Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to ...nearly full estrogen suppression in previous studies.
We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II EM-I and EM-II) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary.
A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings.
Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).
Due to the competitive edge it confers on students, educational institutions, and non-English speaking nations in a globalized economy, English as a medium of instruction (EMI) has been gaining ...popularity in tertiary education in non-native English-speaking (NNES) countries. Institute-wide EMI implementation has often been imposed by top-down decisions, in combination with the optimistic view that the horse should always be placed before the cart. However, emerging evidence suggests that the delivery of such programs to NNES students has led to new pedagogical challenges and learning problems that go beyond the scope of language learning and teaching and deserve immediate attention. For example, how would an instructor respond to situations in which students’ learning of content is compromised by their limited language proficiency? This book draws on the current practice of EMI in diverse disciplines and university settings and examines how these new pedagogical and learning issues can be addressed. The discussion also involves a reflection on the essence of EMI in relation to the use of the first language (L1) as the medium of instruction in tertiary education. In addition, the book includes discussion about how to ensure and maintain the quality of EMI programs and assess the readiness of stakeholders for such programs, which include administrators, teachers, and students. The discussion is led by exemplars in Hong Kong and Taiwan, where the majority of students are native Chinese speakers, in the hope of developing critical perspectives and practical guidelines as references for EMI in other NNES settings.
Background There has been a dramatic proliferation of precautionary labeling by manufacturers to mitigate the perceived risk from low-level contamination from allergens in food. This has resulted in ...a significant reduction in choice of potentially safe foods for allergic consumers. Objectives We aimed to establish reference doses for 11 commonly allergenic foods to guide a rational approach by manufacturers based on all publically available valid oral food challenge data. Methods Reference doses were developed from statistical dose-distribution modeling of individual thresholds of patients in a dataset of more than 55 studies of clinical oral food challenges. Sufficient valid data were available for peanut, milk, egg, and hazelnut to allow assessment of the representativeness of the data used. Results The data were not significantly affected by the heterogeneity of the study methodology, including little effect of age on results for those foods for which sufficient numbers of adult challenge data were available (peanut and hazelnut). Thus by combining data from all studies, the eliciting dose for an allergic reaction in 1% of the population estimated for the following were 0.2 mg of protein for peanut, 0.1 mg for cow's milk, 0.03 mg for egg, and 0.1 mg for hazelnut. Conclusions These reference doses will form the basis of the revised Voluntary Incidental Trace Allergen Labeling (VITAL) 2.0 thresholds now recommended in Australia. These new levels will enable manufacturers to apply credible precautionary labeling and provide increased consumer confidence in their validity and reliability, as well as improving consumer safety.
Summary
It is unclear whether optimal levels of 25-hydroxyvitamin D (25(OH)D) in whites are the same as in minorities. In adult participants of NHANES, the relationships between 25(OH)D, bone mineral ...density (BMD), and parathyroid hormone (PTH) differed in blacks as compared to whites and Mexican-Americans, suggesting that optimal 25(OH)D levels for bone and mineral metabolism may differ by race.
Introduction
Blacks and Hispanics have lower 25-hydroxyvitamin D concentrations than whites. However, it is unclear whether 25(OH)D levels considered “optimal” for bone and mineral metabolism in whites are the same as those in minority populations.
Methods
We examined the relationships between 25(OH)D and parathyroid hormone in 8,415 adult participants (25% black and 24% Mexican-American) in the National Health and Nutrition Examination Surveys 2003–2004 and 2005–2006; and between 25(OH)D and bone mineral density in 4,206 adult participants (24% black and 24% Mexican-American) in the 2003–2004 sample.
Results
Blacks and Mexican-Americans had significantly lower 25(OH)D and higher PTH concentrations than whites (
P
< 0.01 for both). BMD significantly decreased (
P
< 0.01) as serum 25(OH)D and calcium intake declined among whites and Mexican-Americans, but not among blacks (
P
= 0.2). The impact of vitamin D deficiency (25(OH)D ≤ 20 ng/ml) on PTH levels was modified by race/ethnicity (
P
for interaction, 0.001). Whereas inverse relationships between 25(OH)D and PTH were observed above and below a 25(OH)D level of 20 ng/ml in whites and Mexican-Americans, an inverse association between 25(OH)D and PTH was only observed below this threshold in blacks, with the slope of the relationship being essentially flat (
P
= 0.7) above this cut-point, suggesting that PTH may be maximally suppressed at lower 25(OH)D levels in blacks than in whites or Mexican-Americans.
