The description of the dynamics of an electron in an external electromagnetic field of arbitrary intensity is one of the most fundamental outstanding problems in electrodynamics. Remarkably, to date, ...there is no unanimously accepted theoretical solution for ultrahigh intensities and little or no experimental data. The basic challenge is the inclusion of the self-interaction of the electron with the field emitted by the electron itself—the so-called radiation reaction force. We report here on the experimental evidence of strong radiation reaction, in an all-optical experiment, during the propagation of highly relativistic electrons (maximum energy exceeding 2 GeV) through the field of an ultraintense laser (peak intensity of4×1020W/cm2). In their own rest frame, the highest-energy electrons experience an electric field as high as one quarter of the critical field of quantum electrodynamics and are seen to lose up to 30% of their kinetic energy during the propagation through the laser field. The experimental data show signatures of quantum effects in the electron dynamics in the external laser field, potentially showing departures from the constant cross field approximation.
We conducted a phase IIa, multi-centre, open label, single arm study (RADICAL; NCT01791985) of AZD4547 (a potent and selective inhibitor of Fibroblast Growth Factor Receptor (FGFR)-1, 2 and 3 ...receptor tyrosine kinases) administered with anastrozole or letrozole in estrogen receptor positive metastatic breast cancer patients who had become resistant to aromatase inhibitors. After a safety run-in study to assess safety and tolerability, we recruited 52 patients. The primary endpoint was change in tumour size at 12 weeks, and secondary endpoints were to assess response at 6 weeks, 20 weeks and every 8 weeks thereafter and tolerability of the combined treatment. Two partial responses (PR) and 19 stable disease (SD) patients were observed at the 12-week time point. At 28 weeks, according to centrally reviewed Response Evaluation Criteria in Solid Tumours (RECIST) criteria, five PR and 8 SD patients were observed in 50 assessable cases. Overall, objective response rate (5 PR) was of 10%, meeting the pre-specified endpoint. Fourteen patients discontinued due to adverse events. Eleven patients had retinal pigment epithelial detachments which was asymptomatic and reversible in all but one patient. Exploratory ribonucleic acid sequencing (RNA-Seq) analysis was done on patients' samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547.
The dynamics of energetic particles in strong electromagnetic fields can be heavily influenced by the energy loss arising from the emission of radiation during acceleration, known as radiation ...reaction. When interacting with a high-energy electron beam, today’s lasers are sufficiently intense to explore the transition between the classical and quantum radiation reaction regimes. We present evidence of radiation reaction in the collision of an ultrarelativistic electron beam generated by laser-wakefield acceleration (ϵ>500MeV) with an intense laser pulse (a0>10). We measure an energy loss in the postcollision electron spectrum that is correlated with the detected signal of hard photons (γrays), consistent with a quantum description of radiation reaction. The generatedγrays have the highest energies yet reported from an all-optical inverse Compton scattering scheme, with critical energyϵcrit>30MeV.
The diversity, frequency, and scale of human impacts on coral reefs are increasing to the extent that reefs are threatened globally. Projected increases in carbon dioxide and temperature over the ...next 50 years exceed the conditions under which coral reefs have flourished over the past half-million years. However, reefs will change rather than disappear entirely, with some species already showing far greater tolerance to climate change and coral bleaching than others. International integration of management strategies that support reef resilience need to be vigorously implemented, and complemented by strong policy decisions to reduce the rate of global warming.
STUDY QUESTION
How variable is the length of human pregnancy, and are early hormonal events related to gestational length?
SUMMARY ANSWER
Among natural conceptions where the date of conception ...(ovulation) is known, the variation in pregnancy length spanned 37 days, even after excluding women with complications or preterm births.
WHAT IS KNOWN ALREADY
Previous studies of length of gestation have either estimated gestational age by last menstrual period (LMP) or ultrasound (both imperfect measures) or included pregnancies conceived through assisted reproductive technology.
