Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “double robustness”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 415 records · Page 23Linked to original sources
PubMed2005

Cost-effectiveness of once-daily treatment with calcipotriol/betamethasone dipropionate followed by calcipotriol alone compared with tacalcitol in the treatment of Psoriasis vulgaris.

BACKGROUND: Daivobet is a once-daily treatment of psoriasis vulgaris containing betamethasone dipropionate and calcipotriol in a new ointment vehicle. OBJECTIVE: To assess the cost-effectiveness of once-daily treatment with Daivobet (4 weeks) followed by calcipotriol (4 weeks) compared to tacalcitol (8 weeks). METHODS: Resource utilization was assessed within a double-blind 8-week clinical trial (all treatments for psoriasis, adverse events and concomitant dermatological medication), estimated from the French societal perspective. RESULTS: Total direct medical costs for psoriasis were comparable (Daivobet: EUR 107.53 and tacalcitol EUR 113.50) despite a higher acquisition cost for Daivobet. The probability of > or =75% reduction in the Psoriasis Area and Severity Index (effectiveness criterion) was 46.6% with Daivobet and 13.9% with tacalcitol at 4 weeks, and 44.6 and 23.8%, respectively, at 8 weeks (both: p < 0.001). Over 8 weeks, Daivobet was almost twice as cost-effective as tacalcitol (EUR 241.22 per successful treatment vs. EUR 476.70); this result was robust to sensitivity assumptions. CONCLUSION: Daivobet is more effective and less costly than tacalcitol for treating psoriasis.

Administration, Topical↗
PubMedDate not supplied

Adaptive blood pool segmentation in three-dimensions: application to MR cardiac evaluation.

MRI is an established method of imaging the cardiac blood pool in four dimensions and evaluating global cardiac function. However, segmentation of the cardiac blood pool from the myocardial wall continues to be a time-consuming task and is operator dependent. This has hampered the widespread use of cardiac MRI in evaluating global cardiac function. We propose the use of an adaptive threshold-based, three-dimensional region-growing technique to segment the cardiac blood pool from the myocardium and to compute left ventricular blood volumes. It uses a unique double segmentation approach incorporating information from the myocardium to help better detect the edges of the blood pool. The adaptive threshold segmentation technique was evaluated on four human subjects by comparing with manual segmentation. Further, it requires minimal operator input and is robust and user friendly. The conclusion is that adaptive thresholds and a multidimensional region-growing approach is an appropriate method to segment the left ventricular blood pool.

Adult↗
PubMed2007

Analysis of antiretroviral immunotherapy trials with potentially non-normal and incomplete longitudinal data.

For many HIV-infected patients, use of antiretroviral therapy (ART) results in a sustained suppression of plasma viral load to undetectable levels. However, due to lack of antigenic stimulation, this may also result in a gradual loss of cell-mediated immune (CMI) responses that help control HIV infection. In concept, augmenting ART with periodic administrations of an HIV vaccine that boosts CMI responses could enhance control of viral replication. Researchers are designing 'antiretroviral immunotherapy' (ARI) trials to test this hypothesis. In a typical ARI trial, HIV-infected patients with sustained viral suppression will receive inoculations of an experimental HIV vaccine or a placebo, and subsequently stop taking their antiretroviral drugs. The goal is to assess whether plasma viral loads during the ART interruption phase are generally lower in the vaccine group. Assessment of a vaccine effect will be challenging if some subjects resume ART or drop out before the end of the treatment interruption phase. To tackle this 'missing' data problem and potential non-normality of the viral loads in ARI trials, we propose a two-step approach: multiple imputation of the missing values followed by use of the Wei-Lachin method with Wilcoxon scores. We use a numerical example and extensive simulations to illustrate the robustness and power advantages of our proposed method compared with other methods for incomplete longitudinal data, including REML, weighted GEE, last observation carried forward, and 'worst-rank' methods. Our proposed method is general enough for the robust analysis of longitudinal data in other therapeutic areas as well.

AIDS Vaccines↗
PubMed1995

Differential effects of the BKCa channel openers NS004 and NS1608 in porcine coronary arterial cells.

