Population Pharmacokinetics of Unbound and Total Teicoplanin in Critically Ill Pediatric Patients.

BACKGROUND AND OBJECTIVES: Teicoplanin is a highly protein-bound antibiotic, increasingly used to treat serious Gram-positive infections in critically ill children. Maturational and pathophysiological intensive care unit-related changes often lead to altered pharmacokinetics. In this study, the objectives were to develop a pediatric population-pharmacokinetic model of unbound and total teicoplanin concentrations, to investigate the impact of plasma albumin levels and renal function on teicoplanin pharmacokinetics, and to evaluate the efficacy of the current weight-based dosing regimen. METHODS: An observational pharmacokinetic study was performed and blood samples were collected for quantification of unbound and total concentrations of teicoplanin after the first dose and in assumed steady-state conditions. A population-pharmacokinetic analysis was conducted using a standard sequential approach and Monte Carlo simulations were performed for a probability of target attainment analysis using previously published pharmacokinetic-pharmacodynamic targets. RESULTS: A two-compartment model with allometric scaling of pharmacokinetic parameters and non-linear plasma protein binding best described the data. Neither the inclusion of albumin nor the renal function significantly improved the model and no other covariates were supported for inclusion in the final model. The probability of target attainment analysis showed that the standard dosing regimen does not satisfactory attain the majority of the proposed targets. CONCLUSIONS: We successfully characterized the pharmacokinetics of unbound and total teicoplanin in critically ill pediatric patients. The highly variable unbound fraction of teicoplanin could not be predicted using albumin levels, which may support the use of therapeutic drug monitoring of unbound concentrations. Poor target attainment was shown for the most commonly used dosing regimen, regardless of the pharmacokinetic-pharmacodynamic target evaluated.

Erythritol Functional Roles in Oral-Systemic Health.

Erythritol belongs chemically to the family of polyols (or sugar alcohols), yet it is metabolized by animals and humans very differently compared to all other polyols. While polyols have been used traditionally (for about 80 y) to replace sugar in sweet foods to reduce demineralization of tooth enamel and to reduce postprandial blood glucose levels, benefits achieved merely through the absence of sugar, emerging evidence shows that erythritol can play a number of functional roles to actively support maintenance of oral and systemic health. Oral health studies revealed that erythritol can reduce dental plaque weight, reduce dental plaque acids, reduce counts of mutans streptococci in saliva and dental plaque, and reduce the risk for dental caries better than sorbitol and xylitol, resulting in fewer tooth restorations by dentist intervention. Systemic health studies have shown that erythritol, unlike other polyols, is readily absorbed from the small intestine, not systemically metabolized, and excreted unchanged within the urine. This metabolic profile renders erythritol to be noncaloric, to have a high gastrointestinal tolerance, and not to increase blood glucose or insulin levels. Published evidence also shows that erythritol can act as an antioxidant and that it may improve endothelial function in people with type 2 diabetes. This article reviews the key research demonstrating erythritol's oral and systemic health functionalities and underlying mechanisms.

Pregnancy related anxiety and general anxious or depressed mood and the choice for birth setting: a secondary data-analysis of the DELIVER study.

BACKGROUND: In several developed countries women with a low risk of complications during pregnancy and childbirth can make choices regarding place of birth. In the Netherlands, these women receive midwife-led care and can choose between a home or hospital birth. The declining rate of midwife-led home births alongside the recent debate on safety of home births in the Netherlands, however, suggest an association of choice of birth place with psychological factors related to safety and risk perception. In this study associations of pregnancy related anxiety and general anxious or depressed mood with (changes in) planned place of birth were explored in low risk women in midwife-led care until the start of labour. METHODS: Data (n = 2854 low risk women in midwife-led care at the onset of labour) were selected from the prospective multicenter DELIVER study. Women completed the Pregnancy Related Anxiety Questionnaire-Revised (PRAQ-R) to assess pregnancy related anxiety and the EuroQol-6D (EQ-6D) for an anxious and/or depressed mood. RESULTS: A high PRAQ-R score was associated with planned hospital birth in nulliparous (aOR 1.92; 95% CI 1.32-2.81) and parous women (aOR 2.08; 95% CI 1.55-2.80). An anxious or depressed mood was associated with planned hospital birth (aOR 1.58; 95% CI 1.20-2.08) and with being undecided (aOR 1.99; 95% CI 1.23-2.99) in parous women only. The majority of women did not change their planned place of birth. Changing from an initially planned home birth to a hospital birth later in pregnancy was, however, associated with becoming anxious or depressed after 35 weeks gestation in nulliparous women (aOR 4.17; 95% CI 1.35-12.89) and with pregnancy related anxiety at 20 weeks gestation in parous women (aOR 3.91; 95% CI 1.32-11.61). CONCLUSION: Low risk women who planned hospital birth (or who were undecided) more often reported pregnancy related anxiety or an anxious or depressed mood. Women who changed from home to hospital birth during pregnancy more often reported pregnancy related anxiety or an anxious or depressed mood in late pregnancy. Anxiety should be adequately addressed in the process of informed decision-making regarding planned place of birth in low risk women.

