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PubMed2003

Ecological constraints on extra-pair paternity in the bluethroat.

The mating system of the bluethroat (Luscinia s. svecica) involves a high level of sperm competition, and consequently a high frequency of extra-pair paternity (EPP). There is considerable variation in the frequency of EPP. Over the course of ten study years in a population in Norway, the frequency has fluctuated between 7% and 33% of young, and 8% and 76% of broods. In this paper, we address the issue of whether ecological factors can explain some of the variation in EPP between years and broods. Factors include breeding density, breeding synchrony and two meteorological variables (ambient temperature and precipitation) during the period of peak female fertility. There were no significant relationships between annual averages of the four variables and the annual level of EPP, but the statistical power of these tests was low, due to a restricted sample (n=10 years). Focussing on individual broods, none of the factors had significant effects when including all broods in the analyses (including those with zero EPP). When limiting the analyses to broods with one or more extra-pair offspring, morning temperature had a significant effect on the frequency of EPP. When the temperature was low during the peak of the fertile period, EPP occurred less frequently. Male extra-pair behaviour was not generally constrained by synchrony between the fertile periods of the social mate and the extra-pair mate, but for a subgroup of males ("unattractive males") there appeared to be a trade-off between mate guarding and pursuing extra-pair copulations. Our results indicate that ecological conditions have no influence on whether or not a brood will contain extra-pair offspring, but when EPP does occur, its frequency is influenced by air temperature. Possibly, there is a causal relationship between weather conditions and the frequency of extra-pair encounters in this species. The breeding season is initiated at a phenologically early stage, when large parts of the territories are still covered with snow, and cold weather conditions may force the birds to devote most of their time to maintenance and thereby constrain sexual activities.

Animals↗
PubMed2005

Serum immunoglobulin G levels are positively related to reproductive performance in a long-lived seabird, the common tern (Sterna hirundo).

The evolution of longevity requires a low risk of mortality from extrinsic factors, relative to intrinsic factors, so that individuals that differentially invest in physiological self-maintenance and minimize their annual reproductive costs will maximize lifetime fitness through a prolonged reproductive lifespan. The trade-off between reproductive effort and self-maintenance, as measured by immune function, has been well documented in short-lived birds, but is difficult to demonstrate in long-lived birds. To assess self-maintenance in a long-lived seabird, we measured serum protein levels, including immunoglobulin G (IgG = IgY), in 30 breeding pairs of common terns (Sterna hirundo) and their first-hatched (A) chicks. Most parents were of known age from banding as hatchlings; our sample was selected to contrast young breeders (6-9 years) with very old birds (17-23 years). Body-mass of the parents declined by 5% during the chick-rearing period, while serum protein levels were stable. Serum IgG levels were higher in parents of offspring with faster growth rates, while IgG levels were lower in parents whose broods were reduced by starvation. A-chicks in broods of two had higher IgG levels than singleton chicks. Albumin levels were not related to reproductive performance. Thus, despite adequate statistical power, we could find no evidence for a trade-off between reproduction and self-maintenance in common terns, even in old age. The results are consistent with life-history predictions for long-lived vertebrates, in which selection favors sustained self-maintenance across the reproductive lifespan. The positive relationships between IgG levels and reproductive performance indicate that IgG can be used as an index of parental "quality."

Aging↗
PubMed2005

Impact of chemotherapy-induced neutropenia on quality of life: a prospective pilot investigation.

