. This decrease is relatively large if a) the covariance structure is compound symmetric or b) the structure approaches compound symmetry and the correlation between two repeated measures does not exceed 0.80, or c) the correlation between two repeated measures does not exceed 0.60 if the time-lag goes to zero. In case the sample sizes and number of repeated measures are limited by budget constraints and the covariance structure includes a first-order auto-regression part, two repeated measures per subject yield highly efficient treatment effect estimators. Otherwise, it is more efficient to have more than two repeated measures. If the covariance structure is unknown, the optimal design based on a first-order auto-regressive structure with measurement error is preferable in terms of robustness against misspecification of the covariance structure. The numerical results are illustrated by three examples.

Background: Pain is a common and major problem among nursing home residents. The prevalence of pain in elderly nursing home people is 40-80%, showing that they are at great risk of experiencing pain. Since assessment of pain is an important step towards the treatment of pain, there is a need for manageable, valid and reliable tools to assess pain in elderly people with dementia., Methods: This systematic review identifies pain assessment scales for elderly people with severe dementia and evaluates the psychometric properties and clinical utility of these instruments. Relevant publications in English, German, French or Dutch, from 1988 to 2005, were identified by means of an extensive search strategy in Medline, Psychinfo and CINAHL, supplemented by screening citations and references. Quality judgement criteria were formulated and used to evaluate the psychometric aspects of the scales., Results: Twenty-nine publications reporting on behavioural pain assessment instruments were selected for this review. Twelve observational pain assessment scales (DOLOPLUS2; ECPA; ECS; Observational Pain Behavior Tool; CNPI; PACSLAC; PAINAD; PADE; RaPID; Abbey Pain Scale; NOPPAIN; Pain assessment scale for use with cognitively impaired adults) were identified. Findings indicate that most observational scales are under development and show moderate psychometric qualities., Conclusion: Based on the psychometric qualities and criteria regarding sensitivity and clinical utility, we conclude that PACSLAC and DOLOPLUS2 are the most appropriate scales currently available. Further research should focus on improving these scales by further testing their validity, reliability and clinical utility.

In repeated measures studies, equidistant time-points do not always yield efficient treatment effect estimators. In the present paper, the optimal allocation of time-points is calculated for a small number of repeated measures, different covariance structures and linearly divergent treatment effects. The gain in efficiency of the treatment effect estimator by using optimally allocated time-points instead of equidistant time-points or by adding optimally spaced measures (at the expense of patients) is then computed. The assumed covariance structure is crucial for the results. For a compound symmetric covariance structure, a large gain in efficiency is obtained by adding repeated measures at the end of the study. For a first-order auto-regressive covariance structure, highly efficient treatment effect estimators are obtained with only two repeated measures, i.e. at the start and at the end of the study. For a first-order auto-regressive covariance structure including measurement error, the gain in efficiency by adding optimally spaced measures depends on the covariance parameter values. The gain in efficiency is similar with or without a random intercept. For a fixed study budget, the commonly used design with more than two equally spaced measures was never optimal for the linear cost function and covariance structures that were used. If the covariance structure is unknown, the optimal design based on a first-order auto-regressive covariance structure with measurement error is preferable in terms of robustness against misspecification of the covariance structure. The numerical results are illustrated by two examples., (Copyright 2005 John Wiley & Sons, Ltd.)

General information about the effects of massage to prevent pressure ulcers is limited. A literature search was conducted to provide more detailed knowledge about the effects of massage in general and in preventing the development of pressure ulcers in particular. Using the keywords massage, rubbing, prevention of pressure ulcers/pressure ulcers, and paying particular attention to referenced articles yielded a summary of different manual massage techniques and indications/contraindications of this intervention for both healthy tissues and tissues in patients at risk for developing pressure ulcers. A careful review of this information; the clinical, physical, and pathophysiological aspects of pressure ulcers, including extrinsic and intrinsic factor; and the time-pressure relationship suggests that one type of massage may be beneficial for persons who are at risk for developing pressure ulcers. Specifically, effleurage applied with moderate pressure is the most preferred massage in the treatment of pressure ulcers, although based on currently existing studies, it cannot be proven statistically that massage is an adequate preventive method for pressure ulcers. Although many guidelines advised against use of massage in people at risk for pressure ulcers, current evidence suggests that research to increase knowledge about the mechanism behind the effects of massage as part of an individualized prevention and treatment plan should be conducted.