Gastrointestinal tolerance of erythritol-containing beverage in young children: a double-blind, randomised controlled trial.

BACKGROUND/OBJECTIVE: To determine gastrointestinal (GI) responses and maximum tolerated dose of erythritol in young children given as a single oral dose in a 250-ml non-carbonated fruit-flavoured beverage in between meals. This is a multicentre double-blind study with sequential design for multiple dose groups and randomised crossover for comparators of placebo vs dose. SUBJECTS/METHODS: A total of 185 healthy young children aged 4-6 years were recruited at three clinical investigation centres after informed consent of both parents; 184 children completed the study. Children were included in one of the four dose groups (5, 15, 20 or 25 g erythritol) and exposed randomly to only one single dose vs an isosweet sucrose placebo. After consumption in the clinic and an observation period, GI symptoms and stooling patterns were recorded during the next 48 h. RESULTS: Statistically significantly more episodes of diarrhoea and/or severe GI symptoms were observed in the 20 and 25 g groups compared with placebo, but not in the 5 and 15 g groups. Stool consistency, as measured by Bristol stool scale, was lower in the 15-, 20- and 25 g groups for the first 24 -h period, but not at later time points. Incidences of nausea, vomiting, borborygmi, excess flatus and abdominal pain were not significantly different from the placebo controls at all doses of erythritol. CONCLUSIONS: Rapid ingestion of up to and including 15 g (6% w/v) of erythritol in a beverage in between meals by young children aged 4-6 years was well tolerated. The no observed effect level for diarrhoea and/or severe GI symptoms was 15 g (0.73 g/kg body weight (bw)). Children appeared not to be more sensitive to the GI effects of erythritol than published for adults on a g/kg bw basis.

Prenatal counseling for congenital anomaly tests: parental preferences and perceptions of midwife performance.

OBJECTIVE: Evidence-based instruments to evaluate the preferences and experiences of future parents regarding prenatal counseling for congenital anomaly tests are currently lacking. We developed the quality of care through clients' eyes prenatal questionnaire (QUOTE(prenatal) ), a client-centered instrument, and assessed its components. Furthermore, the QUOTE(prenatal) was used to provide insight into (1) clients' previsit preferences and (2) clients' postvisit experience, that is, perceived care provider performance regarding the counseling they received. METHOD: In the questionnaire survey, a principal component analysis was used to gain insight into the underlying components of the questionnaire. Regression analysis was performed to examine differences between groups. RESULTS: In 17 Dutch midwifery practices, 941 pregnant women and their partners (response rate 79%) completed the 59-item QUOTE(prenatal) previsit and postvisit, measuring preferences and perceived performances, respectively. A principal component analysis revealed three counseling components: client-midwife relation, health education and decision-making support. Reponses showed that, previsit, most clients consider the client-midwife relationship and health education to be (very) important. One third of the clients consider decision-making support to be (very) important. Nulliparae had higher preferences for health education and decision-making support than multiparae. CONCLUSION: Clients perceive that their midwives perform well in building the client-midwife relationship and in giving health education. Improvement is needed in decision-making support.

See me, feel me. Using physiology to validate behavioural observations of emotions of people with severe or profound intellectual disability.