The effects of newly claimed BKCa channel openers NS004 (5-trifluoromethyl-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benzimidazo le-2- one) and NS1608 (N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl)urea) were investigated on whole-cell K+ current (IK) in enzymatically isolated porcine coronary arterial cells using patch-clamp technique with a double holding potential protocol. When cells were held at 0 mV, IK was augmented by NS004 in a concentration-dependent manner. With a holding potential of -60 mV, however, IK was moderately inhibited by NS004 between 0.5 and 10 microM, but robustly stimulated by 50 microM NS004 at highly depolarized potentials. The effects of NS1608 on IK did not differ due to change in holding potential. At -60 mV and 0 mV, NS1608 activated IK with bell-shaped concentration-response curves peaked between 5 and 10 microM. The differential mode of action of the two compounds suggested an involvement of mechanism(s) other than an opening of BKCa channel.

Animals↗
PubMed2026

Redefining the real problem in psychedelic trials: Why fighting the Lessebo matters more than blinding integrity.

Imperfect blinding is not specific to psychedelic trials. In randomized trials, treatment allocation is frequently correctly guessed, yet blinding integrity is rarely assessed outside of psychedelic research and is generally not considered a barrier in regulatory evaluation. The intense debate in psychedelics may reflect a broader double standard affecting mental health research, when uncertainties arising from imperfect blinding are confounded by those linked to patient-reported outcome measures. Indeed, people living with mental disorders are often viewed as unreliable reporters, despite well-documented limitations of clinician-rated scales and the absence of robust biological markers of symptomatic change. Importantly, it is the maintenance of reasonable doubt of treatment allocation that sustains internal validity and ethical feasibility of placebo-controlled designs, rather than perfect blinding. Concerns about expectancy bias in psychedelic trials are closely tied to blinding debates. When allocation is inferred, expectations may cluster in the arm perceived as active or in stereotyped experiences and influence outcomes differently in active and control arms, leading to a risk of lessebo, a negative placebo effect due to the negative expectation related to receiving a placebo. However, we argue that an underrecognized mechanism of lessebo is disappointment. This risk may reflect insufficient clinical management of disappointment rather than pre-treatment expectation alone. We therefore propose shifting the emphasis from preserving inevitably imperfect blinding towards mitigating disappointment in both arms. Establishing non-stereotyped expectations prior to treatment through structured psychoeducation, strengthened therapeutic alliance, and realistic preparation would help avoid lessebo effects. Such strategies would enhance ethical rigor, interpretability, and the clinical usefulness of psychedelic trials.

Humans↗
PubMed1985

Efficacy of lithium-tranylcypromine treatment in refractory depression.

Twelve inpatients with major depression refractory to at least two controlled antidepressant trials had tranylcypromine added to ongoing lithium treatment. Eleven patients showed reliable improvement in nurses' depression ratings compared with a prior trial of lithium added to an antidepressant that was not a monoamine oxidase inhibitor (MAOI). Eight patients were blindly judged much or very much improved, and all 12 patients improved sufficiently to be discharged. Preclinical studies of conjointly administered lithium and MAOIs suggest that central serotonergic pathways may mediate this robust clinical effect.

Adult↗
PubMed1992

Forced-choice versus free-choice procedures: caffeine self-administration in humans.

Methodological comparisons of procedures for drug self-administration are rare. In studies examining the reinforcing effect of caffeine in humans, caffeine self-administration usually has been inferred from performance under forced-choice procedures. In the present experiment, caffeine self-administration via coffee was compared under forced-choice and free-choice conditions; i.e., when subjects were and were not required to use a minimum number of coffees. Ten moderate coffee drinkers (2-7 cups/day) were assigned to forced- and free-choice conditions using a randomized cross-over design. Under each choice condition, subjects completed six independent, double-blind trials, consisting of a 2-day exposure period followed by a 2-day test period. During exposure, subjects consumed either decaffeinated or caffeinated (100 mg/serving) coffee on day 1 and the other coffee on day 2. During the test period, subjects had concurrent access to the same decaffeinated and caffeinated coffees. Under the forced-choice condition, subjects were required to drink at least four cups of coffee per day during the test period. Under the free-choice condition, subjects did not have a minimum-cup requirement. In general, the relative rate at which subjects self-administered caffeinated versus decaffeinated coffee was similar across choice conditions, even though subjects self-administered significantly fewer cups of both coffee types under the free-choice than the forced-choice condition. These results suggest that, at least for caffeine, forced-choice and free-choice procedures produce comparable results. Whether this finding generalizes to a context in which caffeine or another drug is more robustly self-administered, remains to be determined.

