Safety, Pharmacokinetics, and Pharmacodynamics of Osivelotor for Sickle Cell Disease: First-in-Human Studies in Healthy Participants and Patients.

The investigational agent osivelotor, a small molecule hemoglobin (Hb) modifier in development for the treatment of sickle cell disease (SCD), acts by increasing Hb-oxygen affinity and inhibiting the polymerization of sickle Hb. We report safety, pharmacokinetic (PK), and pharmacodynamic (PD) data from the first two phase 1 clinical trials of osivelotor in healthy participants and participants with SCD. Healthy participants (N = 129) were randomized to receive either osivelotor or placebo in single-ascending doses (50-3,000 mg) or multiple-ascending doses (loading doses, then 15-100 mg once-daily maintenance doses through 14 days).

Comparison of estrogens and selective estrogen receptor modulators (SERMs) used for menopausal hormone therapy.

A variety of natural and synthetic steroidal estrogens, as well as selective estrogen receptor modulators (SERMs), are used for menopausal hormone therapy (MHT) by oral and/or parenteral routes of administration. Two of the most widely used estrogens for MHT are conjugated equine estrogens (CEE) and estradiol (E2); other estrogens include esterified estrogens, piperazine estrone sulfate, estriol, estetrol (E4), E2 valerate, and ethinyl estradiol. Commonly used SERMs include tamoxifen, raloxifene, ospemifene, lasofoxifene, and bazedoxifene.

Contraceptive Efficacy and Comparative Side Effects of a Mini Copper Intrauterine Device.

Background: Intrauterine devices (IUDs) are highly effective, yet acceptability and continuation differ by user and device characteristics. We evaluated the efficacy of the NTCu380 Mini, a 380-mm copper IUD available in Europe and Canada, and compared safety and continuation with the TCu380A IUD, the 380-mm copper IUD available in the United States.

Methods: We randomly assigned participants between 16 and 40 years of age in a 4:1 ratio to the NTCu380 Mini or TCu380A and assessed over 37 months.

Characterizing pregnancy outcomes in a humanized mouse model of sickle cell disease.

Although increased risk for adverse pregnancy outcomes has been well characterized in women with sickle cell disease (SCD), there remains unexplored value in the characterization of a preclinical model which could minimize human risk. This study aimed to characterize pregnancy outcomes in the SCD mouse model with emphasis on analogous clinical correlates and biological contributors. As such, we identified worsened outcomes including reduced litter sizes (haemoglobin HbSS (SS) 5.

Complement is activated in patients with acute chest syndrome caused by sickle cell disease and represents a therapeutic target.

Despite being the first genetic disease described, sickle cell disease (SCD) continues to result in severe complications. Of these complications, acute chest syndrome (ACS), a form of acute lung injury, leads all-cause mortality. However, the pathophysiology of ACS remains incompletely understood, resulting in patients with ACS receiving only supportive measures.

Selecting performance indicators for farms and ranches engaged in collaborative agroecosystem research.

The pace of global change complicates the assessment of the outcomes of agricultural management, hindering decision-making by producers, researchers, and consumers. The Long-Term Agroecosystem Research Network (LTAR) is in a unique position to advance monitoring to inform decision-making. Here, we describe how the network selected performance indicators designed to measure the trade-offs from various farming and ranching approaches.

Hydroxyurea blunts mitochondrial energy metabolism and osteoblast and osteoclast differentiation exacerbating trabecular bone loss in sickle cell mice.

Sickle cell disease (SCD) is a severe hematological disorder characterized by erythrocyte sickling that causes significant morbidity and mortality. Skeletal complications of SCD include a high incidence of bone loss, especially in vertebrae, leading to fragility fractures that contribute to disease burden. Whether hydroxyurea (HU), a front-line therapy for SCD ameliorates bone disease has not been established.

The LTAR Grazing Land Common Experiment at Northern Plains.

The USDA Long-Term Agroecosystem Research (LTAR) network aims to enhance sustainable agricultural management practices through a coordinated, cross-site common experiment involving 18 locations across the United States. The objective of this paper is to provide an overview of the LTAR Grazing Land Common Experiment at the Northern Plains (NP) site, where an experiment was initiated in 2019 to answer producers' and researchers' questions about whether the tactical application of fire or grazing can reduce the dominance of invasive Kentucky bluegrass in northern Great Plains ecosystems. As part of the LTAR common experiment, we contrast a prevailing practice (season-long grazing at moderate stocking rate) with four alternative practices at a half-hectare plot scale: (1) mob grazing by cattle, (2) multi-species grazing (mob grazing by cattle, with goats foraging at key times of the year), (3) prescribed fire, and (4) prescribed fire followed by cattle grazing.

