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

Pooled analysis of bleeding profile, efficacy and safety of oral oestradiol valerate/dienogest in women aged 25 and under

Purpose: To evaluate differences in key outcomes between younger and older women receiving the oral contraceptive oestradiol valerate/dienogest (E2V/DNG). Methods: We conducted a pooled post hoc analysis of primary data from 12 studies of E2V/DNG, stratified by age (≤25 [n = 1309] and >25 [n = 2132] years). Outcomes included safety, efficacy, bleeding profile and hormone-withdrawal-associated symptoms (HWAS). Bleeding and HWAS analyses are also presented for women aged ≤20 years (n = 362). Discontinuations were considered a proxy for patient satisfaction. Results: Results were generally similar for younger and older women. The percentage of women aged ≤25 and >25 years experiencing intracyclic bleeding did not differ between groups (13.4% and 12.8% at cycle 12, respectively), with similar results in women aged ≤20 years (12.7%, cycle 12). Rates of withdrawal bleeding were very similar in women aged ≤25 and >25 years (78.5% and 78.9%, respectively, cycle 12). We also found a similar adjusted Pearl index in the two age groups (0.45 vs 0.57, respectively), similar rates of AEs and HWAS and no difference in discontinuations. Conclusions: Women aged ≤25 and >25 years have a similar experience with an E2V/DNV oral contraceptive, supporting this as an appropriate contraceptive option in younger and older women

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

The Decline in Vitamin Research Funding:A Missed Opportunity?

Background: The National Nutrition Research Roadmap has called for support of greater collaborative, interdisciplinary research for multiple areas of nutrition research. However, a substantial reduction in federal funding makes responding to these calls challenging. Objectives: The objectives of this study were to examine temporal trends in research funding and to discuss the potential consequences of these trends. Methods: We searched the NIH RePORTER database to identify NIH research grants and USASpending to identify National Science Foundation and USDA research grants awarded from 1992 to 2015. We focused on those that pertained to vitamin research. For the years 2000 to 2015, we examined funding trends for different vitamins, including vitamins A, B (one-carbon B-vitamins were considered separately from other B-vitamins), C, D, E, and K. Results: From 1992 to 2015, total federal research spending increased from similar to$14 to$45 billion (2016 US dollars). Although vitamin research spending increased from similar to$89 to$95 million, the proportion of grants awarded for vitamin research declined by more than two-thirds, from 0.65% in 1992 to 0.2% in 2015. Federal agencies awarded 6035 vitamin research grants over the time period, with vitamin A associated with the most research projects per year on average (n = 115) and vitamin K the fewest (n = 8). Vitamin D research projects were associated with the greatest average yearly project value ($34.8 million). Conclusions: Vitamin research has faced a disproportionate decline in research funding from 1992 to 2015. Insufficient federal research funding streams risk stalling progress in vitamin research and leaving important advancements unrealized

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Endometrial safety of an oral contraceptive containing estradiol valerate and dienogest

The purpose of this study was to investigate the endometrial safety of an oral contraceptive containing estradiol valerate/dienogest (E(2)V/DNG) administered as an estrogen step-down and progestogen step-up regimen in women of reproductive age (18-50 years), using histological assessment of endometrial biopsy samples