Adult↗
PubMed2006

Galantamine improves cognition in schizophrenic patients stabilized on risperidone.

BACKGROUND: Cognition in schizophrenia is impaired in a variety of cognitive domains. Galantamine, a cholinesterase inhibitor with putative nicotinic agonist-like effects, improves cognition in Alzheimer's patients. METHODS: Sixteen schizophrenic or schizoaffective patients stabilized on risperidone were administered galantamine (n=8) or placebo (n=8) in a randomized, double-blind trial. The Repeatable Battery for Assessment of Neuropsychological Status (RBANS) assessed changes in cognitive performance over an eight-week treatment interval. RESULTS: Clinical symptoms improved in both groups during the trial with no evidence that galantamine exacerbated extrapyramidal symptoms. Patients treated with galantamine experienced an overall improvement in cognitive performance (RBANS Total scale score; galantamine = 12.1 +/- 12.8 SD, placebo = .5 +/- 13.5, t = 2.32, p < .04). Confidence intervals suggest that RBANS Attention and Delayed Memory subscale performance was robustly improved in galantamine patients by approximately one standard deviation, effectively normalizing cognitive performance in these domains. CONCLUSIONS: Adjunctive treatment with galantamine improves memory and attention in patients with schizophrenia who are stabilized on risperidone, providing the opportunity to improve functional outcome in these patients.

Adult↗
PubMed2002

A double-blind comparison of desipramine and placebo in children and adolescents with chronic tic disorder and comorbid attention-deficit/hyperactivity disorder.

BACKGROUND: Currently, there is no consensus on the best therapeutic approach to chronic tic disorders and comorbid attention-deficit/hyperactivity disorder (ADHD). To address this issue, we evaluated the tolerability and efficacy of the noradrenergic tricyclic antidepressant desipramine hydrochloride in the treatment of children and adolescents with chronic tic disorders and comorbid ADHD. METHODS: Forty-one children and adolescents with chronic tic disorders, including Tourette disorder and comorbid ADHD, were studied in a 6-week, double-blind, placebo-controlled, parallel trial. Desipramine was titrated weekly up to 3.5 mg/kg per day. We rated ADHD and tic symptoms weekly and monitored adverse effects, laboratory findings, and cardiovascular parameters. RESULTS: Treatment with desipramine (mean total daily dose, 3.4 mg/kg per day) was well tolerated without meaningful adverse effects. Desipramine significantly reduced core symptoms of ADHD (ADHD Rating Scale; 42% decrease from baseline relative to placebo, P<.001), with equal response in inattentive symptoms and hyperactive/impulsive symptoms (P<.001 for both). The ADHD response rate was robust (71% vs 0%; desipramine vs placebo, P<.001). Likewise, desipramine significantly reduced tic symptoms (Yale Global Tic Severity Scale; 30% decrease from baseline relative to placebo, P<.001), with equal response in motor and phonic tic symptoms (P<.01 for both). The tic response rate was substantial (58% vs 5%; desipramine vs placebo, P<.001). There were small but statistically significant differences between desipramine and placebo in heart rate and blood pressure. CONCLUSIONS: Treatment with desipramine was well tolerated and was associated with robust clinically significant reductions in tic and ADHD symptoms in children and adolescents with chronic tic disorders and ADHD diagnoses.

Adolescent↗
PubMed2002

Early induction of secretoneurin expression following kainic acid administration at convulsant doses in the rat and gerbil hippocampus.

