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Mood stabilizers in hospitalized children with bipolar disorder: a retrospective review.

A paucity of naturalistic data supported a rationale for the present retrospective review of clinical changes during hospitalization in 44 bipolar pre-adolescents, treated with monotherapy lithium, carbamazepine (CBZ) or divalproex sodium (DVP). Daily staff progress notes and discharge summaries on each patient were read by four trained clinicians blind to treatment group, and rated according to the Clinical Global Impression Improvement (CGI-I) scale. Consensus rating was measured by kappa reliability. Data were analyzed using a general linear model (sas mixed) analysis of variance (anova) with repeated measures. The medication groups did not differ in length of hospitalization, overall severity of illness at the time of admission, or comorbidity. Prior treatment was considered as a covariate. Each group approached serum therapeutic levels at day 7 of the medication period. The estimated mean CGI-I scores for CBZ were systematically higher (i.e. worse) than those for lithium and DVP, which overlapped and crossed over time. The difference became increasingly apparent and was statistically significant by week 2 (P = 0.036). The present study was limited in that the sample sizes, particularly in the case of CBZ, were small, commensurate with the low prevalence of the disorder. Lack of structured interviews, as an independent assessment of diagnoses was an intrinsic limitation of the study. Although constrained by its retrospective nature, our findings suggest that by week 2 of hospitalization both lithium and DVP may be more efficacious than CBZ in bipolar pre-adolescents. Any significant finding must be viewed as tentative and subject to confirmation in other studies.

Analysis of Variance↗

Are psychoactive-drug-induced changes in plasma lipid and lipoprotein levels of significance for clinical remission in psychiatric disorders?

In the present pilot study, our aim was to investigate whether associations could be demonstrated in psychiatric patients between the changes in plasma lipid and lipoprotein levels expected during treatment with psychoactive drugs and the changes in the patients' depressive and hostile behavior. One hundred and fourteen patients with various psychiatric disorders (depressive episode in bipolar affective disorder, depressive episode or recurrent depressive disorder, paranoid schizophrenia, and schizoaffective disorders) were included in the study. The following examinations were carried out in each patient on admission and at discharge: (1) the plasma lipid parameters total cholesterol (TC), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), high-density lipoprotein (HDL), and triglycerides (TRI) were determined, and (2) the psychopathological features were recorded employing the AMDP system and the AMDP Syndrome Scales. Within the context of a naturalistic clinical setting with a choice of psychoactive drugs available, patients were subdivided at the end of treatment into eight treatment groups, as follows: group 1, treatment with butyrophenones; group 2, treatment with tricyclics; group 3, treatment with butyrophenones and tricyclics; group 4, treatment with butyrophenones, tricyclics and selective serotonin reuptake inhibitors; group 5, treatment with butyrophenones and lithium; group 6, treatment with tricyclics and lithium; group 7, treatment with butyrophenones, tricyclics and lithium; and group 8, treatment with butyrophenones, tricyclics, selective serotonin reuptake inhibitors and lithium. To compare the changes in the eight treatment groups, mixed general linear models including diagnosis, gender, age, body mass index changes, and baseline values were applied using proc GLM of SAS. Butyrophenones induce an increase in TC, LDL, and TC/TRI ratio, whereas tricyclics lead to an increase in TC, LDL, VLDL, and TRI. In combined medication of butyrophenones and tricyclics the effects of tricyclics predominate. Comedication of lithium inhibits the increase in TC and LDL induced by butyrophenones and/or tricyclics. Treatment groups with lipid changes of the same type (decrease, no change, or increase) were combined in "lipid change groups". Analyses of variance or covariance (with psychopathological admission value as covariate where there were significant differences in psychopathological admission mean values between the groups) of these lipid change groups with regard to the changes in the Depressive Syndrome Scale and the Hostility Syndrome Scale gave results which are interpreted as follows: an increase in TC or LDL inhibits the remission of hostility, whereas an increase in TRI with concomitant decrease in TC, or else a relatively greater increase in TRI than in TC promotes the remission of hostility. A decrease in TRI or VLDL promotes the remission of depression. Our data and findings published in the literature may suggest that systemic changes in plasma lipid parameters, at the cellular level, induce changes in the fluidity of brain cell membranes. We hypothesize that an increase in plasma TC or LDL and/or a decrease in plasma TRI or VLDL may induce a relative decrease in brain cell membrane fluidity with decreased presynaptic serotonin reuptake and increased postsynaptic serotonin function. This proposed increase in brain serotonin function would finally result in an anti-depressive, aggression-promoting effect. Conversely, a decrease in plasma TC or LDL and/or an increase in plasma TRI or VLDL may induce a relative increase in brain cell membrane fluidity with increased presynaptic serotonin reuptake and decreased postsynaptic serotonin function. This proposed decrease in brain serotonin function would result in an anti-aggressive, depression-promoting effect.