Conclusions
The relationships between 25(OH)D, BMD, and PTH may differ by race among US adults. Whether race-specific ranges of optimal vitamin D are needed to appropriately evaluate the adequacy of vitamin D stores in minorities requires further study.
The TEX86 proxy, based on the distribution of marine isoprenoidal glycerol dialkyl glycerol tetraether lipids (GDGTs), is increasingly used to reconstruct sea surface temperature (SST) during the ...Eocene epoch (56.0–33.9 Ma). Here we compile published TEX86 records, critically reevaluate them in light of new understandings in TEX86 palaeothermometry, and supplement them with new data in order to evaluate long‐term temperature trends in the Eocene. We investigate the effect of archaea other than marine Thaumarchaeota upon TEX86 values using the branched‐to‐isoprenoid tetraether index (BIT), the abundance of GDGT‐0 relative to crenarchaeol (%GDGT‐0), and the Methane Index (MI). We also introduce a new ratio, %GDGTRS, which may help identify Red Sea‐type GDGT distributions in the geological record. Using the offset between TEX86H and TEX86L (ΔH‐L) and the ratio between GDGT‐2 and GDGT‐3 (2/3), we evaluate different TEX86 calibrations and present the first integrated SST compilation for the Eocene (55 to 34 Ma). Although the available data are still sparse some geographic trends can now be resolved. In the high latitudes (>55°), there was substantial cooling during the Eocene (~6°C). Our compiled record also indicates tropical cooling of ~2.5°C during the same interval. Using an ensemble of climate model simulations that span the Eocene, our results indicate that only a small percentage (~10%) of the reconstructed temperature change can be ascribed to ocean gateway reorganization or paleogeographic change. Collectively, this indicates that atmospheric carbon dioxide (pCO2) was the likely driver of surface water cooling during the descent toward the icehouse.
Key Points
Archaea other than marine Thaumarchaeota exert a minimal impact on most Eocene temperatures
Tropical and high‐latitude cooling during the descent towards the icehouse
Carbon dioxide is the most likely driver of long‐term Eocene cooling
•Reference Doses for allergenic foods can provide guidance for public health agencies, and the food industry.•An international expert panel proposed Reference Doses for 11 allergenic foods.•Reference ...Doses were based upon results from low-dose oral challenges of 1800 food-allergic individuals for the 11 foods.•Reference Doses can inform the process for the establishment of population thresholds for allergenic foods.
In 2011, an expert panel was assembled to establish appropriate Reference Doses for allergenic food residues as a part of the VITAL (Voluntary Incidental Trace Allergen Labeling) program of The Allergen Bureau of Australia & New Zealand (ABA). These Reference Doses would guide advisory labeling decisions for use on food labels. Individual NOAELs and LOAELs were obtained from clinical challenges of food-allergic subjects. Statistical dose-distribution models (log-normal, log–logistic, Weibull) were applied to the individual NOAELs and LOAELs for each allergenic food. The Reference Doses, in terms of mg of total protein from the allergenic food, were based upon either the ED01 (for peanut, cow’s milk), the 95% lower confidence interval of the ED05 (for wheat, soybean, cashew, shrimp, sesame seed, mustard, and lupine), or both (egg, hazelnut) using all appropriate statistical dose-distribution models. Reference Doses were established for 11 allergenic foods ranging from 0.03mg for egg protein to 10mg for shrimp protein. Reference Doses were not established for fish or celery due to poor model fits with existing data. Reference Doses were not established for other tree nuts beyond hazelnut and cashew because of the absence of data on NOAELs and LOAELs from individual subjects.