The expression of secretogranin-II and its major proteolytic product secretoneurin (SN) is under the control of neuronal excitation, as demonstrated by treating rats with the excitotoxic kainic acid (KA). Differences in the structure and function of the hippocampus in rats and gerbils have been described; these suggest possible differential reactive responses to KA. In the present study, the SN immunostaining pattern in relation with cell damage is analyzed from 6 h to 4 days following KA administration in rats and gerbils. Dramatic differences in the expression of SN were found in the hippocampal complex following KA administration in gerbils and rats. A robust increase in SN immunoreactivity was detected in the pyramidal cell layer of the rat hippocampus, especially in the CA1 area. In the gerbil, however, a strong increase in SN immunostaining was detected in interneurons of the hippocampal formation, as shown by double-labeling immunohistochemistry to SN and the calcium-binding proteins parvalbumin, calbindin, and calretinin. In addition, no damage (in the hippocampal formation) or moderate damage (in the entorhinal cortex) was observed in the gerbil, in contrast to the rat. The administration of KA and the GABA-B receptor inhibitors (CGP56999A or CGP36742) to the gerbil resulted in a strong rise in SN immunoreactitivty in the CA1 pyramidal cell layer of the hippocampus, as in the rat. However, no increased cell damage was observed under these conditions. The present data provide evidence of a species-differential reactive response to KA that might be based, in part, on distinct inhibitory intrahippocampal circuitry.

Animals↗
PubMed2006

Binding hot spots in the TEM1-BLIP interface in light of its modular architecture.

Proteins bind one another in aqua's solution to form tight and specific complexes. Previously we have shown that this is achieved through the modular architecture of the interaction network formed by the interface residues, where tight cooperative interactions are found within modules but not between them. Here we extend this study to cover the entire interface of TEM1 beta-lactamase and its protein inhibitor BLIP using an improved method for deriving interaction maps based on REDUCE to add hydrogen atoms and then by evaluating the interactions using modifications of the programs PROBE, NCI and PARE. An extensive mutagenesis study of the interface residues indeed showed that each module is energetically independent on other modules, and that cooperativity is found only within a module. By solving the X-ray structure of two interface mutations affecting two different modules, we demonstrated that protein-protein binding occur via the structural reorganization of the binding modules, either by a "lock and key" or an induced fit mechanism. To explain the cooperativity within a module, we performed multiple-mutant cycle analysis of cluster 2 resulting in a high-resolution energy map of this module. Mutant studies are usually done in reference to alanine, which can be regarded as a deletion of a side-chain. However, from a biological perspective, there is a major interest to understand non-Ala substitutions, as they are most common. Using X-ray crystallography and multiple-mutant cycle analysis we demonstrated the added complexity in understanding non-Ala mutations. Here, a double mutation replacing the wild-type Glu,Tyr to Tyr,Asn on TEM1 (res id 104,105) caused a major backbone structural rearrangement of BLIP, changing the composition of two modules but not of other modules within the interface. This shows the robustness of the modular approach, yet demonstrates the complexity of in silico protein design.

Alanine↗
PubMed2002

Cortical expression of endothelin receptor subtypes A and B following middle cerebral artery occlusion in rats.

This work aimed to define the spatial expression of endothelin A (ET(A)) and B (ET(B)) receptors in the cerebral cortex after permanent middle cerebral artery occlusion (MCAO) and to identify the phenotype of cells expressing ET(A) and ET(B) receptors. Cortical expression of ET(A) and ET(B) receptors was determined at the mRNA level by semi-quantitative reverse transcription-polymerase chain reaction and at the protein level by immunofluorescence staining, 12, 24 and 72 h after MCAO. Cells expressing endothelin receptors were phenotyped by double labelling with antibodies, anti-protein gene product (PGP9.5) and anti-ED1, towards neurons and activated microglia/macrophages, respectively. Both ET(A) and ET(B) receptor mRNA expressions increased significantly in the ipsilateral cortex in a time-dependent manner after MCAO. Robust expression of ET(A) receptors was noted in most neurons of the ischemic core and in several neurons in laminae 3 and 4 of the peri-infarct region 24 and 72 h after MCAO. ET(B) receptor immunoreactivity was observed in activated microglia/macrophages, beginning 24 h after MCAO. These results provide the first evidence that the action of endothelin during ischemia may be mediated by neuronal ET(A) receptors and activated microglia/macrophage ET(B) receptors. This differential localization of ET(A) and ET(B) receptors suggests that endothelin is involved in some complex neuron-glial interactions in addition to its vascular modulatory activity during ischemia.