PURPOSE: In this exploratory, prospective study evaluated quality of life (QoL) changes in patients with diverse cancers during the first cycle of myelosuppressive chemotherapy. PATIENTS AND METHODS: Of 80 patients enrolled, 71 were observed during one of five chemotherapy regimens: docetaxel; CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone); carboplatin-paclitaxel; carboplatin-docetaxel; and carboplatin-gemcitabine. Complete blood counts were taken weekly. QoL and symptom burden measures were administered at baseline and throughout the cycle, and included SF-36, Cancer Care Monitor (CCM), Hospital Anxiety and Depression Scale (HADS), and Psychosocial Adjustment to Illness Scale (PAIS). Using generalized estimating equations, we modeled the change in each measure from baseline to the end of each week using the following covariates: baseline QoL measure, baseline SF-36 Physical and Mental Health Summary scores, sex, age, cycle week, grade 4 neutropenia any time in the past 7 days (yes/no), and the interaction of the latter two covariates. RESULTS: Of the 71 patients observed, 33 developed grade 4 neutropenia during the first 2 weeks. Changes from baseline in SF-36 Bodily Pain, HADS Anxiety, and PAIS Social Environment scores were significantly less favorable (P<0.05) when patients experienced grade 4 neutropenia any time in the past 7 days compared to when they did not (grade 0-3). A similar, but non-significant, trend was also observed for 12 other QoL measures. CONCLUSION: QoL may be adversely affected up to 7 days after patients experience grade 4 (versus grade 0-3) neutropenia. Such findings need to be examined further in studies with adequate statistical power to test a priori hypotheses regarding specific QoL measures.

Adaptation, Psychological↗
PubMed2006

Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample.

Alterations in the serotonergic pathway have been implicated in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate seven genetic variants in three genes (serotonin transporter (5-HTT), serotonin receptor 1B (5-HTR1B) and serotonin receptor 2A (5-HTR2A)), which have previously been shown to be associated with ADHD. The polymorphisms under investigation were the 5-HTTLPR, the VNTR in intron 2 and the 3'UTR SNP in 5-HTT, the 5-HTR1B variations 861G>C and 102T>C, and the 5-HTR2A variations His452Tyr and 1438G>A. We genotyped these variants in a sample of 102 families with 229 children with ADHD according to DSM-IV criteria. Among the affected children, 69% fulfilled criteria for the combined type, 27% for the predominantly inattentive type, and 4% for the predominantly hyperactive-impulsive type. Associations were tested by the pedigree transmission disequilibrium test (PDT). All investigated polymorphisms in serotonergic candidate genes showed no association to ADHD in our sample. Earlier studies of these polymorphisms had also shown inconsistent results, with some studies reporting significant associations and others demonstrating no association. This discordance between studies may reflect variation in patient ascertainment criteria, genetic heterogeneity, too low statistical power for the expected effects or false positive results in the initial reports. We cannot rule out the possibility that other variations in the investigated genes contribute to the etiology of ADHD.

Adult↗
PubMed2000

No association between the alpha2-macroglobulin (A2M) deletion and Alzheimer's disease, and no change in A2M mRNA, protein, or protein expression.

A polymorphism consisting of a deletion near the 5' splice site of exon 18 on the alpha2-macroglobulin (A2M) gene (A2M-2) has been suggested to be associated with Alzheimer's disease (AD) in family-based studies. We studied the A2M-2 allele together with the ApoE alleles in a large series on patients with AD (n = 449) and age-matched controls (n = 349). Neuropathologically confirmed diagnoses were available in 199 cases (94 AD and 107 control cases). We found no increase in A2M-2 genotype or allele frequencies in AD (27.5% and 14.6%) versus controls (26.4% and 14.9%). In contrast, a marked increase (p < 0.0001) in ApoE epsilon4 genotype or allele frequencies was found in AD (66.6% and 41.2%) as compared with controls (29.8% and 16.5%), suggesting sufficient statistical power in our sample. No relation was found between the A2M-2 and the ApoE epsilon4 allele. No change in A2M exon 17-18 mRNA size or sequence or A2M protein size was found in cases carrying the A2M-2 deletion, suggesting that there is no biological consequences of the A2M intronic deletion. No change in A2M protein level in cerebrospinal fluid was found in AD, suggesting that the A2M-2 allele does not effect the A2M protein expression in the brain. The lack of an association between the A2M-2 allele and AD in the present study, and the lack of abnormalities in the A2M mRNA or protein suggest that the A2M-2 allele is not associated with AD.

Aged↗
PubMed2004

A step too far? Randomized trial of cognitive-behaviour therapy delivered by social workers to depressed adolescents.