BACKGROUND: Behavioural observations are the most frequently used source of information about emotions of people with severe or profound intellectual disabilities but have not yet been validated against other measures of emotion. In this study we wanted to validate the behavioural observations of emotions using respiration (rib cage contribution, total breath duration, inspiratory time, expiratory time, tidal volume, mean inspiratory flow, minute ventilation) and heart rate variability. METHOD: Twenty-seven participants were presented with four negative and four positive stimuli. During the presentation the participants' respiration and heart rate variability was measured. Each behaviour of the participant was coded as emotive or not. RESULTS: We found the hypothesised higher percentage rib cage contribution, marginal lower mean inspiratory flow and lower heart rate variability when the expressed emotions became more positive. CONCLUSIONS: These results validate the use of behavioural observations to make inferences about emotions.

Investigating the relationship between observed mood and emotions in people with severe and profound intellectual disabilities.

BACKGROUND: The measurement of subjective well-being in people with severe and profound intellectual disabilities (ID) is a difficult challenge. As they cannot self-report about their life satisfaction, because of severe communicative and cognitive limitations, behavioural observations of their emotions and moods are important in the measurement of their subjective well-being. It is, however, not known if observations of mood and emotion can be differentiated in people with severe and profound ID and if mood and emotions can give unique information about their affect. Therefore, the aim of this study is to examine the relationship between mood and emotions in people with severe and profound ID, using behavioural observations. As recommended in the literature, we investigated the frequency and intensity of the emotion separately. METHOD: In a period of 3 weeks 27 participants with severe and profound ID were presented with four staff-selected negative and four staff-selected positive stimuli. During the presentation participants were videotaped using the observational method of Petry & Maes where each behaviour is coded on a 5-point scale, ranging from indicating a very negative emotion to indicating a very positive emotion. As a measure of mood, the staff completed the MIPQ in the beginning of the 3 weeks. RESULTS: We found a positive relationship between mood and respectively the total emotion score and the frequency of the emotion when the stimuli were positive but not when the stimuli were negative. There was no relationship between mood and the intensity of the emotion. CONCLUSIONS: Our results indicate that mood and emotions can be distinguished from each other using behavioural observations. Both can give specific information about the affective life of people with severe or profound ID. Moreover, if further research could replicate the results of this study, an implication is that the direct support workers should be aware of a decline in the frequency of their clients reactions to positive stimuli as this could indicate a decline in their mood.

To what extent is mean EMG frequency during gait a reflection of functional muscle strength in children with cerebral palsy?

The aim of the current paper was to analyze the potential of the mean EMG frequency, recorded during 3D gait analysis (3DGA), for the evaluation of functional muscle strength in children with cerebral palsy (CP). As walking velocity is known to also influence EMG frequency, it was investigated to which extent the mean EMG frequency is a reflection of underlying muscle strength and/or the applied walking velocity. Surface EMG data of the lateral gastrocnemius (LGAS) and medial hamstrings (MEH) were collected during 3DGA. For each muscle, 20 CP children characterized by a weak and 20 characterized by a strong muscle (LGAS or MEH) were selected. A weak muscle was defined as a manual muscle testing score <3; a strong muscle was defined as a manual muscle testing score ≥4. Patient selection was based on the following inclusion criteria: (a) predominantly spastic type of CP (3-15 years old), (b) either (near) normal muscle strength or muscle weakness in at least one of the studied lower limb muscles, (c) no lower limb Botulinum Toxin-A treatment within 6 months prior to the 3DGA, (d) no history of lower limb surgery, and (e) high-quality noise-free EMG-data. For each muscle, twenty age-related typically developing (TD) children were included as controls. In both muscles a consistent pattern of increasing mean EMG frequency with decreasing muscle strength was observed. This was significant in the LGAS (TD versus weak CP). Walking velocity also had a significant effect on mean EMG frequency in the LGAS. Furthermore, based on R(2) and partial correlations, it could be concluded that both walking velocity and muscle strength have an impact on EMG, but the contribution of muscle strength was always higher. These findings underscore the potential of the mean EMG frequency recorded during 3DGA, for the evaluation of functional muscle strength in children with CP.