Validation of an In Vitro Diagnostic Test for Endometriosis: Impact of Confounding Medical Conditions and Lesion Location.

With the aim to shorten the time for diagnosis and accelerate access to correct management, a non-invasive diagnostic test for endometriosis was developed and validated. The IVD test combines an ELISA test kit to quantify CA125 and BDNF concentrations in serum and a data treatment algorithm hosted in medical software processing results from the ELISA test and responses to six clinical variables. Serum samples and clinical variables extracted from psychometric questionnaires from 77 patients were collected from the Oxford Endometriosis CaRe Centre biobank (UK).

Prostaglandin E regulates the plasminogen activator pathway in human endometrial endothelial cells: a new in vitro model to investigate heavy menstrual bleeding.

Objective: To study the role of PGE in regulating plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in human primary endometrial endothelial cells (HEECs) from women with normal menstrual bleeding (NMB) and heavy menstrual bleeding (HMB).

Design: In vitro study using endometrial endothelial cells.

Setting: Research laboratory setting.

Double dosing ulipristal acetate emergency contraception for individuals with obesity: a randomised crossover trial.

Objective: To determine whether increasing the dose of ulipristal acetate (UPA)-containing emergency contraception (EC) improves pharmacodynamic outcomes in individuals with obesity.

Study Design: We enrolled healthy, regularly-cycling, confirmed ovulatory, reproductive-age individuals with body mass index (BMI) >30 kg/m and weight >80 kg in a randomised crossover study. We monitored participants with transvaginal ultrasound and blood sampling for progesterone, luteinising hormone (LH), and estradiol every other day until a dominant follicle measuring >15 mm was visualised.

Determining female-specific high-intensity activity GPS thresholds in women's rugby union: Use of current use of male-derived absolute speed thresholds underestimates true levels.

GPS speed thresholds in women's rugby union are usually based on data derived from the men's game. However, evidence suggests the maximum speeds achieved by female players are 2-8 km.h slower and the volume of high-intensity running (HIR) in women's rugby may be underestimated.

The Long-Term Agroecosystem Research Cropland Common Experiment at Northern Plains.

Cropland agriculture in the northern Great Plains is challenged by variable weather, agricultural intensification, and competing use for energy development. Innovative cropland practices that address these challenges are needed to ensure regional agriculture can sustainably meet future food, fuel, and fiber demand. In response to this need, the Northern Plains Long-Term Agroecosystem Research network site established a cropland experiment in 2019 that contrasts prevailing and alternative practices at plot and field scales over a proposed 30-year time frame.

Recommended measurement instruments for genitourinary symptoms associated with menopause: the COMMA (Core outcomes in menopause) consortium.

Objective: The aim of the study is to identify appropriate definitions and patient-reported outcome measures (PROMs) for each of the eight core outcomes previously selected for genitourinary symptoms associated with menopause: pain with sex, vulvovaginal dryness, vulvovaginal discomfort or irritation, discomfort or pain when urinating, change in most bothersome symptom, distress, bother or interference of genitourinary symptoms, satisfaction with treatment, and side effects.

Methods: We conducted a systematic review to identify possible definitions and PROMs, including their measurement properties. Identified definitions and relevant PROMs with acceptable measurement properties were entered into an international consensus process involving 28 participants from 10 countries to achieve final recommendations for each core outcome.

Recommended measurement instruments for menopausal vasomotor symptoms: the COMMA (Core Outcomes in Menopause) consortium.

Objective: The aim of the study is to identify suitable definitions and patient-reported outcome measures (PROMs) to assess each of the six core outcomes previously identified through the COMMA (Core Outcomes in Menopause) global consensus process relating to vasomotor symptoms: frequency, severity, distress/bother/interference, impact on sleep, satisfaction with treatment, and side effects.

Methods: A systematic review was conducted to identify relevant definitions for the outcome of side-effects and PROMs with acceptable measurement properties for the remaining five core outcomes. The consensus process, involving 36 participants from 16 countries, was conducted to review definitions and PROMs and make final recommendations for the measurement of each core outcome.

Use of serum evaluation of contraceptive and ovarian hormones to assess reduced risk of pregnancy among women presenting for emergency contraception in a multicenter clinical trial.

Objectives: To evaluate ovulation risk among women enrolling in an emergency contraception (EC) study by measuring contraceptive steroids and ovarian hormones.