STUDY DESIGN, SIZE, DURATION
The Early Pregnancy Study was a prospective cohort study (1982–85) that followed 130 singleton pregnancies from unassisted conception to birth, with detailed hormonal measurements through the conception cycle; 125 of these pregnancies were included in this analysis.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We calculated the length of gestation beginning at conception (ovulation) in 125 naturally conceived, singleton live births. Ovulation, implantation and corpus luteum (CL) rescue pattern were identified with urinary hormone measurements. We accounted for events that artificially shorten the natural length of gestation (Cesarean delivery or labor induction, i.e. ‘censoring’) using Kaplan–Meier curves and proportional hazards models. We examined hormonal and other factors in relation to length of gestation. We did not have ultrasound information to compare with our gold standard measure.
MAIN RESULTS AND THE ROLE OF CHANCE
The median time from ovulation to birth was 268 days (38 weeks, 2 days). Even after excluding six preterm births, the gestational length range was 37 days. The coefficient of variation was higher when measured by LMP (4.9%) than by ovulation (3.7%), reflecting the variability of time of ovulation. Conceptions that took longer to implant also took longer from implantation to delivery (P = 0.02). CL rescue pattern (reflecting ovarian response to implantation) was predictive (P = 0.006): pregnancies with a rapid progesterone rise were longer than those with delayed rise (a 12-day difference in the median gestational length). Mothers with longer gestations were older (P = 0.02), had longer pregnancies in other births (P < 0.0001) and were heavier at birth (P = 0.01). We did not see an association between the length of gestation and several factors that have been associated with gestational length in previous studies: body mass index, alcohol intake, parity or offspring sex.
LIMITATIONS, REASONS FOR CAUTION
The sample size was small and some exposures were rare, reducing power to detect weak associations.
WIDER IMPLICATIONS OF THE FINDINGS
Human gestational length varies considerably even when measured exactly (from ovulation). An individual woman's deliveries tend to occur at similar gestational ages. Events in the first 2 weeks after conception are predictive of subsequent pregnancy length, and may suggest pathways underlying the timing of delivery.
STUDY FUNDING/COMPETING INTEREST
This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. None of the authors has any conflict of interest to declare.
Steaks from muscles (
n
=
19 from nine beef carcasses) were evaluated over the course of retail display (0-, 1-, 2-, 3-, 4- or 5-d) for objective measures of discoloration (metmyoglobin, ...oxymyoglobin,
L*-,
a*-, and
b*-values), reducing ability (metmyoglobin reductase activity (MRA), resistance to induced metmyoglobin formation (RIMF), and nitric oxide metmyoglobin reducing ability (NORA)), oxygen consumption rate (OCR), oxygen penetration depth, myoglobin content, oxidative rancidity, and pH. Muscles were grouped according to objective color measures of discoloration.
M. longissimus lumborum,
M. longissimus thoracis,
M. semitendinosus, and
M. tensor fasciae latae were grouped as “high” color stability muscles,
M. semimembranosus,
M. rectus femoris, and
M. vastus lateralis were grouped as “moderate” color stability muscles,
M. trapezius,
M. gluteus medius, and
M. latissimus dorsi were grouped as “intermediate” color stability muscles,
M. triceps brachi – long head,
M. biceps femoris,
M. pectoralis profundus,
M. adductor,
M. triceps brachi – lateral head, and
M. serratus ventralis were grouped as “low” color stability muscles, and
M. supraspinatus,
M. infraspinatus, and
M. psoas major were grouped as “very low” color stability muscles. Generally, muscles of high color stability had high RIMF, nitric oxide reducing ability, and oxygen penetration depth and possessed low OCRs, myoglobin content, and oxidative rancidity. In contrast, muscles of low color stability had high MRA, OCRs, myoglobin content, and oxidative rancidity and low RIMF, NORA, and oxygen penetration depth. Data indicate that discoloration differences between muscles are related to the amount of reducing activity relative to the OCR.
Abstract
STUDY QUESTION
Is pre-conception 25(OH)D associated with the per cycle probability of conception, i.e fecundability, in a prospective cohort study?
SUMMARY ANSWER
There are suggestive ...associations of high 25(OH)D (at least 50 ng/ml) with increased fecundability and low 25(OH)D (<20 ng/ml) with reduced fecundability, but the estimates were imprecise.