Adult↗

Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.

BACKGROUND: The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin. METHODS: We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples. RESULTS: We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination. CONCLUSIONS: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level.

Anticoagulants↗

Preterm infants born at less than 31 weeks' gestation have improved growth in cycled light compared with continuous near darkness.

OBJECTIVES: Our purpose was to evaluate the benefits of cycled light (CL) versus near darkness (ND) on health in preterm infants born at <31 weeks' gestational age. STUDY DESIGN: Randomized, interventional study comparing infants receiving (1) CL from birth, (2) CL at 32 weeks' postconceptional age (PCA), and (3) CL at 36 weeks' PCA in transition for discharge home. Statistical significance was assessed with segmented mixed general linear models, analysis of covariance, general estimating equations, chi(2), and Fisher's exact procedure. RESULTS: Infants receiving CL at birth and 32 weeks' PCA gained weight faster than infants not receiving CL until 36 weeks' PCA. There were no differences among the groups in length of hospitalization stay or number of ventilator days, but the power was low for these variables. CONCLUSIONS: These findings suggest that CL has significant weight gain benefits over ND, and there are no short-term advantages of ND over cycled light for health in preterm infants.

Body Weight↗

Long-term stability of salivary cortisol.

The measurement of salivary cortisol provides a simple, non-invasive, and stress-free measure frequently used in studies of the hypothalamic-pituitary-adrenal axis activity. In research projects, samples are often required to be stored for longer periods of time either because of the protocol of the project or because of lack of funding for analysis. The aim of the present study was to explore the effects of long-term storage of samples on the amounts of measurable cortisol. Ten pools of saliva were collected on polyester Salivette tampons from five subjects. After centrifugation the samples were either stored in small vials or spiked to polyester Salivette tampons before analysis for cortisol using Spectria RIA kits. The effects of storage were evaluated by a linear regression model (mixed procedure) on a logarithmic scale. No effects on cortisol concentrations were found after storage of saliva at 5 degrees C for up to 3 months or at -20 degrees C and -80 degrees C for up to one year. In contrast, concentrations of cortisol were found to decrease by 9.2% (95% confidence interval (CI): 3.8%; 14.3%) per month in samples stored at room temperature. Repeated freezing and thawing of samples up to four times before analysis did not affect the measured concentrations of cortisol. The coefficient of residual variation (CVresid) for samples stored on Salivette tampons were twice the CVresid for samples stored in separate vials after centrifugation. In conclusion, centrifuged saliva samples for analysis of cortisol may be stored at 5 degrees C for up to 3 months or at -20 degrees C or -80 degrees C for at least one year. However, long-term storage at room temperature cannot be recommended. Repeated cycles of freezing and thawing did not appear to affect the concentrations of cortisol.

Freezing↗

Estimating dose equivalence for new routes of drug administration.

For patient's convenience, dose administration of insulin via oral inhalation is often considered as an alternative to subcutaneous administration. An important statistical problem is to estimate dose equivalence, which is the amount of drug needed to be delivered by inhalation to generate an equivalent pharmacokinetic (PK) response produced by a therapeutic dose of subcutaneous insulin. Because of high intersubject variability, a crossover design clinical trial is typically used where data from both routes of administration are obtained from the same subject. A linear mixed effects model is proposed to describe the relationship between AK response and insulin dose for the two routes of administration. Estimation of dose equivalence in this setting has not been discussed in the statistical literature. Several competing methods for estimating dose equivalence are proposed and contrasted. A formula for calculating an approximate sample size necessary to estimate dose equivalence with a desired precision for the new route of administration is also provided.