OBJECTIVE: To test the hypothesis that depressed adolescents given brief cognitive behaviour therapy by trained social workers will be less depressed after this treatment than depressed adolescents who have routine care from their social workers. METHOD: Open study, two randomized parallel groups. 86 social workers were randomized to training in brief CBT or delayed training by remote telephone randomization. 25 social workers who attended CBT training recruited 29 depressed adolescents. 22 social workers in the control group recruited 23 depressed adolescents. RESULTS: Social workers' perceptions of their knowledge and skills in dealing with adolescent depression were better after the training than before. However, in intention to treat analyses, adolescents who had therapy from trained social workers had a similar level of depression post treatment (mean depression score 17.5, 95% CI 11.8 to 23.3) to those who did not have such therapy (mean depression score 16.7, 95 % CI 11.3 to 22.1). There were no significant differences between the groups on other outcomes or at follow-up. CONCLUSIONS: This study failed to recruit enough cases and probably did not therefore have enough statistical power to detect an effect of the intervention. It was also based on a severely impaired sample with many comorbid problems. However, the results suggest that training community-based social workers in cognitive behaviour therapy is neither practical nor effective in improving the outcomes of their clients.

Adolescent↗
PubMed2002

Conduit choice for above-knee femoropopliteal bypass grafting in patients with limb-threatening ischemia.

Many surgeons consider PTFE to be the conduit of choice for above-knee femoropopliteal bypass grafting, since PTFE is relatively easy to implant and spares autogenous saphenous vein (ASV) for subsequent peripheral or coronary artery bypass grafting (CABG). This practice has recently been challenged, as some studies have suggested that ASV may exhibit superior patency in certain patient subgroups. The purpose of this retrospective study was to examine the contemporary outcome of above-knee femoropopliteal bypass grafting in patients with limb-threatening ischemia. Between January 1995 and December 2000, 159 above-knee femoropopliteal bypass grafts were created for limb-threatening ischemia (rest pain or tissue loss). There was a high incidence of comorbid illness, including open foot wounds at the time of operation (62%), hypertension (58%), coronary artery disease (53%), diabetes mellitus (36%), cerebrovascular disease (23%), prior contralateral bypass or amputation (21%), disadvantaged or "blind" outflow (19%), prior ipsilateral bypass (14%), prior CABG (11%) end-stage renal failure (7%). The use of PTFE predominated (n = 11), with a minority of grafts comprising single-segment ipsilateral or contralateral ASV (n = 18). Although the small number of patients undergoing ASV grafting limited the statistical power of comparison, our results suggest that above-knee ASV performs better than PTFE in patients with limb-threatening ischemia.

Aged↗
PubMed2006

Study of AZFc partial deletion gr/gr in fertile and infertile Japanese males.

A recurrent partial azoospermia factor C (AZFc) deletion, called gr/gr, has been reported to be a male infertility risk factor. A specific type of Y chromosome observed in approximately 30% of Japanese males (haplogroup D derived at YAP+) is believed to have a fixed gr/gr deletion. A recent study claimed that spermatogenic failure is more likely in males with D Y chromosomes, because of the gr/gr deletion, the presence of which is not well characterized among D haplogroup chromosomes. We therefore decided to perform a systematic study of the frequency of the gr/gr deletion in the Japanese. We studied fertile and infertile males to investigate the possibility of different gr/gr frequencies. The deletions were detected by use of single tagged-sequences (STSs) and the D haplogroup sub-lineages typing were done by use of the biallelic markers M174, M64, M116.1, 12f2.2, M15, M151, and M125. Analysis of gr/gr deleted Y chromosomes showed that all are classified as haplogroup D2, suggesting a lineage association. The subtype D2b1 was most frequent among the Japanese, in control and infertile samples. The haplogroups D2b2, D*, and D1 were not found in any population group. Remarkably, we observed no statistical difference between haplogroup D sub-lineages of the infertile and control groups, although the statistical power of this study is low. This study suggests lack of significant evidence of increased infertility risk in haplogroup D Japanese males. We were also able to establish the ancestral chromosome that suffered a gr/gr deletion, and propose a new Y chromosome phylogeny for haplogroup D and its derivatives. In summary, we were able to define the frequency of gr/gr deletion in Japanese males and show that the gr/gr deletion was probably present in the ancestral Y chromosome that entered Japan at least 12,000 years ago.

