Increasing depth of sleep corresponds to an increasing gain in the neuronal feedback loops that generate the low-frequency (slow-wave) electroencephalogram (EEG). We derived the maximum-likelihood estimator of the feedback gain and applied it to quantify sleep depth. The estimator computes the fraction (0%-100%) of the current slow wave which continues in the near-future (0.02 s later) EEG. Therefore, this percentage was dubbed slow-wave microcontinuity (SW%). It is not affected by anatomical parameters such as skull thickness, which can considerably bias the commonly used slow-wave power (SWP). In our study, both of the estimators SW% and SWP were monitored throughout two nights in 22 subjects. Each subject took temazepam (a benzodiazepine) on one of the two nights. Both estimators detected the effects of age, temazepam, and time of night on sleep. Females were found to have twice the SWP of males, but no gender effect on SW% was found. This confirms earlier reports that gender affects SWP but not sleep depth. Subjectively assessed differences in sleep quality between the nights were correlated to differences in SW%, not in SWP. These results demonstrate that slow-wave microcontinuity, being based on a physiological model of sleep, reflects sleep depth more closely than SWP does.

No relevant alteration was observed in the endometrial development in the early and mid-luteal phases in women undergoing controlled ovarian stimulation for oocyte donation following daily treatment with a standard- or high-dose GnRH antagonist. In addition, the endometrial development after GnRH antagonist mimics the natural endometrium more closely than after GnRH agonist.

for the Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) Study Group IMPORTANCE The patents for the first approved treatments for relapsing-remitting multiple sclerosis are expiring, creating the opportunity to develop generic alternatives.OBJECTIVE To evaluate in the Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) study whether generic glatiramer acetate (hereafter generic drug) is equivalent to the originator brand glatiramer acetate (hereafter brand drug) product, as measured by imaging and clinical end points, safety, and tolerability. DESIGN, SETTING, AND PARTICIPANTS Randomized, multicenter, double-blind, active and placebo-controlled phase 3 trial. The setting included academic medical centers and clinical practices. Participants were patients with relapsing-remitting multiple sclerosis 18 to 55 years old with at least 1 relapse in the prior year and 1 to 15 gadolinium-enhancing brain magnetic resonance imaging lesions. They were randomized between December 7, 2011, and March 21, 2013. The last participant completed follow-up December 2, 2013.INTERVENTIONS Participants were randomized 4.3:4.3:1 to receive generic glatiramer acetate (20 mg), brand glatiramer acetate (20 mg), or placebo by daily subcutaneous injection for 9 months. MAIN OUTCOMES AND MEASURESThe primary end point was the total number of gadolinium-enhancing lesions during months 7, 8, and 9. Additional end points included other magnetic resonance imaging parameters, annualized relapse rate, and Expanded Disability Status Scale score. Safety and tolerability were assessed by monitoring adverse events, injection site reactions, and laboratory test results. RESULTSIn total, 794 participants were randomized and treated with generic drug (n = 353), brand drug (n = 357), or placebo (n = 84). The estimated mean numbers of gadolinium-enhancing lesions with generic drug and brand drug were lower than with placebo (ratio, 0.488; 95% CI, 0.365-0.651; P < .001), confirming study sensitivity. For gadolinium-enhancing lesions, the estimated ratio of generic drug to brand drug was 1.095 (95% CI, 0.883-1.360), which was within the predefined equivalence margin of 0.727 to 1.375. The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the generic drug and brand drug groups. CONCLUSIONS AND RELEVANCEAs treatment for relapsing-remitting multiple sclerosis, glatiramer acetate generic drug and brand drug had equivalent efficacy, safety, and tolerability.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01489254

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Objective To assess maximal volume reduction of leiomyomas and uterus and the duration of treatment required to reach these reductions with daily GnRH antagonist treatment. Design Prospective, open-label study.Setting Large teaching hospital in The Netherlands.Population Premenopausal women with symptomatic fibroids, who were scheduled for surgery.Methods Twenty women were treated with daily 2 mg of subcutaneous ganirelix. Prior to the first injection and weekly during treatment, the volume of leiomyomas and the uterus were assessed by ultrasound (USS) and serum hormones were measured. Prior to treatment and when maximal size reduction was observed by USS, the volume of the leiomyomas and the uterus were also assessed by magnetic resonance imaging (MRI). Main outcome measures Leiomyoma and uterine size reduction, time to maximal reduction.Results One woman was excluded from the study due to incorrect administration dose of ganirelix. Data on the remaining 19 women (average age 39 years) with subserosal (n ¼ 9), submucosal (n ¼ 7), intramural (n ¼ 10) and transmural (n ¼ 1) leiomyomas were evaluated. Baseline leiomyoma volumes ranged from small (3 -4 mL) to large (>1000 mL). The median duration of treatment up to maximal leiomyoma size reduction was 19 days (range 1 -65 days). The maximal size reduction in leiomyomas measured by USS was À42.7% (À77.0% to 14.1%) and À29.2% (À62.2% to 35.6%) by MRI. Comparable uterine size reductions of À46.6% (À78.6% to À6.1%) and À25.2% (À63.6% to 28.9%) were observed by USS and MRI. During the first three weeks of treatment, 8 out of 19 women reported adverse events related to the induced hypoestrogenic state. Most of these events resolved within one week after treatment was discontinued. Conclusion Daily treatment with 2 mg of ganirelix results in rapid reduction of leiomyoma and uterine volume in premenopausal women with minor side effects. If longer-acting GnRH antagonists become available, pretreatment with GnRH antagonist should be preferred over GnRH agonists prior to surgery.

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Background:Open-label 15-month follow-up of the double-blind, placebo-controlled Glatiramer Acetate clinical Trial to assess Equivalence with Copaxone® (GATE) trial.Objective:To evaluate efficacy, safety, and tolerability of prolonged generic glatiramer acetate (GTR) treatment and to evaluate efficacy, safety, and tolerability of switching from brand glatiramer acetate (GA) to GTR treatment.Methods:A total of 729 patients received GTR 20 mg/mL daily. Safety was assessed at months 12, 15, 18, 21, and 24 and Expanded Disability Status Scale and magnetic resonance imaging (MRI) scans at months 12, 18, and 24. The presence of glatiramer anti-drug antibodies (ADAs) was tested at baseline and months 1, 3, 6, 9, 12, 18, and 24.Results:The mean number of gadolinium-enhancing lesions in the GTR/GTR and GA/GTR groups was similar at months 12, 18, and 24. The change in other MRI parameters was also similar in the GTR/GTR and GA/GTR groups. The annualized relapse rate (ARR) did not differ between the GTR/GTR and GA/GTR groups, 0.21 and 0.24, respectively. The incidence, spectrum, and severity of reported adverse events did not differ between the GTR/GTR and GA/GTR groups. Glatiramer ADA titers were similar in the GTR/GTR and GA/GTR groups.Conclusion:Efficacy and safety of GTR is maintained over 2 years. Additionally, switching from GA to GTR is safe and well tolerated.