Administration, Inhalation↗

Human immunodeficiency virus type 1-specific cytotoxic T lymphocyte activity is inversely correlated with HIV type 1 viral load in HIV type 1-infected long-term survivors.

HIV-1-specific cytotoxic T cell (CTL) activity has been suggested to correlate with protection from progression to AIDS. We have examined the relationship between HIV-specific CTL activity and maintenance of peripheral blood CD4+ T lymphocyte counts and control of viral load in 17 long-term survivors (LTSs) of HIV-1 infection. Longitudinal analysis indicated that the LTS cohort demonstrated a decreased rate of CD4+ T cell loss (18 cells/mm3/year) compared with typical normal progressors (approximately 60 cells/mm3/year). The majority of the LTSs had detectable, variable, and in some individuals, quite high (>10(4) RNA copies/ml) plasma viral load during the study period. In a cross-sectional analysis, HIV-specific CTL activity to HIV Gag, Pol, and Env proteins was detectable in all 17 LTSs. Simultaneous analysis of HIV-1 Gag-Pol, and Env-specific CTLs and virus load in protease inhibitor-naive individuals showed a significant inverse correlation between Pol-specific CTL activity and plasma HIV-1 RNA levels (p = 0.001). Furthermore, using a mixed linear effects model the combined effects of HIV-1 Pol- and Env-specific CTL activity on the viral load were significantly stronger than the effects of HIV-1 Pol-specific CTL activity alone on predicted virus load. These data suggest that the presence of HIV-1-specific CTL activity in HIV-1-infected long-term survivors is an important component in the effective control of HIV-1 replication.

CD4 Lymphocyte Count↗

Trimester-specific changes in maternal thyroid hormone, thyrotropin, and thyroglobulin concentrations during gestation: trends and associations across trimesters in iodine sufficiency.

OBJECTIVES: To describe the interrelationships of thyroid functions based on trimester-specific concentrations in healthy, iodine-sufficient pregnant women across trimesters, and postpartum. METHODS: Circulating total 3,5,3'- triidothyronine (T(3)) and thyroxine (T(4)) concentrations were determined simultaneously using liquid chromatography tandem mass-spectrometry (LC/MS/MS). Free thyroxine (FT(4)), thyroid-stimulating hormone (TSH), and thyroglobulin (Tg) were measured using immunoassay techniques. Linear mixed effects models and correlations were calculated to determine trends and associations, respectively, in concentrations. RESULTS AND CONCLUSIONS: Trimester-specific T(3), FT(4), TSH, and Tg concentrations were significantly different between the first and third trimesters (all p < 0.05); second and third trimester values were not significantly different for FT(4), TSH, and Tg (all p > 0.25) although T3 was significantly higher in the third, relative to the second trimester. T(4) was not significantly different at any trimester (all p > 0.80). With two exceptions, analyte concentrations tended not to be correlated at each trimester and at 1-year postpartum. One exception was that T(3) and T(4) tended to be associated (all p < 0.05) at all time points except the third trimester (rho = 0.239, p > 0.05). T(4) and FT(4) concentrations tended to correlate positively during pregnancy (rho 0.361-0.382, all p < 0.05) but not postpartum (rho = 0.179, p > 0.05). Trends suggest that trimester-specific measurements of T(3), FT(4), Tg, and possibly TSH are warranted.

Adult↗

Relation of body mass index and body fatness to energy expenditure: longitudinal changes from preadolescence through adolescence.