Asian People↗
PubMed2005

Validation of glutathione quantitation from STEAM spectra against edited 1H NMR spectroscopy at 4T: application to schizophrenia.

OBJECTIVE: Quantitation of glutathione (GSH) in the human brain in vivo using short echo time 1H NMR spectroscopy is challenging because GSH resonances are not easily resolved. The main objective of this study was to validate such quantitation in a clinically relevant population using the resolved GSH resonances provided by edited spectroscopy. A secondary objective was to compare several of the neurochemical concentrations quantified along with GSH using LCModel analysis of short echo time spectra in schizophrenia versus control. MATERIALS AND METHODS: GSH was quantified at 4T from short echo STEAM spectra and MEGA-PRESS edited spectra from identical volumes of interest (anterior cingulate) in ten volunteers. Neurochemical profiles were quantified in nine controls and 13 medicated schizophrenic patients. RESULTS: GSH concentrations as quantified using STEAM, 1.6 +/- 0.4 micromol/g (mean +/- SD, n = 10), were within error of those quantified using edited spectra, 1.4 +/- 0.4 micromol/g, and were not different (p = 0.4). None of the neurochemical measurements reached sufficient statistical power to detect differences smaller than 10% in schizophrenia versus control. As such, no differences were observed. CONCLUSIONS: Human brain GSH concentrations can be quantified in a clinical setting using short-echo time STEAM spectra at 4T.

Adult↗
PubMed2004

Long-term survival after local excision for T1 carcinoma of the rectum.

PURPOSE: Many authors have reported high rates of local recurrence after local excision for early carcinoma of the rectum, which raises the question of whether oncologic resection gives better results. This study was designed to compare the long-term recurrence rate, long-term survival, and risk factors for T1 adenocarcinoma of the rectum treated with local excision or oncologic resection. METHODS: We identified 144 patients who had T1 sessile adenocarcinoma in the lower third or middle third of the rectum. Patients who received adjuvant therapy or who had pedunculated lesions were excluded. Data included age, gender, size of lesion, histologic type of carcinoma, grade, presence of lymphovascular invasion, and depth of invasion. Outcomes were defined as five-year and ten-year cumulative probabilities of local recurrence, distant metastasis, overall survival, and cancer-free survival. The mean follow-up was 9.2 years; median follow-up was 8.1 years. RESULTS: We compared 70 patients who underwent local excision with 74 patients who underwent oncologic resection. Among patients with lesions in the middle or lower third of the rectum, 1) the five-year and ten-year outcomes were significantly better for overall survival and cancer-free survival in the oncologic resection group, but there were no significant differences in local recurrence or distant metastasis; 2) the multivariate risk factors for long-term, cancer-free survival were invasion into the lower third of the submucosa, local excision, and older than aged 68 years; and 3) for lesions with invasion into the lower third of the submucosa, the oncologic resection group had lower rates of distant metastasis and better survival. Among patients with lesions in the lower third of the rectum, 1) the five-year and ten-year outcomes showed no significant differences in survival, local recurrence, or distant metastasis between the two groups; and 2) for lesions with invasion into the lower third of the submucosa, the oncologic resection group showed a trend of improved survival, which was not statistically significant, possibly because of low statistical power from the small sample size. CONCLUSIONS: Patients who undergo local excision or oncologic resection for T1 carcinoma in the lower two-thirds of the rectum have a high incidence of local recurrence and distant metastasis. To improve the cure rate, the rate of recurrence must decrease. A randomized, controlled study is needed to determine whether adjuvant therapy may be beneficial.

Adenocarcinoma↗
PubMedDate not supplied

Effects of topical phenylephrine on blood flow in the posterior segments of monkey and aged human eyes.