Animals↗
PubMed2005

Mechanism of nonhomologous end-joining in mycobacteria: a low-fidelity repair system driven by Ku, ligase D and ligase C.

DNA double-strand breaks (DSBs) can be repaired either via homologous recombination (HR) or nonhomologous end-joining (NHEJ). Both pathways are operative in eukaryotes, but bacteria had been thought to rely on HR alone. Here we provide direct evidence that mycobacteria have a robust NHEJ pathway that requires Ku and a specialized polyfunctional ATP-dependent DNA ligase (LigD). NHEJ of blunt-end and complementary 5'-overhang DSBs is highly mutagenic ( approximately 50% error rate). Analysis of the recombination junctions ensuing from individual NHEJ events highlighted the participation of several DNA end-remodeling activities, including template-dependent fill-in of 5' overhangs, nontemplated addition of single nucleotides at blunt ends, and nucleolytic resection. LigD itself has the template-dependent and template-independent polymerase functions in vitro that compose the molecular signatures of NHEJ in vivo. Another ATP-dependent DNA ligase (LigC) provides a backup mechanism for LigD-independent error-prone repair of blunt-end DSBs. We speculate that NHEJ allows mycobacteria to evade genotoxic host defense.

Antigens, Nuclear↗
PubMed2002

Nuclear DNA C-values in 30 species double the familial representation in pteridophytes.

Nuclear DNA C-values and genome size are important biodiversity characters with fundamental biological significance. Yet C-value data for pteridophytes, a diverse group of vascular plants with approx. 9000 extant species, remain scarce. A recent survey by Bennett and Leitch (2001, Annals of Botany 87: 335-345) found that C-values were reported for only 48 pteridophyte species. To improve phylogenetic representation in this group and to check previously reported estimates, C-values for 30 taxa in 17 families were measured using flow cytometry for all but one species. This technique proved generally applicable, but the ease with which C-value data were generated varied greatly between materials. Comparing the new data with those previously published revealed several large discrepancies. After discounting doubtful data, C-values for 62 pteridophyte species remained acceptable for analysis. The present work has increased the number of such species' C-values by 93 %, and more than doubled the number of families represented (from 10 to 21). Analysis shows that pteridophyte C-values vary approx. 450-fold, from 0-16 pg in Selaginella kraussiana to 72.7 pg in Psilotum nudum var. gasa. Superimposing C-value data onto a robust phylogeny of pteridophytes suggests some possible trends in C-value evolution and highlights areas for future work.

Cell Nucleus↗
PubMed1997

Risperidone: how good is the evidence for efficacy?

This article reviews the published literature evaluating the efficacy of risperidone. The literature includes three multicenter, double-blind studies that compared risperidone, haloperidol, and placebo, as well as three comparisons of risperidone with a standard neuroleptic. Efficacy of risperidone is reported, but most studies involved chronically hospitalized patients who were relatively refractory; the response to standard neuroleptics was not robust. Also, the reported superiority of risperidone on negative symptoms may be artifactual, since standard neuroleptics, because of extrapyramidal symptoms, can mimic or exacerbate negative symptoms. Finally, risperidone may have an antidepressant effect. It is as yet unclear whether risperidone is as effective as standard neuroleptics for positive schizophrenia symptoms in neuroleptic-responsive patients.

Antipsychotic Agents↗
PubMed2005

On the modeling of breath-by-breath oxygen uptake kinetics at the onset of high-intensity exercises: simulated annealing vs. GRG2 method.