BACKGROUND: Although it is widely accepted that weight gain results when energy intake exceeds energy expenditure (EE), how reduced EE contributes to the development of obesity remains unclear. OBJECTIVE: We tested the hypothesis that reduced EE in the premenarcheal period in girls constitutes a risk factor for an increase in relative weight [body mass index (BMI) z score] and percentage of body fat (%BF) during adolescence. DESIGN: We measured EE at study entry in 196 premenarcheal nonobese girls. Resting metabolic rate (RMR) was measured by indirect calorimetry. Total energy expenditure (TEE) was measured by the doubly labeled water method. Activity energy expenditure (AEE) was calculated from RMR and TEE. After the baseline study, girls were followed annually until 4 y after menarche (x+/- SD: 7.1 +/- 2.6 y). At each visit, height, weight, and %BF by bioelectrical impedance were measured. Girls also completed annual food-frequency and activity questionnaires. Linear mixed effects modeling was used to evaluate the longitudinal relation between BMI z score and %BF and measures of baseline EE. RESULTS: We found no significant relation in change in %BF with RMR, AEE, or TEE. We observed a small positive relation between BMI z score and AEE and TEE (P < 0.05) but no significant relation with RMR. When we stratified by parental overweight, the findings were unchanged for RMR. TEE and AEE were positively related to BMI z score in girls of overweight parents. CONCLUSIONS: Our findings suggest that EE in the premenarcheal period is not a risk factor for increases in %BF or BMI z score in girls during adolescence.

Adipose Tissue↗

Variability of task-based dermal exposure measurements from a variety of workplaces.

INTRODUCTION: The RISKOFDERM project collected task-based estimates of potential dermal exposure from a wide range of industries and services from around Europe. A formal statistical analysis was carried out to explore the main components of variability in dermal exposure levels. The central research question was to what extent dermal exposure levels could be explained by generic grouping variables like 'exposure scenarios' and 'dermal exposure operation units' (DEOs) (grouping of scenarios on the basis of similarity in exposure patterns). METHODS: Mixed effect linear models were used to estimate variance components of potential dermal exposure for DEOs or scenarios and for factories, workers and time. In addition within- and between-worker variance components were estimated for single groups of workers performing a specific scenario in a specific location with potential dermal exposure to a specific agent. RESULTS: Variability in potential dermal exposure is very large. Differences in geometric mean potential dermal exposure can range over 3-5 orders of magnitude both for DEOs and scenarios. The range depends on how dermal exposure is expressed (amount or rate). Both DEOs and scenarios explain a considerable amount of variability, but large differences in dermal exposure still existed within DEOs and scenarios. In contrast, between-worker variability in mean potential dermal exposure is minimal for a given scenario carried out within a specific location with exposure to a particular agent. Temporal variability, however, is considerable, most likely due to the event-based nature of the dermal exposure process. CONCLUSION: The classification of tasks in DEOs and scenarios has proven to be useful since large differences in average dermal exposure estimates exist between DEOs and between scenarios. However, large differences also exist between scenarios within a DEO and even within a scenario. These differences are governed by local conditions determined by the actual handling of the agent, the agent's physical and chemical properties, its intrinsic toxicity, control measures taken and training and attitude of workers. For the time being, actual dermal exposure measurements and a better understanding of actual determinants of dermal exposure seem to be a necessity in order to evaluate dermal exposure hazards properly.

Analysis of Variance↗

X chromosome-wide association studies for quantitative trait loci based on the mixture of general pedigrees and additional unrelated individuals.