PURPOSE: The aim of this study was to evaluate the effects of topical 5% phenylephrine on circulation in the optic nerve head (ONH) of cynomolgus monkeys and in the central retinal artery (CRA) of aged patients. METHODS: In five monkeys, ONH tissue blood velocity (NB(ONH)), determined using the laser speckle method, and intraocular pressure (IOP), blood pressure (BP), and pulse rate (PR) were measured 2 h after a single unilateral instillation and after a 7-day twice-daily unilateral instillation of phenylephrine. In 20 aged patients (mean age: 70.4 years), the CRA circulation indices were determined by color Doppler imaging (CDI), and IOP, BP, and PR were measured before and after four serial unilateral instillations at 30-min intervals of phenylephrine. RESULTS: In the monkeys, there was no significant change in IOP, BR, or PR, while NB(ONH) decreased 2 h after a single instillation ( P = 0.080) and after a 7-day instillation ( P = 0.043). In theaged patients, IOP in the phenylephrine-treated eyes significantly increased ( P = 0.022), while the CDI indices, BR, and PR did not. In this CDI assessment, the statistical power to detect significant changes (P < 0.05) in the resistive index was estimated as 4.8% of the standard deviation. CONCLUSIONS: Topical phenylephrine decreased the ONH tissue blood velocity in monkeys, suggesting possible risks regarding circulation in the posterior portion of the eye. However, these effects were not observed in the CRA circulation in the patients.

Administration, Topical↗
PubMed2005

Reformulating and simplifying the DF analysis model.

DeFries-Fulker (DF) Analysis for unselected populations is reformulated as a no-intercept model with centered variables and only two independent variables. The reformulation serves three purposes. First, the original formulation implicitly estimated two different values for c2 and two values for h2. The new formulation resolves this ambiguity. Second, because the original formulation estimated h2 with the coefficient from a regression-interaction term, whether to center the interaction variables was unclear. The new formulation explicitly resolves this issue. Finally, the new formulation estimates fewer parameters, and therefore improves estimation efficiency and statistical power.

Fertility↗
PubMed2004

Designing the future shape of breast cancer diagnosis, prognosis and treatment.

Translational research is intended to efficiently and accurately validate the most promising preclinical biomarkers and ensure that their diagnostic or prognostic potential is rapidly adopted in the clinic. Translational research therefore needs to take into account the biological complexity that is inherent in all cellular pathways, such as the estrogen and progesterone receptor pathways, and yet produce conclusions that will have sufficient statistical power to define and shape clinical practice. This will be achieved through the incorporation of new concepts of trial design, including neoadjuvant or preoperative hypothesis-generating studies, and the increasing use of high-throughput proteomic and genomic approaches. Clinical trials will be increasingly designed to incorporate biomarker analyses, and ongoing trials may employ the retrospective collection of archival tissues to allow the use of prospectively planned biomarker analyses. This approach is being utilized in the TA01 program, which is based upon the 'Arimidex', tamoxifen, alone or in combination (ATAC) trial. The resulting incorporation of new biomarkers and revised trial designs should promote the future development of more precise and increasingly active interventions directed towards the treatment of breast cancer.

Biomarkers, Tumor↗
PubMed2004

Expression of sigma 1 receptor in human breast cancer.

