Ovulation inhibition with four variations of a four-phasic estradiol valerate/dienogest combined oral contraceptive : results of two prospective, randomized, open-label studies

Background: Attempts to improve the tolerability of combined oral contraceptives (COCs) have included the substitution of ethinylestradiol (EE) with 17beta-estradiol (E2). However, this has proved unsatisfactory, specifically in terms of cycle control. To improve upon the poor cycle control seen previously, E2 (in the form of estradiol valerate [E2V], 1 mg E2V contains 0.76 mg E2) was combined with dienogest (DNG) in a novel four-phasic regimen. In the current studies the ovulation inhibition potency of four variations of this regimen was assessed. Study design: Two randomized, open-label, phase II studies were performed. The first study compared two regimens (1A, 2A) with similar dosages of DNG but different lengths of application. Having established in Study 1 that the length of application of regimen 2A was most suitable but that the dosages of DNG were too low for effective ovulation inhibition, a second study was undertaken, which compared two regimens (2B, 2C) with similar lengths of application but increased dosages of DNG. The primary efficacy variable in both studies was the proportion of women with a Hoogland score of 5/6 during Cycle 2. Results: The full analysis set comprised 192 and 203 women in Study 1 and 2, respectively. In Study 1, 10 women (10.9%) in regimen 1A and 6 women (6.4%) in regimen 2A had a Hoogland score of 5/6. In Study 2, 3 women (3.1 %) in regimen 2B and 1 woman (1.0%) in regimen 2C had a Hoogland score of 5/6. There were no safety concerns with any of the regimens

COPD-Lower Respiratory Tract Infection Visual Analogue Score (c-LRTI-VAS) validation in stable and exacerbated patients with COPD

BACKGROUND: We developed the chronic obstructive pulmonary disease (COPD)-Lower Respiratory Tract Infection-Visual Analogue Score (c-LRTI-VAS) in order to easily quantify symptoms during exacerbations in patients with COPD. This study aimed to validate this score. METHODS: In our study, patients with stable COPD as well as those with an acute exacerbations of COPD (AECOPD) were included. The results of c-LRTI-VAS were compared with other markers of disease activity (lung function parameters, oxygen saturation and two health related quality of life questionnaires (St Georges Respiratory Questionnaire (SGRQ) and Clinical COPD Questionnaire (CCQ)) and validity, reliability and responsiveness were assessed. RESULTS: Eighty-eight patients with clinically stable COPD and 102 patients who had an AECOPD completed the c-LRTI-VAS questionnaire. When testing on two separate occasions for repeatability, no statistically significant difference between total scores was found 0.143 (SD 5.42) (p=0.826). Internal consistency was high across items (Cronbach's apha 0.755). Correlation with SGRQ and CCQ total scores was moderate to high. After treatment for hospitalised AECOPD, the mean c-LRTI-VAS total score improved 8.14 points (SD 9.13; p≤0.001). CONCLUSIONS: c-LRTI-VAS showed proper validity, responsiveness to change and moderate to high correlation with other questionnaires. It, therefore, appears a reliable tool for symptom measurement during AECOPD. TRIAL REGISTRATION NUMBER: NCT01232140

Dutch translation and adaptation of the Barkley Deficits in Executive Functioning Scale (BDEFS)

Background: Based on his model of self-regulation and executive functions, Barkley developed a self- and other-report questionnaire (the Barkley Deficits in Executive Functioning Scale – BDEFS). The BDEFS measures deficits in executive functions as expressed in daily life activities like self-management of time, self-organization, self-restraint, self-motivation, and self-regulation of emotion. Objectives: This study created and analyzed a Dutch translation and adaptation in conformance with official guidelines. Methods: The Dutch and English BDEFS were completed by 25 bilingual Dutch adults to evaluate semantic correspondence. Consequently, 60 Dutch participants completed the Dutch BDEFS, Barratt Impulsiveness Scale-Eleventh edition (BIS-11) and the Dysexecutive Questionnaire (DEX) to evaluate concurrent validity and internal consistency. Results: The versions demonstrated sufficient semantic equivalence and Spearman’s rho of total scores was high; items mostly showed moderate-to-high correlations. Regression analysis showed no proportional bias. Internal consistency was also high. Correlations between BDEFS, BIS-11 and DEX supported concurrent validity. Discussion: We conclude that a successful BDEFS translation and adaptation was created with satisfactory reliability and validity. Further research should assess the utility of the BDEFS in Dutch clinical practice

Ovulation inhibition with four variations of a four-phasic estradiol valerate/dienogest combined oral contraceptive : results of two prospective, randomized, open-label studies

Background: Attempts to improve the tolerability of combined oral contraceptives (COCs) have included the substitution of ethinylestradiol (EE) with 17beta-estradiol (E2). However, this has proved unsatisfactory, specifically in terms of cycle control. To improve upon the poor cycle control seen previously, E2 (in the form of estradiol valerate [E2V], 1 mg E2V contains 0.76 mg E2) was combined with dienogest (DNG) in a novel four-phasic regimen. In the current studies the ovulation inhibition potency of four variations of this regimen was assessed. Study design: Two randomized, open-label, phase II studies were performed. The first study compared two regimens (1A, 2A) with similar dosages of DNG but different lengths of application. Having established in Study 1 that the length of application of regimen 2A was most suitable but that the dosages of DNG were too low for effective ovulation inhibition, a second study was undertaken, which compared two regimens (2B, 2C) with similar lengths of application but increased dosages of DNG. The primary efficacy variable in both studies was the proportion of women with a Hoogland score of 5/6 during Cycle 2. Results: The full analysis set comprised 192 and 203 women in Study 1 and 2, respectively. In Study 1, 10 women (10.9%) in regimen 1A and 6 women (6.4%) in regimen 2A had a Hoogland score of 5/6. In Study 2, 3 women (3.1 %) in regimen 2B and 1 woman (1.0%) in regimen 2C had a Hoogland score of 5/6. There were no safety concerns with any of the regimens

CRISPR-Cas9 correction of a nonsense mutation in LCA5 rescues lebercilin expression and localization in human retinal organoids

Mutations in the lebercilin-encoding gene LCA5 cause one of the most severe forms of Leber congenital amaurosis, an early-onset retinal disease that results in severe visual impairment. Here, we report on the generation of a patient-specific cellular model to study LCA5-associated retinal disease. CRISPR-Cas9 technology was used to correct a homozygous nonsense variant in LCA5 (c.835C>T; p.Q279∗) in patient-derived induced pluripotent stem cells (iPSCs). The absence of off-target editing in gene-corrected (isogenic) control iPSCs was demonstrated by whole-genome sequencing. We differentiated the patient, gene-corrected, and unrelated control iPSCs into three-dimensional retina-like cells, so-called retinal organoids. We observed opsin and rhodopsin mislocalization to the outer nuclear layer in patient-derived but not in the gene-corrected or unrelated control organoids. We also confirmed the rescue of lebercilin expression and localization along the ciliary axoneme within the gene-corrected organoids. Here, we show the potential of combining precise single-nucleotide gene editing with the iPSC-derived retinal organoid system for the generation of a cellular model of early-onset retinal disease