Genome-wide association studies have successfully identified many genetic variants associated with complex traits. However, most existing methods target autosomes rather than X chromosome, and several existing X chromosome-wide association studies (XWAS) at quantitative trait loci (QTL) largely focus on unrelated individuals, with limited attention to general pedigrees or mixture of general pedigrees and additional unrelated individuals (called the mixed data for brevity). In this study, we propose nine novel methods for XWAS at QTL in the mixed data (${\mathrm{MQX}}_{\mathrm{cat}}$, ${\mathrm{MQZ}}_{\mathrm{max}}$, ${\mathrm{MT}}_{\mathrm{plinkw}}$, ${\mathrm{MT}}_{\mathrm{chenw}}$, $\mathrm{MwM}3\mathrm{VNA}$, ${\mathrm{MQMVX}}_{\mathrm{cat}}$, ${\mathrm{MQMVZ}}_{\mathrm{max}}$, $\mathrm{MpMV}$, and $\mathrm{McMV}$), also applicable to general pedigrees alone. The first four methods test for mean differences across genotypes; the latter four test for differences in both means and variances; $\mathrm{MwM}3\mathrm{VNA}$ tests for variance differences only. All mean-based and mean-variance-based methods incorporate X chromosome inactivation information, and all nine methods consider genetic relatedness in pedigrees. Simulation studies confirm well-controlled type I error rates, and inclusion of pedigrees significantly improves statistical power. Note that there has been no study focusing on X chromosome for the mixed data or general pedigrees from UK Biobank database, so we apply our proposed methods to this dataset, which identify five total cholesterol (TC)-associated and 13 low-density lipoprotein cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs). Linkage disequilibrium (LD) analysis reveals that these SNPs fall into three distinct LD blocks. Functional annotation and gene ontology enrichment analysis reveal 16 and 28 enriched pathways for TC-associated and LDL-C-associated genes, respectively. These methods provide robust and powerful tools for XWAS at QTL in both mixed data and general pedigrees.

Quantitative Trait Loci↗

PROLONG: penalized regression for outcome guided longitudinal omics analysis with network and group constraints.

MOTIVATION: There is a growing interest in longitudinal omics data paired with some longitudinal clinical outcome. Given a large set of continuous omics variables and some continuous clinical outcome, each measured for a few subjects at only a few time points, we seek to identify those variables that co-vary over time with the outcome. To motivate this problem we study a dataset with hundreds of urinary metabolites along with Tuberculosis mycobacterial load as our clinical outcome, with the objective of identifying potential biomarkers for disease progression. For such data clinicians usually apply simple linear mixed effects models which often lack power given the low number of replicates and time points. We propose a penalized regression approach on the first differences of the data that extends the lasso + Laplacian method [Li and Li (Network-constrained regularization and variable selection for analysis of genomic data. Bioinformatics 2008;24:1175-82.)] to a longitudinal group lasso + Laplacian approach. Our method, PROLONG, leverages the first differences of the data to increase power by pairing the consecutive time points. The Laplacian penalty incorporates the dependence structure of the variables, and the group lasso penalty induces sparsity while grouping together all contemporaneous and lag terms for each omic variable in the model. RESULTS: With an automated selection of model hyper-parameters, PROLONG correctly selects target metabolites with high specificity and sensitivity across a wide range of scenarios. PROLONG selects a set of metabolites from the real data that includes interesting targets identified during EDA. AVAILABILITY AND IMPLEMENTATION: An R package implementing described methods called "prolong" is available at https://github.com/stevebroll/prolong. Code snapshot available at 10.5281/zenodo.14804245.

Humans↗

Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive caret.

BACKGROUND: The pharmacokinetics of the alpha-2 adrenoceptor agonist dexmedetomidine were studied in 10 patients requiring postoperative sedation and mechanical ventilation in the intensive care unit (ICU), and compared with previous volunteer data. METHODS: On arrival in the ICU, sedation with dexmedetomidine was commenced with a loading dose of 2.5 microg kg(-1) h(-1) over 10 min followed by a maintenance infusion of 0.7 microg kg(-1) h(-1) into a central vein. Blood samples for measurement of plasma dexmedetomidine concentrations were taken during and after sedative infusions at predetermined intervals. Pharmacokinetic variables were estimated using non-compartmental methods. In addition, non-linear mixed effects modelling was used to obtain variable estimates not readily attainable from non-compartmental methods. Respiratory and haemodynamic data were recorded to enable correlation of any adverse events with the calculated pharmacokinetic profile. RESULTS: The harmonic mean distribution half-life of dexmedetomidine was 8.6 min and the harmonic mean terminal half-life was 3.14 h. Steady-state volume of distribution averaged 173 litres, clearance averaged 48.3 litres h(-1), and the mean residence time averaged 3.86 h. CONCLUSIONS: Mean dexmedetomidine pharmacokinetic variables seen in postoperative, intensive care patients were similar to those previously found in volunteers, with the exception of the steady-state volume of distribution. A small loading dose provided effective sedation with no adverse events.