The sigma 1 receptor (S1R) represents a unique drug-binding site that is distinct from any other receptors. We examined S1R expression in human breast cancer and assessed the activity of S1R ligands in breast cancer cell lines. One-hundred nine breast specimens from normal breast, benign breast disease and cancer were examined with immunohistochemistry or RT-PCR and six different cell lines were also evaluated. S1R mRNA overexpression was detected in 64% of breast cancers compared to normal breast tissue. Immunohistochemistry showed positive epithelial cell staining in 60% of invasive and 41% of in situ cancers, 75% of ductal hyperplasia and in 33% of normal breast. The pattern of expression was more diffuse in invasive breast carcinoma compared to other conditions (p = 0.02). S1R expression was neither a prognostic nor a predictive factor for efficacy of adjuvant chemotherapy but the study only included 58 cancer patients and therefore the statistical power is limited. MDA-MB-361, MDA-MB-435, BT20 and MCF7 cells all expressed S1R protein by Western blot. The non-specific S1R ligands haloperidol, reduced haloperidol and progesterone produced a dose-dependent inhibition of the growth at high (>10 microM) concentrations. Reduced haloperidol also showed additive cytotoxic effects when combined with doxorubicin, vinorelbine , paclitaxel and docetaxel in vitro. The S1R-specific ligand, SKF 10047 demonstrated the least growth inhibitory activity and showed no interaction with chemotherapy. These results demonstrate that some normal and most neoplastic breast epithelial cells and cell lines commonly express S1R. High concentrations of haloperidol inhibit the growth of these cells and potentiate the effect of chemotherapy in vitro.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Influence of timing of initiation of adjuvant chemotherapy over survival in breast cancer: a negative outcome study by the Spanish Breast Cancer Research Group (GEICAM).

PURPOSE: This retrospective trial evaluates whether the timing of initiation of the adjuvant chemotherapy has any influence over survival in early-stage breast cancer. PATIENTS AND METHODS: A total of 2782 patients from El Alamo project (from 1990 to 1997; n = 15,400) were selected with stages I-III, surgery and adjuvant chemotherapy. Data were gathered about prognostic factors such as age, tumor size, vessel permeation (vascular or lymphatic), histological grade, and number of involved nodes, hormonal receptor status and administration of hormone therapy. The time interval between surgery and initiation of chemotherapy, and dates of relapse, second primary breast tumor and death were recorded. Patients were assigned in four groups according to the surgery-chemotherapy interval: <3 weeks (group A), 3-6 weeks (group B), 6-9 weeks (group C) and >9 weeks (group D). RESULTS: There were no differences in disease-free survival (DFS), nor in 5-year overall survival (OS), according to the timing of initiation of adjuvant chemotherapy. Cox proportional hazards model was used to adjust analysis for known prognostic factors but the effect of surgery-chemotherapy interval remained non-significant. The variable timing of initiation of adjuvant chemotherapy has also been assessed as a continuous variable and no differences have been detected. CONCLUSION: The optimum time of initiation of adjuvant chemotherapy in early stages of breast cancer is unknown. The delay in the initiation of adjuvant chemotherapy has no influence over survival in the analyzed time intervals. Retrospective analysis like this one with enough statistical power would be necessary to detect differences among groups.

Adult↗
PubMed2006

Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF).

PROBLEM: Intravenous Immunoglobulins (IVIG) are widely used off label in the treatment of early reproductive failure. As IVIG is expensive, and may have side-effects, evidence of efficacy is needed. Previous results have suggested that the pre-conception treatment of primary recurrent abortion patients might be effective, but the data set has been too small for adequate statistical power. More recently it has been suggested that IVIG may improve the success rate of in vitro fertilization and embryo transfer (IVF) in patients with prior IVF failures, but clinical trials have given conflicting results that need explanation. Systematic reviews generating inconclusive results have focused on methodological rigor to the exclusion of biological plausibility. METHODS: Review of current basic science of design, measurement, and evaluation of clinical trials and basic science mechanisms providing a rationale for treatment. Meta-analysis of published randomized controlled and cohort-controlled trials (updated with two unpublished data sets) evaluating IVIG treatment in IVF failure patients. Live birth rate was used as the most relevant endpoint. The ability of different sources of IVIG to suppress natural killer (NK) cell activity was determined using a standard (51)Cr-release assay in vitro. RESULTS AND CONCLUSIONS: Meta-analysis of three published randomized controlled trials (RCTs) of IVIG in IVF failure patients shows a significant increase in the live birth rate per woman (p = 0.012; Number Needed to Treat for 1 additional live birth, NNT = 6.0 women). Using live birth rate per embryo transferred, and adding data from two cohort-controlled trials to the meta-analysis further supports this conclusion (overall p = 0.000015, NNT = 3.7 women). Relevant variables appear to include properties and scheduling of the IVIG, and selection of patients with abnormal immune test results. Different IVIG preparations vary significantly in their ability to suppress NK activity in vitro. A rationale for use of IVIG is provided by a review of mechanisms of IVIG action and mechanisms underlying failure of chromosomally normal embryos.