The LUX-ZEPLIN experiment is a dark matter detector centered on a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility in Lead, South Dakota, USA. This ...Letter reports results from LUX-ZEPLIN's first search for weakly interacting massive particles (WIMPs) with an exposure of 60 live days using a fiducial mass of 5.5 t. A profile-likelihood ratio analysis shows the data to be consistent with a background-only hypothesis, setting new limits on spin-independent WIMP-nucleon, spin-dependent WIMP-neutron, and spin-dependent WIMP-proton cross sections for WIMP masses above 9 GeV/c^{2}. The most stringent limit is set for spin-independent scattering at 36 GeV/c^{2}, rejecting cross sections above 9.2×10^{-48} cm at the 90% confidence level.
The radio galaxy 0402+379 is believed to host a supermassive black hole binary (SMBHB). The two compact-core sources are separated by a projected distance of 7.3 pc, making it the most (spatially) ...compact resolved SMBHB known. We present new multi-frequency VLBI observations of 0402+379 at 5, 8, 15, and 22 GHz and combine them with previous observations spanning 12 years. A strong frequency-dependent core shift is evident, which we use to infer magnetic fields near the jet base. After correcting for these shifts we detect significant relative motion of the two cores at at . With some assumptions about the orbit, we use this measurement to constrain the orbital period yr and SMBHB mass . While additional observations are needed to confirm this motion and obtain a precise orbit, this is apparently the first black hole system resolved as a visual binary.
Oceanic production of calcium carbonate is conventionally attributed to marine plankton (coccolithophores and foraminifera). Here we report that marine fish produce precipitated carbonates within ...their intestines and excrete these at high rates. When combined with estimates of global fish biomass, this suggests that marine fish contribute 3 to 15% of total oceanic carbonate production. Fish carbonates have a higher magnesium content and solubility than traditional sources, yielding faster dissolution with depth. This may explain up to a quarter of the increase in titratable alkalinity within 1000 meters of the ocean surface, a controversial phenomenon that has puzzled oceanographers for decades. We also predict that fish carbonate production may rise in response to future environmental changes in carbon dioxide, and thus become an increasingly important component of the inorganic carbon cycle.
Phosphorus (P) eutrophication is a major pollution problem globally, with unprecedented amount of P emanating from agricultural sources. But little is known about the optimization of soil-biochar P ...sorption capacity. The study objective was to determine how biochar feedstocks and pyrolysis conditions influences carbon (C) thermal stability, C composition and pH and in turn influence the phosphorus sorption optimization. Biochar was produced from switchgrass, kudzu and Chinese tallow at 200, 300, 400, 500, 550, 650,750 °C. Carbon thermal stability was determined by multi-element scanning thermal analysis (MESTA), C composition was determined using solid state 13C NMR. Phosphorus sorption was determined using a mixture of 10% biochar and 90% sandy soil after incubation. Results indicate increased P sorption (P < 0.0001) and decreased P availability (P < 0.0001) with increasing biochar pyrolysis temperature. However, optimum P sorption was feedstock specific with switchgrass indicating P desorption between 200 and 550 °C. Phosphorus sorption was in the order of kudzu > switchgrass > Chinese tallow. Total C, C thermal stability, aromatic C and alkalinity increased with elevated pyrolysis temperature. Biochar alkalinity favored P sorption. There was a positive relationship between high thermal stable C and P sorption for Kudzu (r = 0.62; P = 0.0346) and Chinese tallow (r = 0.73; P = 0.0138). In conclusion, biochar has potential for P eutrophication mitigation, however, optimum biochar pyrolysis temperature for P sorption is feedstock specific and in some cases might be out of 300–500 °C temperature range commonly used for agronomic application. High thermal stable C dominated by aromatic C and alkaline pH seem to favor P sorption.
•Increased biochar pyrolysis temperature led to increased high thermal stable carbon (C) and aromatic C.•Elevated biochar pyrolysis temperature led to increased alkalinity and reduced phosphorus (P) availability.•High thermal stable C dominated by aromatic C favored P sorption.•Increased alkalinity dominated by Ca related positively with P sorption.•Biochar has potential for mitigation of P eutrophication, when optimization point is identified.
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