Adrenergic alpha-Agonists↗

Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children.

BACKGROUND: Descriptions of the pharmacokinetics and metabolism of morphine and its metabolites in young children are scant. Previous studies have not differentiated the effects of size from those related to age during infancy. METHODS: Postoperative children 0-3 yr old were given an intravenous loading dose of morphine hydrochloride (100 micro g kg(-1) in 2 min) followed by either an intravenous morphine infusion of 10 micro g h(-1) kg(-1) (n=92) or 3-hourly intravenous morphine boluses of 30 micro g kg(-1) (n=92). Additional morphine (5 micro g kg(-1)) every 10 min was given if the visual analogue (VAS, 0-10) pain score was >/=4. Arterial blood (1.4 ml) was sampled within 5 min of the loading dose and at 6, 12 and 24 h for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The disposition of morphine and formation clearances of morphine base to its glucuronide metabolites and their elimination clearances were estimated using non-linear mixed effects models. RESULTS: The analysis used 1856 concentration observations from 184 subjects. Population parameter estimates and their variability (%) for a one-compartment, first-order elimination model were as follows: volume of distribution 136 (59.3) litres, formation clearance to M3G 64.3 (58.8) litres h(-1), formation clearance to M6G 3.63 (82.2) litres h(-1), morphine clearance by other routes 3.12 litres h(-1) per 70 kg, elimination clearance of M3G 17.4 (43.0) litres h(-1), elimination clearance of M6G 5.8 (73.8) litres h(-1). All parameters are standardized to a 70 kg person using allometric 3/4 power models and reflect fully mature adult values. The volume of distribution increased exponentially with a maturation half-life of 26 days from 83 litres per 70 kg at birth; formation clearance to M3G and M6G increased with a maturation half-life of 88.3 days from 10.8 and 0.61 litres h(-1) per 70 kg respectively at birth. Metabolite formation decreased with increased serum bilirubin concentration. Metabolite clearance increased with age (maturation half-life 129 days), and appeared to be similar to that described for glomerular filtration rate maturation in infants. CONCLUSION: M3G is the predominant metabolite of morphine in young children and total body morphine clearance is 80% that of adult values by 6 months. A mean steady-state serum concentration of 10 ng ml(-1) can be achieved in children after non-cardiac surgery in an intensive care unit with a morphine hydrochloride infusion of 5 micro g h(-1) kg(-1) at birth (term neonates), 8.5 micro g h(-1) kg(-1) at 1 month, 13.5 micro g h(-1) kg(-1) at 3 months and 18 micro g h(-1) kg(-1) at 1 year and 16 micro g h(-1) kg(-1) for 1- to 3-yr-old children.

Aging↗

Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age.

BACKGROUND: There are few data describing levobupivacaine pharmacokinetics in infants (<3 months) after caudal administration. METHODS: An open-label study was undertaken to examine the pharmacokinetics of levobupivacaine 2.5 mg ml(-1), 2 mg kg(-1) in children aged less than 3 months after single-shot caudal epidural administration. Plasma concentrations were determined at intervals from 0.5 to 4 h after injection. A population pharmacokinetic analysis of levobupivacaine time-concentration profiles (84 observations) from 22 infants with mean postnatal age (PNA) 2.0 (range 0.6-2.9) months was undertaken using non-linear mixed effects models (NONMEM). Time-concentration profiles were analysed using a one-compartment model with first-order input and first-order elimination. Estimates were standardized to a 70 kg adult using allometric size models. RESULTS: Population parameter estimates (between-subject variability) for total levobupivacaine were clearance (CLt) 12.8 [coefficient of variation (CV) 50.6%] litre h(-1) 70 kg(-1), volume of distribution (Vt) 202 (CV 31.6%) litre 70 kg(-1), absorption half-life (Tabs) 0.323 (CV 18.6%) h 70 kg(-1). Estimates for the unbound drug were clearance (CLfree) 104 (CV 43.5%) litre h(-1) 70 kg(-1), volume of distribution (Vfree) 1700 (CV 44.9%) litre 70 kg(-1), absorption half-life (Tabsfree) 0.175 (CV 83.7%) h 70 kg(-1). There was no effect attributable to PNA on CL or V. Time to peak plasma concentration (Tmax) was 0.82 (CV 18%) h. Peak plasma concentration (Cmax) was 0.69 (CV 25%) microg ml(-1) for total levobupivacaine and 0.09 (CV 37%) microg ml(-1) for unbound levobupivacaine. CONCLUSIONS: Clearance in infants is approximately half that described in adults, suggesting immaturity of P450 CYP3A4 and CYP1A2 enzyme isoforms that metabolize levobupivacaine in infants. This lower clearance delays Tmax, which was noted to occur approximately 50 min after administration of caudal epidural levobupivacaine.

