Moderators and predictors of response to cognitive-behavioral therapy augmentation of pharmacotherapy in obsessive-compulsive disorder.

BACKGROUND: Cognitive-behavioral therapy (CBT) consisting of exposure and response prevention (EX/RP) is efficacious as a treatment for obsessive-compulsive disorder (OCD). However, about half of patients have a partial or poor response to EX/RP treatment. This study examined potential predictors and moderators of CBT augmentation of pharmacotherapy, to identify variables associated with a poorer response to OCD treatment. METHOD: Data were drawn from a large randomized controlled trial that compared the augmenting effects of EX/RP to stress management training (SMT; an active CBT control) among 108 participants receiving a therapeutic dose of a serotonin reuptake inhibitor (SRI). Stepwise regression was used to determine the model specification. RESULTS: Pretreatment OCD severity and gender were significant moderators of outcome: severity affected SMT (but not EX/RP) outcome; and gender affected EX/RP (but not SMT) outcome. Adjusting for treatment type and pretreatment severity, significant predictors included greater co-morbidity, number of past SRI trials, and lower quality of life (QoL). Significant moderators, including their main-effects, and predictors accounted for 37.2% of the total variance in outcome, comparable to the impact of treatment type alone (R2=30.5%). These findings were replicated in the subgroup analysis of EX/RP alone (R2=55.2%). CONCLUSIONS: This is the first randomized controlled study to examine moderators and predictors of CBT augmentation of SRI pharmacotherapy. Although effect sizes for individual predictors tended to be small, their combined effect was comparable to that of treatment. Thus, future research should examine whether monitoring for a combination of these risk factors and targeting them with multi-modular strategies can improve EX/RP outcome.

Very long baseline interferometric observations made with an orbiting radio telescope.

An orbiting spacecraft and ground observatories have been used to obtain interferometric observations of cosmic radio sources. The Tracking and Data Relay Satellite System (TDRSS) was used as the orbiting observatory in conjunction with two 64- meter radio telescopes at ground observatories, one in Australia and one in Japan. The quasars 1730-130 (NRAO 530), 1510-089, and 1741-038 were observed at a frequency of 2.3 gigahertz, and a maximum projected baseline of 1.4 earth diameters was achieved. All quasar observations for which valid data were acquired resulted in detected fringes. Many of the techniques proposed for a dedicated very long baseline interferometry observatory in space were used successfully in this experiment.

Investigation of the role of surface residues in the ferredoxin from Clostridium pasteurianum.

Eleven mutant forms of the ferredoxin from Clostridium pasteurianum (CpFd; 2 Fe4S4; 6200 Da) have been isolated in which six surface carboxylates are changed systematically to their uncharged but stereochemically equivalent carboxamide analogues. Such changes provide molecules which vary in overall charge and its surface distribution but vary minimally in structure and reduction potential. Glu-17 and Asp-6, -27, -33, -35, and -39 were converted providing six single mutants, four double mutants and one triple mutant. The proteins were characterised by UV-visible spectroscopy, square-wave voltammetry and 1H NMR. Their ability to mediate electron transfer between spinach NADH:ferredoxin oxidoreductase and horse heart cytochrome c was assessed. Each mutant is 30-100% as active as the recombinant protein with the triple mutant D33,35,39N being least active. Second-order rate constants k2 for the oxidation of reduced mutant ferredoxins by [Co(NH3)6]3+ were measured at 25 degrees C and I = 0.1 M by stopped-flow techniques. Each mutant displayed saturation kinetics with k2 being 30-100% of that for the recombinant protein. The rates were moderately sensitive to ionic strength. Variation in association constant K could not be detected within the confidence limits of the data. Overall the effects of the mutations were minor. In contrast to human and Anabaena 7120 [Fe2S2]-ferredoxins, electron transfer does not appear to rely on the presence of one or two specific surface carboxylate residues. It may occur from multiple sites on the surface of CpFd with recognition processes for its many physiological redox partners being controlled by relative reduction potentials, in addition to unidentified criteria. The conclusions are consistent with previous results for another series of mutant CpFd proteins interacting with physiological redox partners pyruvate: Fd oxidoreductase and hydrogenase (J.M. Moulis, V. Davasse (1995) Biochemistry 34, 16781-16788).