Screening for cerebral visual impairment: value of a CVI questionnaire.

The objective of the study was to investigate the screening utility of a questionnaire for cerebral visual impairment (CVI) by correlating the questionnaire with diagnostic tools such as the L94, the Test of Visual Perceptual Skills - Revised and the Visual Perception subtask of the Beery test of VisuoMotor Integration.The questionnaire consisted of 46 items, exploring different characteristics of CVI. We consecutively recruited 91 children. Parents filled out the questionnaire after which all children were seen for a diagnostic evaluation of CVI.There were 58 boys. Subjects' mean age was 6.10 years. A median of 12 items was ticked in the 45 children with CVI and 7 in the children without impairment. The domain 'visual attitude' scored positive most frequently. A logistic regression model using individual items, yielded Receiver Operating Curves for the questionnaire with good areas under the curve of 0.81 against the L94, 0.78 against the TVPS-R and 0.84 against the VP subtask. The sum score of the 6 domains was found to be an easy-obtainable score with a good sensitivity and specificity profile.This CVI questionnaire is a viable tool that has the potential of being implemented as part of a routine screening procedure for CVI.

A systematic review of arm activity measures for children with hemiplegic cerebral palsy.

OBJECTIVE: To identify psychometrically sound and clinically feasible assessments of arm activities in children with hemiplegic cerebral palsy for implementation in research and clinical practice. DATA SOURCES: PubMed, CINAHL, Cochrane Library, Web of Science and reference lists of relevant articles were searched. REVIEW METHODS: A systematic search was performed based on the following inclusion criteria: (1) evaluative tools at the activity level according to the International Classification of Functioning, Disability and Health; (2) previously used in studies including children with hemiplegic cerebral palsy aged 2-18 years; (3) at least one aspect of reliability and validity in children with cerebral palsy should be established. Descriptive information, psychometric properties and clinical utility were reviewed. RESULTS: Eighteen assessments were identified of which 11 met the inclusion criteria: eight functional tests and three questionnaires. Five functional tests were condition-specific, three were generic. All functional tests measure different aspects of activity, including unimanual capacity and performance during bimanual tasks. The questionnaires obtain information about the child's abilities at home or school. The reliability and validity have been established, though further use in clinical trials is necessary to determine the responsiveness. CONCLUSIONS: To obtain a complete view of what the child can do and what the child actually does, we advise a capacity-based test (Melbourne Assessment of Unilateral Upper Limb Function), a performance-based test (Assisting Hand Assessment) and a questionnaire (Abilhand-Kids). This will allow outcome differentiation and treatment guidance for the arm in children with cerebral palsy.

Duplication of the VHL and IRAK2 genes in a patient with mental retardation/multiple congenital anomalies, epilepsy and ectomorphic habitus.

Partial 3p duplications are very rare. Often they are reported in translocations involving other chromosomes, whereas deletions encompassing the VHL gene in 3p25.3 predispose to Van-Hippel Lindau syndrome. We report here a paternally-inherited microduplication of 3p25.3 detected by array comparative genomic hybridisation (aCGH) in a 17 year-old male patient presenting with mental retardation and multiple congenital anomalies (MR/MCA), epilepsy and ectomorphic habitus. He has no tumour and there is no history of familial cancer. We refined the duplication by Multiplex Ligation-dependent Probe Amplification (MLPA) to a 251 kb region encompassing the VHL and IRAK2 genes. The duplication is likely to be causal. Interestingly, duplication of IRAK2 can cause epilepsy. Disruption of the GHRL gene can explain the ectomorphic habitus. To our knowledge, this is the smallest 3p duplication encompassing the VHL region. Its prognosis is unknown and a long-term follow-up is essential for an early diagnosis of malignancy.

Rating scales for dystonia in cerebral palsy: reliability and validity.