Study Design: We used standard chemiluminescent assays to evaluate endogenous hormones (estradiol, progesterone, follicle stimulating hormone, luteinizing hormone) and liquid chromatography-tandem triple quadrupole mass spectrometry to simultaneously analyze concentrations of ethinylestradiol, dienogest, norelgestromin (NGMN), norethindrone (NET), gestodene, levonorgestrel (LNG), etonogestrel (ENG), segesterone acetate, medroxyprogesterone acetate (MPA), and drospirenone in serum samples obtained at the time of enrollment in a recent study comparing oral ulipristal acetate and LNG EC in women with weight ≥80 kg reporting no recent use of hormonal contraception.

Results: We enrolled 532 and obtained a valid baseline blood sample from 520 women.

Emergency contraception for individuals weighing 80 kg or greater: A randomized trial of 30 mg ulipristal acetate and 1.5 mg or 3.0 mg levonorgestrel.

Objectives: To compare the efficacy of emergency contraception (EC) regimens used within 72 hours of unprotected intercourse in individuals weighing ≥80 kg.

Study Design: We enrolled reproductive-aged healthy women in a multicenter, single-blind, randomized study of levonorgestrel 1.5 mg (LNG1X) and 3.

Voxelotor improves red blood cell functionality in children with sickle cell anaemia: An ancillary study of the HOPE-KIDS 1 trial.

Introduction: Sickle haemoglobin (HbS) polymerisation perturbs red blood cell (RBC) rheology and drives sickle cell disease (SCD) pathophysiology. Voxelotor is an HbS polymerisation inhibitor that increases haemoglobin (Hb)-oxygen affinity.

Methods/results: In this 48-week, prospective, single-centre translational study, 10 children aged 4-11 years with SCD were treated with voxelotor.

Adaptation to sorbic acid in low sugar promotes resistance of yeast to the preservative.

The weak acid sorbic acid is a common preservative used in soft drink beverages to control microbial spoilage. Consumers and industry are increasingly transitioning to low-sugar food formulations, but potential impacts of reduced sugar on sorbic acid efficacy are barely characterised. In this study, we report enhanced sorbic acid resistance of yeast in low-glucose conditions.

Comparison of estrogenic components used for hormonal contraception.

Attempts have been made over the years to replace ethinyl estradiol (EE) in combined oral contraceptives (COCs) with the less potent natural estrogen estradiol (E), or its prodrug, E valerate (EV), to improve their safety and tolerability. Recently, a COC incorporating a novel weak natural estrogen, estetrol (E), combined with drospirenone, has become available. We present a comparative analysis of the three prevailing estrogens used in COCs, focusing on their structure-function relationships, receptor-binding affinity, potency, metabolism, pharmacokinetic parameters, and pharmacodynamics.

Accelerated atherosclerosis in beta-thalassemia.

Children with beta-thalassemia (BT) present with an increase in carotid intima-medial thickness, an early sign suggestive of premature atherosclerosis. However, it is unknown if there is a direct relationship between BT and atherosclerotic disease. To evaluate this, wild-type (WT, littermates) and BT (Hbb) mice, both male and female, were placed on a 3-mo high-fat diet with low-density lipoprotein receptor suppression via overexpression of proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation (D377Y).

The efficacy, safety, and tolerability of an estrogen-free oral contraceptive drospirenone 4 mg (24/4-day regimen) in obese users.

Objectives: This study aimed to compare contraceptive efficacy and safety of drospirenone 4 mg in a 24/4-day regimen in nonobese and obese users and describe pharmacokinetics according to bodyweight.

Study Design: We analyzed data from three drospirenone 4 mg trials (2 European and 1 United States) to report outcomes in nonobese (body mass index <30 kg/m) and obese (body mass index ≥30 kg/m) users. We used data from the US trial to calculate the Pearl Index (pregnancies per 100 woman-years) in nonbreastfeeding participants aged ≤35 years at enrollment for confirmed pregnancies.

Evaluating the potential of natural product combinations with sorbic acid for improving preservative action against food-spoilage yeasts.

Fungal control methods commonly involve the use of antifungals or preservatives, which can raise concerns about broader effects of these stressors on non-target organisms, spread of resistance and regulatory hurdles. Consequently, control methods enabling lower usage of such stressors are highly sought, for example chemical combinations that synergistically inhibit target-organisms. Here, we investigated how well such a principle extends to improving efficacy of an existing but tightly controlled food preservative, sorbic acid.

Biosynthesis of estetrol in human pregnancy: Potential pathways.

Estetrol (E) has emerged as a novel and highly promising estrogen for therapeutic use. E is a weak natural estrogen produced only in pregnancy. Because of its novelty, there is considerable interest by clinicians in how it is produced in pregnancy.