Modeling in the time domain, the non-steady-state O2 uptake on-kinetics of high-intensity exercises with empirical models is commonly performed with gradient-descent-based methods. However, these procedures may impair the confidence of the parameter estimation when the modeling functions are not continuously differentiable and when the estimation corresponds to an ill-posed problem. To cope with these problems, an implementation of simulated annealing (SA) methods was compared with the GRG2 algorithm (a gradient-descent method known for its robustness). Forty simulated Vo2 on-responses were generated to mimic the real time course for transitions from light- to high-intensity exercises, with a signal-to-noise ratio equal to 20 dB. They were modeled twice with a discontinuous double-exponential function using both estimation methods. GRG2 significantly biased two estimated kinetic parameters of the first exponential (the time delay td1 and the time constant tau1) and impaired the precision (i.e., standard deviation) of the baseline A0, td1, and tau1 compared with SA. SA significantly improved the precision of the three parameters of the second exponential (the asymptotic increment A2, the time delay td2, and the time constant tau2). Nevertheless, td2 was significantly biased by both procedures, and the large confidence intervals of the whole second component parameters limit their interpretation. To compare both algorithms on experimental data, 26 subjects each performed two transitions from 80 W to 80% maximal O2 uptake on a cycle ergometer and O2 uptake was measured breath by breath. More than 88% of the kinetic parameter estimations done with the SA algorithm produced the lowest residual sum of squares between the experimental data points and the model. Repeatability coefficients were better with GRG2 for A1 although better with SA for A2 and tau2. Our results demonstrate that the implementation of SA improves significantly the estimation of most of these kinetic parameters, but a large inaccuracy remains in estimating the parameter values of the second exponential.

Algorithms↗
PubMed1994

Panic disorder: treatment with valproate.

BACKGROUND: To determine the efficacy of divalproex sodium in the treatment of panic disorder, divalproex sodium was administered in a 6-week open clinical trial to 12 patients who had a primary DSM-III-R diagnosis of panic disorder. METHOD: Treatment was begun at 500 mg of divalproex sodium daily and was increased according to clinical response and side effects. Clinicians completed a Clinical Global Impressions Scale weekly and a Hamilton Rating Scale for Anxiety every other week. Patients completed a panic-attack diary and a Brief Symptom Inventory weekly. RESULTS: All 12 patients completed the study, and all were moderately to markedly improved. Measures of panic attacks and anxiety improved more quickly and robustly than measures of phobic avoidance. Eleven of the 12 patients elected to remain in treatment and at 6-month follow-up had sustained improvement. CONCLUSION: These findings suggest that valproic acid may be effective for the treatment of panic disorder. Double-blind studies will be required to further verify these findings.

Adult↗
PubMed2001

A novel strategy for human papillomavirus detection and genotyping with SybrGreen and molecular beacon polymerase chain reaction.

Human papillomaviruses (HPVs) play an important role in the pathogenesis of cervical cancer. For identification of the large number of different HPV types found in (pre)malignant lesions, a robust methodology is needed that combines general HPV detection with HPV genotyping. We have developed for formaldehyde-fixed samples a strategy that, in a homogeneous, real-time fluorescence polymerase chain reaction (PCR)-based assay, accomplishes general HPV detection by SybrGreen reporting of HPV-DNA amplicons, and genotyping of seven prevalent HPV types (HPV-6, -11, -16, -18, -31, -33, -45) by real-time molecular beacon PCR. The false-positive rate of the HPV SybrGreen-PCR was 4%, making it well suited as a prescreening, general HPV detection technology. The type specificity of the seven selected HPV molecular beacons was 100% and double infections were readily identified. The multiplexing capacity of the HPV molecular beacon PCR was analyzed and up to three differently labeled molecular beacons could be used in one PCR reaction without observing cross talk. The inherent quantitation capacities of real-time fluorescence PCR allowed the determination of average HPV copy number per cell. We conclude that the HPV SybrGreen-PCR in combination with the HPV molecular beacon PCR provides a robust, sensitive, and quantitative general HPV detection and genotyping methodology.

Animals↗