Aging↗

Body weight changes in elderly psychogeriatric nursing home residents.

OBJECTIVE: This study was undertaken to identify predictors of body weight change in nursing home patients with possible to severe dementia. METHODS: For 24 weeks, 108 elderly residents of a nursing home were followed. Body weight was measured every 2 weeks. Other anthropometric characteristics, dietary intake, food behavior restrictions, psychological characteristics, medical status, and use of medicines were measured at baseline. Dietary intake was measured with a combined 3-day food record and by observations during the hot meals. Food behavior restrictions were measured following the classification of Berkhout. Dependency was measured by a questionnaire (Care Index Geriatrics), which measures restrictions in cognitive, physical, and social functioning. A generalized linear mixed effects model was used to investigate weight changes over time. The model was adjusted for age and sex. RESULTS: During the follow-up period, 26% of the participants lost and 22% gained at least 2 kg of body weight. Dependency (beta = -0.11, 95% confidence interval [CI] = -0.21, -0.01) and decreased appetite (beta = -2.17, 95% CI = -4.32, -0.01) were significantly associated with body weight loss, whereas body mass index (beta = 2.25, 95% CI = 1.98, 2.51) and intake of fat (beta = 0.07, 95% CI = 0.01, 0.15) were predictors of weight gain. CONCLUSION: Dependency, body mass index, intake of fat, and decreased appetite are significant predictors of body weight changes.

Activities of Daily Living↗

Self-rated health in a longitudinal perspective: a 9-year follow-up twin study.

OBJECTIVES: This study first considers age and cohort explanations for age-related changes in mean values and variance in self-rated health. Second, it evaluates the contributions of genes and environments to self-rated health measured longitudinally. METHODS: Subjects were participants in the Swedish Adoption/Twin Study of Aging. Self-rated health assessments were collected in four waves over a 9-year follow-up period, from one or both members of 788 twin pairs. Linear mixed effect models were used to test for differences in means and variances. Structural equation modeling provided estimates of genetic and environmental components of variance and contributions to stability. RESULTS: Changes in means and variance within cohorts seem to reflect illness. Earlier-born cohorts are more variable and have lower self-rated health. These cohort differences were not explained by childhood socioeconomic status. Correlations between time points reflect both environmental and genetic factors. DISCUSSION: Both genes and environments contribute to self-rated health longitudinally, and both age and cohort effects are seen. Age-related changes in self-rated health can be attributed to illness. Cohort differences are most likely attributable to socially mediated and individual-specific environmental factors.

Adoption↗

The role of mental morbidity in the nursing home experience.

The history of a newly admitted cohort to eight nursing homes (N = 454) was studied prospectively over the first year of residence. Data were gathered at admission, 2 months, and 1 year, and included full psychiatric examination and staff reports of behavior. Chart reviews collected additional data on preadmission and postdischarge information. At admission, 80% of the population had mental illnesses, 60% of which were dementia, and about half of demented patients had other complicating mental illnesses. Use of mixed-effects linear model analysis revealed significant associations of mental morbidity, restraints, and psychotropic medication with behaviors indicative of noncoping and nonadaptation to the nursing home settings.

Adaptation, Psychological↗