Purpose: Small bowel irradiation results in epithelial cell loss and consequently impairs function and metabolism. We investigated whether citrulline, a metabolic end product of small bowel enterocytes, can be used for quantifying radiation-induced epithelial cell loss., Methods and Materials: NMRI mice were subjected to single-dose whole body irradiation (WBI). The time course of citrullinemia was assessed up to 11 days after WBI. A dose-response relationship was determined at 84 h after WBI. In addition, citrullinemia was correlated with morphologic parameters at this time point and used to calculate the dose-modifying factor (DMF) of glutamine and amifostine on acute small bowel radiation damage., Results: After WBI, a time- and dose-dependent decrease in plasma citrulline level was observed with a significant dose-response relationship at 84 h. At this time point, citrullinemia significantly correlated with jejunal crypt regeneration (p < 0.001) and epithelial surface lining (p = 0.001). A DMF of 1.0 and 1.5 was computed at the effective dose 50 (ED50) level for glutamine and amifostine, respectively., Conclusions: Citrullinemia can be used to quantify acute small bowel epithelial radiation damage after single-dose WBI. Radiation-induced changes in citrullinemia are most pronounced at 3 1/2 to 4 days postirradiation. At this time point, citrullinemia correlates with morphologic endpoints for epithelial radiation damage.

This article reviews three traditional methods for the analysis of multicenter trials with persons nested within clusters, i.e., centers, namely naïve regression (persons as units of analysis), fixed effects regression, and the use of summary measures (clusters as units of analysis), and compares these methods with multilevel regression. The comparison is made for continuous (quantitative) outcomes, and is based on the estimator of the treatment effect and its standard error, because these usually are of main interest in intervention studies. When the results of the experiment have to be valid for some larger population of centers, the centers in the intervention study have to present a random sample from this population and multilevel regression may be used. It is shown that the treatment effect and especially its standard error, are generally incorrectly estimated by the traditional methods, which should, therefore, not in general be used as an alternative to multilevel regression.

Background: Acute care hospitals participating in the Dutch national pressure ulcer prevalence survey use the results of this survey to compare their outcomes and assess their quality of care regarding pressure ulcer prevention. The development of a model for case-mix adjustment is essential for the use of these prevalence rates as an outcome measure., Objective: The development of a valid model for case-mix adjustment to compare the prevalence rates in the acute care hospitals that participated in the 1998 Dutch pressure ulcer prevalence survey, for the purpose of performance comparisons among the hospitals., Design: Cross-sectional design., Subjects: Subjects were patients residing in the 43 acute care hospitals that participated in the national pressure ulcer prevalence survey on May 26, 1998., Measures: The study examined the validity of a model for case-mix adjustment of pressure ulcer prevalence rates and compared hospitals to evaluate the impact of adjusted prevalence rates on their performance., Results: A logistic model was developed for case-mix adjustment, using age, malnutrition, incontinence, activity, mobility, sensory perception, friction and shear, and ward specialty. This model was found to have content, construct, and internal validity. Case-mix adjustment influenced the hospitals' performance., Conclusion: The data of the national pressure ulcer prevalence survey can be used to develop a valid model for case-mix adjustment. Conclusions about the quality of care were influenced by the use of case-mix adjusted outcomes as a measure of this quality.

In this article, the optimal selection and allocation of time points in repeated measures experiments is considered. D-optimal cohort designs are computed numerically for the first- and second-degree polynomial models with random intercept, random slope, and first-order autoregressive serial correlations. Because the optimal designs are locally optimal, it is proposed to use a maximin criterion. It is shown that, for a large class of symmetric designs, the smallest relative efficiency over the model parameter space is substantial.

This article discusses the generalization of the local influence measures for normally distributed responses to local influence measures for generalized linear models with random effects. For these models, it is shown that the subject-oriented influence measure is a special case of the proposed observation-oriented influence measure. A two-step diagnostic procedure is proposed. The first step is to search for influential subjects. A search for influential observations is proposed as the second step. An illustration of a two-treatment, multiple-period crossover trial demonstrates the practical importance of the detection of influential observations in addition to the detection of influential subjects.

In medical research the responses of patients to a number of items are often combined into a summary measure or total score for a more general patient characteristic, such as mobility. Clinical and statistical criteria exist for determining the weight of each question in the total score. The choice of weights may affect the differences between patients. The total score is often analysed statistically as if it had interval level of measurement, thereby allowing conclusions about the size of differences between patients, but it has merely an ordinal level. The incorrectness of the interval assumption may also affect differences between patients or patient groups. Finally, differences between patients are less dependent on the weighting of the items and on the assumption of an interval scale as the total score is based on more homogeneous items. Standard statistical software contains statistical methods for determining the homogeneity as well as the weights.