Crystal structure of auracyanin, a "blue" copper protein from the green thermophilic photosynthetic bacterium Chloroflexus aurantiacus.

Auracyanin B, one of two similar blue copper proteins produced by the thermophilic green non-sulfur photosynthetic bacterium Chloroflexus aurantiacus, crystallizes in space group P6(4)22 (a=b=115.7 A, c=54.6 A). The structure was solved using multiple wavelength anomalous dispersion data recorded about the CuK absorption edge, and was refined at 1.55 A resolution. The molecular model comprises 139 amino acid residues, one Cu, 247 H(2)O molecules, one Cl(-) and two SO(4)(2-). The final residual and estimated standard uncertainties are R=0.198, ESU=0.076 A for atomic coordinates and ESU=0.05 A for Cu---ligand bond lengths, respectively. The auracyanin B molecule has a standard cupredoxin fold. With the exception of an additional N-terminal strand, the molecule is very similar to that of the bacterial cupredoxin, azurin. As in other cupredoxins, one of the Cu ligands lies on strand 4 of the polypeptide, and the other three lie along a large loop between strands 7 and 8. The Cu site geometry is discussed with reference to the amino acid spacing between the latter three ligands. The crystallographically characterized Cu-binding domain of auracyanin B is probably tethered to the periplasmic side of the cytoplasmic membrane by an N-terminal tail that exhibits significant sequence identity with known tethers in several other membrane-associated electron-transfer proteins.

Are speed enforcement cameras more effective than other speed management measures? The impact of speed management schemes on 30 mph roads.

This paper presents the results of an evaluation of the impact of various types of speed management schemes on both traffic speeds and accidents. The study controls for general trends in accidents, regression-to-mean effects and migration, separately estimating the accident changes attributable to the impact of the schemes on traffic speed and on traffic volume. It was found that, when judged in absolute terms, all types of speed management scheme have remarkably similar effects on accidents, with an average fall in personal injury accidents of about 1 accident/km/year. In terms of the percentage accident reduction, however, engineering schemes incorporating vertical deflections (such as speed humps or cushions) offer the largest benefits: at 44%, the average reduction in personal injury accidents attributable to such schemes, is twice that at sites where safety cameras were used to control speeds (22%) and they were the only type of scheme to have a significant impact on fatal and serious accidents. Other types of engineering scheme (with a fall of 29% in personal injury accidents) were on average less effective in reducing accidents than schemes with vertical features but more effective than cameras. All types of scheme were generally effective in reducing speeds, with the largest reductions tending to be obtained with vertical deflections and the smallest with other types of engineering schemes.

Are speed enforcement cameras more effective than other speed management measures? An evaluation of the relationship between speed and accident reductions.

In this paper, models are developed which enable a prediction of how the impact of speed management schemes on accidents varies both with speed changes and with site and scheme characteristics. It was found that, the impact of schemes with vertical deflections is independent of the change in mean speed: an accident reduction of 44% is predicted by the model irrespective of the impact on speed. For cameras and other types of engineering schemes, a simple relationship between the change in mean speed and the consequent change in accidents is available. For the range of mean speeds typically found on 30 mph roads, the percentage accident reduction per 1 mph speed reduction is around 4% for cameras and 7-8% for schemes with horizontal features. While larger percentage accident reductions are achieved per 1 mph speed reduction on lower speed roads, larger speed reductions and larger overall percentage accident reductions are obtained on roads with higher before mean speeds. It is possible to predict both changes in speeds and accidents before treatment using the models derived from this study and these models confirm that schemes with vertical deflections are most effective in reducing both speeds and accidents.