AIM: This study investigated the reliability and validity of the Barry-Albright Dystonia Scale (BADS), the Burke-Fahn-Marsden Movement Scale (BFMMS), and the Unified Dystonia Rating Scale (UDRS) in patients with bilateral dystonic cerebral palsy (CP). METHOD: Three raters independently scored videotapes of 10 patients (five males, five females; mean age 13 y 3 mo, SD 5 y 2 mo, range 5-22 y). One patient each was classified at levels I-IV in the Gross Motor Function Classification System and six patients were classified at level V. Reliability was measured by (1) intraclass correlation coefficient (ICC) for interrater reliability, (2) standard error of measurement (SEM) and smallest detectable difference (SDD), and (3) Cronbach's alpha for internal consistency. Validity was assessed by Pearson's correlations among the three scales used and by content analysis. RESULTS: Moderate to good interrater reliability was found for total scores of the three scales (ICC: BADS=0.87; BFMMS=0.86; UDRS=0.79). However, many subitems showed low reliability, in particular for the UDRS. SEM and SDD were respectively 6.36% and 17.72% for the BADS, 9.88% and 27.39% for the BFMMS, and 8.89% and 24.63% for the UDRS. High internal consistency was found. Pearson's correlations were high. Content validity showed insufficient accordance with the new CP definition and classification. INTERPRETATION: Our results support the internal consistency and concurrent validity of the scales; however, taking into consideration the limitations in reliability, including the large SDD values and the content validity, further research on methods of assessment of dystonia is warranted.

Upper limb motor and sensory impairments in children with hemiplegic cerebral palsy. Can they be measured reliably?

PURPOSE: To establish interrater and test-retest reliability of a clinical assessment of motor and sensory upper limb impairments in children with hemiplegic cerebral palsy aged 5-15 years. METHOD: The assessments included passive range of motion (PROM), Modified Ashworth Scale (MAS), manual muscle testing (MMT), grip strength, the House thumb and Zancolli classification and sensory function. Interrater reliability was investigated in 30 children, test-retest reliability in 23 children. RESULTS: For PROM, interrater reliability varied from moderate to moderately high (correlation coefficients 0.48-0.73) and test-retest reliability was very high (>0.81). For the MAS and MMT, total score and subscores for shoulder, elbow, and wrist showed a moderately high to very high interrater reliability (0.60-0.91) and coefficients of >0.78 for test-retest reliability. The reliability for the individual muscles varied from moderate to high. The Jamar dynamometer was found to be highly reliable. The House thumb classification showed a substantial reliability and the Zancolli classification an almost perfect reliability. All sensory modalities had a good agreement. CONCLUSIONS: For all motor and sensory assessments, interrater and test-retest reliability was moderate to very high. Test-retest reliability was clearly higher than interrater reliability. To improve interrater reliability, it was recommended to strictly standardize the test procedure, refine the scoring criteria and provide intensive rater trainings.

Comparison of the Melbourne Assessment of Unilateral Upper Limb Function and the Quality of Upper Extremity Skills Test in hemiplegic CP.

This study investigated interrater reliability and measurement error of the Melbourne Assessment of Unilateral Upper Limb Function (Melbourne Assessment) and the Quality of Upper Extremity Skills Test (QUEST), and assessed the relationship between both scales in 21 children (15 females, six males; mean age 6y 4mo [SD 1y 3mo], range 5-8y) with hemiplegic CP. Two raters scored the videotapes of the assessments independently in a randomized order. According to the House Classification, three participants were classified as level 1, one participant as level 3, eight as level 4, three as level 5, one participant as level 6, and five as level 7. The Melbourne Assessment and the QUEST showed high interrater reliability (intraclass correlation 0.97 for Melbourne Assessment; 0.96 for QUEST total score; 0.96 for QUEST hemiplegic side). The standard error of measurement and the smallest detectable difference was 3.2% and 8.9% for the Melbourne Assessment and 5.0% and 13.8% for the QUEST score on the hemiplegic side. Correlation analysis indicated that different dimensions of upper limb function are addressed in both scales.

A cost-utility analysis of pregabalin in the management of peripheral neuropathic pain.

