Effects of one single-dose methylphenidate compared to one single-dose placebo on QbTest performance in adults with untreated ADHD: a randomized controlled trial.

BACKGROUND: Treatment of adults with attention-deficit/hyperactivity disorder (ADHD) primary involves methylphenidate (MPH). Earlier studies have identified placebo responders to increase toward the end of the treatment periods. However, little is known about the immediate effects of placebo on the core symptoms of ADHD in adults. The present study aimed to examine the effects of one single-dose MPH compared to one single-dose placebo during clinical assessments with continuous performance tests (CPT). METHODS: In a randomized study with cross-over design, 40 adults between 19 and 64 years (72.5% women) with untreated ADHD were consecutively enrolled. The study comprised two trial days with four days in between. The QbTest was performed twice on the same day, before and 80 min after intake of one single-dose 20 mg immediate release methylphenidate (IR-MPH) and with one single-dose placebo, in randomized order. RESULTS: Performance improved in QbInattention, F (3, 117) = 38.25, p < 0.001, after given IR-MPH (mean diff = 1.14) and after placebo (mean diff = 0.60) with the effect sizes 1.17 and 0.63 respectively. IR-MPH improved performance in QbActivity (mean diff = 0.81, p < 0.001) and QbImpulsivity (mean diff = 0.46, p < 0.04). The proportion of improvements (a decrease by ≥ 0.5 Qb-score) in the parameters QbInattention, QbActivity and QbImpulsivity were 90%, 60% and 52.5%, respectively. After given placebo, corresponding proportions were 60%, 30% and 35%, respectively. CONCLUSIONS: There seems to be an immediate placebo response in the core symptom inattention. The effect of placebo cannot be ruled out and must be taken in consideration during drug trials with continuous performance tests (CPTs). TRIAL REGISTRATION: ClinicalTrials.gov; Identifier: NCT02473185.

Contrasting expectancy effects with objective measures in adults with untreated ADHD during QbTest.

Expectancy has been associated with neuropsychological assessments and cognitive performance. However, little is known about the effects of expectations in clinical assessments during drug trials with continuous performance tests (CPTs). In a randomized, double-blind study with cross-over design, we examined if the participants' self-reported expectations changed after one-single dose immediate release methylphenidate (MPH) and after one-single dose placebo during the QbTest. Forty adults between 19 and 64 years (72.5% women) with un treated ADHD were consecutively enrolled in the study and their assessments of expected performance, mental effort, perceived performance and help from the pill were analyzed. The study comprised two trial days with four days in between. The QbTest was performed twice on the same day, before and 80 minutes after a pill. Our study demonstrates that there were expectancy effects during CPTs. Participants reported lower mental effort and improved their performance in the coronary parameter QbInattention both after MPH and after placebo. No significant differences in expected performance were reported. The participants seemed to show some uncertainty when assessing their expected performance, however, they could evaluate their performance afterwards. In clinical practice, the focus should be on reinforcing patients' expectations in order to increase treatment effects.

Do enzymes change the nature of transition states? Mapping the transition state for general acid-base catalysis of a serine protease.

The properties of the transition state for serine protease-catalyzed hydrolysis of an amide bond were determined for a series of subtilisin variants from Bacillus lentus. There is no significant change in the structure of the enzyme upon introduction of charged mutations S156E/S166D, suggesting that changes in catalytic activity reflect global properties of the enzyme. The effect of charged mutations on the pK(a) of the active site histidine-64 N(epsilon)(2)-H was correlated with changes in the second-order rate constant k(cat)/K(m) for hydrolysis of tetrapeptide anilides at low ionic strength with a Brønsted slope alpha = 1.1. The solvent isotope effect (D)2(O)(k(cat)/K(m))(1) = 1.4 +/- 0.2. These results are consistent with a rate-limiting breakdown of the tetrahedral intermediate in the acylation step with hydrogen bond stabilization of the departing amine leaving group. There is an increase in the ratio of hydrolysis of succinyl-Ala-Ala-Pro-Phe-anilides for p-nitroaniline versus aniline leaving groups with variants with more basic active site histidines that can be described by the interaction coefficient p(xy) = delta beta(lg)/delta pK(a) (H64) = 0.15. This is attributed to increased hydrogen bonding of the active site imidazolium N-H to the more basic amine leaving group as well as electrostatic destabilization of the transition state. A qualitative characterization of the transition state is presented in terms of a reaction coordinate diagram that is defined by the structure-reactivity parameters.

Factors that influence outcomes of hyperopic laser in situ keratomileusis.

PURPOSE: To analyze the influence of preoperative corneal curvature, postoperative keratometric power, and the amount of correction on the outcomes of hyperopic laser in situ keratomileusis (LASIK). SETTING: Clínica Baviera, Instituto Oftalmológico Europeo, Madrid, Spain. METHODS: In this retrospective study, the records of 376 eyes that had LASIK for hyperopia using the Moria LSK-One microkeratome and the Technolas-Keracor 217C excimer laser were reviewed. The results were analyzed by preoperative hyperopia (5 subgroups) and by preoperative (more than and less than 43.0 diopters [D]) and postoperative (more than and less than 48.0 D) mean keratometry. RESULTS: A statistically significant keratometry regression was found in the +3.00 to +3.90 D range (P <.01), a significant decrease in predictability in the +4.00 to +4.90 D range (P <.05), and a significant worsening in safety in the highest range (+6.00 to +7.90 D; P <.05). Comparative analysis of the > or = +4.00 D and <+4.00 D groups showed statistically significant differences in most measurement parameters. The preoperative keratometry did not influence postoperative results with the exception of poorer predictability in the group of preoperative flat corneas in which a high degree of hyperopia was corrected; ie, spherical equivalents within +/-0.50 D were found in 40.4% and 61.0% of cases with flat and steep corneas, respectively (P <.05). The efficacy and safety in eyes that achieved a postoperative keratometry >48.00 D did not differ significantly from the efficacy and safety in eyes that had a lower final keratometric power. CONCLUSIONS: The factor that negatively influenced the outcome of hyperopic LASIK was the degree of hyperopia corrected. Preoperative keratometry did not significantly influence the postoperative results, and postoperative keratometry >48 D did not result in significant worsening of visual results when the attempted correction was less than +4.00 D.