A bivariate negative binomial model to explain traffic accident migration.

The phenomenon of "regression to the mean" is now widely known in the study of the effectiveness of remedial treatment of traffic accident blackspots. What happens is that the criterion used for selection of sites at which treatment is to be applied gives rise to bias in the estimate of the effectiveness: the conditional expectation of the after frequency is less than the true mean, even if the treatment is totally ineffective. It has been reported in some previous studies that accident "migration" has been observed. This is the phenomenon whereby the accident rate apparently rises at sites that are untreated but that are neighbours to treated sites. If this were a genuine effect, it would have serious implications for the assessment of remedial treatments. This paper aims to explain this migration effect in purely probabilistic terms, without recourse to the concept of physical migration. The model used is a new bivariate negative binomial distribution, incorporating spatial correlation between the true mean site accident rates. As with the regression to mean effect, the migration effect can then be explained in terms of the conditioning implicit in the selection process.

The identification of accident blackspots: a comparison of current methods.

A recent survey reported that, in order to identify accident blackspots, most highway authorities use annual accident total (AAT), without making any allowance for any measure of exposure or the nature of the site. An alternative, and apparently improved criterion, known as potential accident reduction (PAR), has been proposed. The basis for this is that statistically significant relationships can be established between accident frequency and traffic flow, for a variety of site categories. PAR is calculated, for a site, as the difference between the observed number of accidents and the expected number for that type of site with that level of flow. If this expected frequency can be estimated accurately, then PAR should inevitably perform better than AAT, since AAT tends to identify high flow sites which do not necessarily have the potential for accident reduction. This work attempts to quantify the additional benefits to be gained by the use of PAR instead of AAT. It demonstrates that, because of the inaccuracy of the estimation of the expected frequency at a site required in PAR, it is quite possible for AAT to perform as well as, or better than PAR. If the sites, identified as blackspots, are then given some remedial treatment, the analysis of the effectiveness of this treatment must allow for what has become known as the "regression-to-mean" effect. A method which provides a proper basis for such before and after studies is described.

A comprehensive methodology for the fitting of predictive accident models.

Recent years have seen considerable progress in techniques for establishing relationships between accidents, flows and road or junction geometry. It is becoming increasingly recognized that the technique of generalized linear models (GLMs) offers the most appropriate and soundly-based approach for the analysis of these data. These models have been successfully used in the series of major junction accident studies carried out over the last decade by the U.K. Transport Research Laboratory (TRL). This paper describes the form of the TRL studies and the model-fitting procedures used, and gives examples of the models which have been developed. The paper also describes various technical problems which needed to be addressed in order to ensure that the application of GLMs would produce robust and reliable results. These issues included: the low mean value problem, overdispersion, the disaggregation of data over time, allowing for the presence of a trend over time in accident risk, random errors in the flow estimates, the estimation of prediction uncertainty, correlations between predictions for different accident types, and the combination of model predictions with site observations. Each of these problems has been tackled by extending or modifying the basic GLM methodology. The material described in the paper, then, constitutes a comprehensive methodology for the development of predictive accident models.

Sources of error in road safety scheme evaluation: a quantified comparison of current methods.

This paper considers the various factors that can have a confounding effect in the evaluation of road safety schemes and examines the extent to which current methods can effectively deal with these. A modification to current methods is proposed which allows the reduction in accidents attributable to risk and flow changes to be separately evaluated. Data are presented to demonstrate the relative magnitudes of the various sources of error. It is shown that a principal source of error is normally regression-to-mean (RTM) and a correction for this effect should always be applied. Changes in traffic flow can also result in substantial accident changes and it is important to establish whether flow changes have occurred and if they are attributable to the effect of the scheme.

Sources of error in road safety scheme evaluation: a method to deal with outdated accident prediction models.