OBJECTIVES: To assess the cost per QALY (quality-adjusted life years) of pregabalin in the management of peripheral neuropathic pain. METHODS: We compared pregabalin on top of "usual care" with "usual care" alone. In this study, usual care was defined as a mix of drug therapies, excluding anti-epileptic drugs (AEDs), because the latter represented only 9% of current use, and clinical evidence of pregabalin was demonstrated versus usual care without anti-epileptic drugs. A Markov model was developed to simulate the evolution of a patient cohort over 1 year, and applied cycles of 4 weeks. During each cycle, patients remained in 1 out of 4 possible states: severe, moderate or mild pain, and therapy withdrawal. The health care payers perspective was taken into account. Clinical data were obtained from a trial comparing usual care plus placebo to usual care plus pregabalin, at either 150, 300, or 300/600 mg/day (the latter depending on clearance of creatinin). Resulting effects on pain were transformed into transition-probabilities between different pain levels. Cost and SF36 utility data of pain levels were obtained from a 1-month observational study in 88 patients. RESULTS: Usual care resulted in a yearly cost of Euros 6,200 compared to Euros 5,984 for an all dose pregabalin-mix, meaning a cost saving of Euros 216 per patient. Utility increase was 0.01 for the pregabalin-mix (QALY 0.510 usual care; 0.520 pregabalin-mix). Monte Carlo analysis showed cost savings were not significant. However, the utility gain, albeit small, was statistically significant. CONCLUSIONS: Based on this analysis, it may be concluded, that in the considered patient population, at the specialist level, pregabalin is at least cost neutral to current usual care (without AEDs) and offers a slight but significant increase in quality of life.

Aspects of the validity of the Movement Assessment Battery for Children.

Does the Movement Assessment Battery for Children (M-ABC) measures what it claims to measure? The concurrent validity of the total impairment score and some of the item scores of the second and third age band of the M-ABC test were investigated. One hundred thirty three children, between 7- and 9-year-old, were assessed with the M-ABC test, a ball catching test and two tasks measuring dynamic balance. Ninety of these children were identified as children with a poor ball catching skill and 43 children were typically developing children. One hundred and seven children were assessed with the second age band of the M-ABC (the 7- and 8-year-old children) and 26 with the third age band (the 9-year-old children). The results of the correlation analysis between the ball catching test, the two dynamic balance tasks and the corresponding items of the M-ABC, varied from non-significant to a highly significant correlation coefficient of -0.74. For some items concurrent validity was established but other items seemed less valid, probably due to a lack of discriminative power. The concurrent validity of the total impairment score of the M-ABC was confirmed for the second age band. Correlation coefficients between the ball catching test, the dynamic balance skills and the M-ABC varied between -0.72 and -0.76. The results for the third age band have to be interpreted with prudence because they were based on only 26 children.

Information processing in very-low-birth-weight children with and without attention deficit disorder.

Very-low-birth-weight children (16 with and 45 without attention deficit/hyperactivity disorder) were matched to term-born controls (27 with attention deficit/hyperactivity disorder and 30 without) according to age, intelligence, and social class of their parents. The children were screened for motor, visual, and mental disabilities. The general aim of the study was to evaluate information processing stages using the additive factor method of Sternberg. The tasks consisted of computerized visual-motor letter recognition and arrow detection tasks. The tasks elicited similar prolongations of response times, increases in standard deviation of the response times, and increased error rates in the four groups. We conclude that very-low-birth-weight and control children do not differ in their information processing stages.

Disability in an urban black community in Zimbabwe.

PURPOSE: This study was undertaken to establish which health conditions are primarily responsible for disability and morbidity in a high-density area in Harare, Zimbabwe. METHOD: House-to-house screening visits were followed up by medical examination and interview of those identified as having a functional limitation. RESULTS: Information was obtained during screening on 10,839 residents. Of these, 608 were examined by medical professionals. The rate of disability/morbidity was 5.6% for the whole sample. Headaches and migraine were the most common problem. These were followed by back pain, hypertension and osteoarthritis. HIV/AIDS was the fifth most common condition. Depression, based on responses to a screening tool, was evident in one-third of the subjects. Common activity limitations included difficulty with the performance of housework activities and with walking. HIV/AIDS resulted in the most severe activity limitation, in that cognitive functions were also affected. CONCLUSION: The middle-aged and elderly with osteoarthritis and young women with depression constitute vulnerable groups who are not in a position to demand services. The older women particularly need assistance as they are bearing the double burden of their own degenerative conditions and the results of the HIV/AIDS pandemic.