Adult↗
PubMed2006

The effect of addition of nitrous oxide to a sevoflurane anesthetic on BIS, PSI, and entropy.

OBJECTIVE: N(2)O is a commonly used anesthetic that has amnestic and analgesic properties. Recently, devices that estimate depth of consciousness have been introduced in an attempt to better titrate anesthesia, however the effect of N(2)O on these monitors is unclear. METHODS: General anesthesia was induced and titrated to maintain normal blood pressure and pulse in healthy adults. Data were collected in three 10 minute intervals (Sevo, Sevo + N(2)O, Sevo). In Phase A, sevoflurane concentration was held constant during the N(2)O trial in 60 subjects monitored with either BIS, PSI, or Entropy. In Phase B, sevoflurane concentration was reduced as N(2)O was added, maintaining a constant overall "MAC" in 20 subjects monitored concurrently with BIS and Entropy. Sample size for both phases was designed to detect a 10 unit change in measure of processed EEG with alpha = .05 and statistical power = .80. RESULTS: In Phase A, supplementing sevoflurane with > 65% N(2)O increased MAC from 1.3 +/- 0.05 to 2.2 +/- 0.10, but did not significantly alter BIS nor PSI (p-value for differential MAC is < 0.05). Entropy, however, dropped significantly, with a change in state entropy (SE) from 31.1 +/- 7.3 to 18.9 +/- 3.7 and a corresponding rise when N(2)O was discontinued. In Phase B, supplementing sevoflurane with > 65% N(2)O with a concomitant reduction in sevoflurane resulted in an increase in both BIS (from 34 +/- 5 to 53.9 +/- 11.5) and SE (from 32 +/- 8.2 to 55.4 +/- 21.3). CONCLUSION: Supplementing sevoflurane with > 65% N(2)O did not result in a significant change in either BIS or PSI when sevoflurane concentration was kept constant. Entropy, however, significantly decreased as anesthetic depth increased. When sevoflurane concentration was reduced during N(2)O administration, both BIS and Entropy rose despite maintenance of anesthetic depth, indicating a variable concentration effect between volatiles and N(2)O.

Adult↗
PubMed2005

Propagation of population PK and PD information using a Bayesian approach: dealing with non-exchangeability.

The aim of this work is to implement a conservative prior that safeguards against population non-exchangeability of prior and data likelihood, in the framework of population pharmacokinetic/pharmacodynamic analysis, incorporating multi-level hierarchical modelling. Three different exercises were performed: (i) we investigated the use of parametric priors in the multilevel hierarchical modelling framework; (ii) we assessed the average performance of the multilevel hierarchical model compared to the standard mixed effect model, considering also some interesting extreme cases and (iii) we implemented an application with a small Proof of Principle (PoP) study, which demonstrates the propagation of information across PD studies using multilevel modelling. Fitting with the 4-level model and informative parametric priors performed similar to a meta-analysis of the test datasets combined with the datasets that the priors came from, demonstrating that parametric priors can be used alternatively to meta-analysis. Further, the 4-level model gave posterior distributions which had larger uncertainty but at the same time were unbiased, compared to the 3-level model, and therefore implements a more conservative prior in a formal way, which is appropriate when the prior and the test populations are not exchangeable. For the application with the PoP study, the statistical power of detecting the difference in potency between two drugs, when inter-study variability was present, was greater when an extra level in the hierarchical model to account for it, was used. In conclusion, by applying the prior one hierarchical level above the level of the parameters of interest, we implemented a more conservative prior, compared to applying the prior directly on the parameters of interest. The approach is equivalent to Bayesian individualization, offers a safeguard against bias from the prior and also avoids the danger of the data being overwhelmed by a strong prior.

Bayes Theorem↗