This paper considers the errors that arise in using outdated accident prediction models in road safety scheme evaluation. Methods to correct for regression-to-mean (RTM) effects in scheme evaluation normally rely on the use of accident prediction models. However, because accident risk tends to decline over time, such models tend to become outdated and the estimated treatment effect is then exaggerated. A new correction procedure is described which can effectively eliminate such errors.

Updating outdated predictive accident models.

Reliable predictive accident models (PAMs) (also referred to as safety performance functions (SPFs)) are essential to design and maintain safe road networks however, ongoing changes in road and vehicle design coupled with road safety initiatives, mean that these models can quickly become dated. Unfortunately, because the fitting of sophisticated PAMs including a wide range of explanatory variables is not a trivial task, available models tend to be based on data collected many years ago and seem unlikely to give reliable estimates of current accidents. Large, expensive studies to produce new models are likely to be, at best, only a temporary solution. This paper thus seeks to develop a practical and efficient methodology to allow currently available PAMs to be updated to give unbiased estimates of accident frequencies at any point in time. Two principal issues are examined: the extent to which the temporal transferability of predictive accident models varies with model complexity; and the practicality and efficiency of two alternative updating strategies. The models used to illustrate these issues are the suites of models developed for rural dual and single carriageway roads in the UK. These are widely used in several software packages in spite of being based on data collected during the 1980s and early 1990s. It was found that increased model complexity by no means ensures better temporal transferability and that calibration of the models using a scale factor can be a practical alternative to fitting new models.

Calcium antagonists in the treatment of hypertension: special clinical considerations.

Calcium antagonists are safe and effective in the treatment of systemic hypertension. Several studies have suggested that calcium antagonists slow the rate of progression of renal disease in hypertensives with underlying renal dysfunction. They may also improve ejection fraction in ischemic myocardial stunning and reduce the number of cardiac events in unstable angina.

High dose loperamide suppositories: a novel approach for improving clinical function after restorative proctocolectomy.

The effect of loperamide suppositories on patients following restorative proctocolectomy was studied by means of a randomized, double-blind, crossover trial comparing active suppositories (20 mg b.d. x 1 week) with placebo. Ten patients (8 male, 2 female; 7 J pouch, 3 W pouch; 8 ulcerative colitis, 2 familial adenomatous polyposis) were studied 3-60 months (median, 31.5) after ileostomy closure. Ages ranged from 24 to 63 years (medium, 41.5). All patients kept a diary of their bowel habits and eight underwent a standardized test of pouch compliance. Urgency volume (UV) and maximum tolerable volumes (MTV) and the volume at onset of large isolated pouch contractions (LIC) were recorded. Statistical analysis was by the Wilcoxon test for paired data. Mean daily stool frequency during the placebo phase ranged from 3.7 to 7.8. It was reduced during the active phase in only seven patients (P > 0.1) but was reduced in all six patients whose placebo phase stool frequency was five or more. Urgency volume was increased by use of active suppositories in six of the eight patients tested (P > 0.01). There was no consistent effect on MTV. Large isolated pouch contractions were not seen in either test in one patient. In all of the remaining seven patients LIC were recorded after the placebo phase. After the active phase LIC first appeared at higher volumes in three but were not seen at all in four patients. High dose loperamide suppositories suppress pouch contractions and tend to lower stool frequency especially when high initially. They represent a novel therapeutic approach to high stool frequency in pouch patients.

Rubredoxin from Clostridium pasteurianum. Structures of G10A, G43A and G10VG43A mutant proteins. Mutation of conserved glycine 10 to valine causes the 9-10 peptide link to invert.

The four cysteine ligands which coordinate the Fe atom in the electron-transfer protein rubredoxin lie on loops of the polypeptide which form approximate local twofold symmetry. The cysteine ligands in the protein from Clostridium pasteurianum lie at positions 6, 9, 39 and 42. Two glycine residues adjacent to the cysteine ligands at positions 10 and 43 are conserved in all rubredoxins, consistent with the proposal that a beta-carbon substituent at these positions would eclipse adjacent peptide carbonyl groups [Adman et al. (1975). Proc. Natl Acad. Sci. USA, 72, 4854-4858]. X-ray crystal structures of the three mutant proteins G10A, G43A and G10VG43A are reported. The crystal structures of the single-site mutations are isomorphous with the native protein, space group R3; unit-cell parameters are a = 64.3, c = 32.9 A for G10A and a = 64.4, c = 32.8 A for G43A. The crystals of the double mutant, G10VG43A, were in space group P43212, unit-cell parameters a = 61.9, c = 80.5 A, with two molecules per asymmetric unit. The observed structural perturbations support the hypothesis that mutation of the conserved glycine residues would introduce strain into the polypeptide. In particular, in the G10VG43A protein substitution of valine at Gly10 causes the 9-10 peptide link to invert, relieving steric interaction between Cys9 O and Val10 Cbeta. This dramatic change in conformation is accompanied by the loss of the 10N-HcO6 hydrogen bond, part of the chelate loop Thr5-Tyr11. The new conformation allows retention of the 11N-HcS9 hydrogen bond, but converts it from a type II to a type I hydrogen bond. This occurs at the cost of a less tightly packed structure. The structural insights allow rationalization of 1H NMR data reported previously for the 113CdII-substituted proteins and of the negative shifts observed in the FeIII/FeII mid-point potentials upon mutation.

Mutation of the surface valine residues 8 and 44 in the rubredoxin from Clostridium pasteurianum: solvent access versus structural changes as determinants of reversible potential.

The Pr(i) sidechains of two adjacent valine residues, V8 and V44, define the surface of the rubredoxin from Clostridium pasteurianum and control access to its Fe(S-Cys)4 active site. To assess the effect of systematic change of the steric bulk of the alkyl sidechains, eight single and three double mutant proteins have been isolated which vary G (H), A (Me), V (Pr(i)), L (Bu(i)) and I (Bu(s)) at those positions. X-ray crystal structures of the Fe(III) forms of the V44A and V44I proteins are reported. Positive shifts in reversible potential of up to 116 mV are observed and attributed to increased polarity around the Fe(S-Cys)4 site induced by (1) changes in protein backbone conformation driven by variation of the steric demands of the sidechain substituents and (2) changes in solvent access to the side-chains of ligands C9 and C42. Data for the V44A mutant show that a minor change in the steric requirements of a surface residue can introduce a NH...Sgamma hydrogen bond at the active site and lead to a shift in potential of + 50 mV.

Impact of a drug bulletin on prescribing oral analgesics in a teaching hospital.

The impact of a drug bulletin on prescribing oral analgesics in a teaching hospital was studied. Using an abbreviated time-series design, prescriptions for oral analgesics for all inpatients were surveyed one, three, and five weeks before and one, three, five, and seven weeks after the distribution of one of the hospital's regular drug bulletins. This bulletin contained guidelines for the treatment of minor, moderate, and severe pain. The 493 patients included in the study were classified by drug category, pain severity, and timer period. The drug categories were: (1) propoxyphene, (2) aspirin or acetaminophen alone or with codeine 8 mg or less, and (3) codeine alone or in combination products with more than codeine 8 mg, or other oral narcotic drugs. Each patient's pain severity was determined by interviewing attendant nursing staff; the validity of this approach was confirmed by correlating nurse and physician perception of pain at one time point. Multivariate contingency table analysis revealed that the drug bulletin significantly (p less than or equal to 0.05) reduced the prescribing of propoxyphene hydrochloride across both the minor and moderate pain categories. An increased use of aspirin and acetaminophen was significant three weeks after the release of the drug bulletin. This effect, however, was not significant at other time points. Drug bulletins can be used to achieve a temporary change in physician prescribing patterns of oral analgesics. For a sustained effect, alternative strategies are needed.