WHAT IS KNOWN ALREADY
Vitamin D has been associated with reproductive function and fertility in animal studies, but few human studies exist.
STUDY DESIGN, SIZE, DURATION
This community-based prospective cohort study included 522 women attempting to become pregnant between 2010 and 2016. The women completed online daily and monthly diaries until a positive home pregnancy test was observed or 12 months had elapsed.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The study included women from central North Carolina who were aged 30–44 with no history of infertility, with no more than 3 months of attempt time at recruitment. Women recorded vaginal bleeding so that the ongoing number of attempt cycles could be counted and used to quantify a woman’s pregnancy attempt time. Blood collected at the study entry was analysed for 25(OH)D using liquid chromatography tandem mass spectrometry. Associations with fecundability were estimated with a log-binomial discrete time-to-event model.
MAIN RESULTS AND THE ROLE OF CHANCE
Among 522 women, 257 conceived during the study. The mean age was 33 years and the mean 25(OH)D was 36 ng/ml. There was an estimated 10% higher fecundability with each 10 ng/ml increase in 25(OH)D (fecundability ratio (FR) 1.10, 95% CI: 0.96, 1.25). The suggestive dose-response association with the continuous measure of 25(OH)D was driven by women in the lowest and the highest categories of 25(OH)D. Compared to women with 25(OH)D of 30–40 ng/ml, women below 20 ng/ml had an estimated 45% reduction in fecundability (FR (CI): 0.55 (0.23, 1.32)), and women with at least 50 ng/ml had an estimated 35% increase in fecundability (FR (CI): 1.35 (0.95, 1.91)). Across these three categories (25(OH)D of <20 ng/ml, 30–40 ng/ml and > 50 ng/ml), the probability of taking longer than 6 months to conceive was, respectively, 51% (17%, 74%), 28% (17%, 39%) and 15% (10%, 37%).
LIMITATIONS, REASONS FOR CAUTION
While the distribution of 25(OH)D was wide, the number of observed cycles with high 25(OH)D (N = 107) or low 25(OH)D (N = 56) was small.
WIDER IMPLICATIONS OF THE FINDINGS
Our findings are consistent with prior reports of reduced fertility in women with 25(OH)D concentrations below the clinically defined deficiency level (20 ng/ml). Further studies are needed to evaluate the possible reproductive benefits of considerably higher 25(OH)D concentration (>50 ng/ml).
STUDY FUNDING/COMPETING INTEREST(S)
This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) under award numbers R00HD079659 and R01HD067683 and supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, under projects ES103086, ES049003 and ES044003. ClearBlue ovulation predictor kits were generously donated to AMZJ and AJW by Swiss Precision Diagnostics. Drs Wilcox and Jukic report non-financial support from Swiss Precision Diagnostics during the conduct of the study; Dr Jukic reports non-financial support from Theralogix, LLC, outside the submitted work. Otherwise there are no competing interests.
Trial registration number
N/A
Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a ...larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity.
Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8.
We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months.
Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases.
2009-017817-31.
•Epertinib (S-222611) is a new potent oral inhibitor of EGFR, HER2 and HER4.•Seventy-six patients treated, with cancers expressing EGFR or HER2, including breast.•Well-tolerated with long-term dosing, predominantly grade I/II adverse events.•Response rates in HER2-positive breast and upper GI cancers were 19% and 20%.•Breast cancer responses included metastatic brain disease.
Three groups of steers (A, B, C) were used to study the effect of temperament (Calm, Intermediate, and Excitable) on meat quality. Temperament was based on exit velocity, pen scores, and chute ...scores. Temperament traits were consistent across evaluations, and values decreased (
P
<
0.05) in magnitude over time. Increasing excitability was associated with higher (
P
<
0.05) serum cortisol concentrations. Carcasses from cattle with calm temperaments had higher (
P
<
0.05) 0.5
h postmortem pH values than those from Intermediate and Excitable cattle (0.1 and 0.2 units, respectively). Group C Excitable steers had higher (
P
<
0.05) WBS values than the calmer Group C steers. This trend was observed in Group A steers, although the values were not statistically different. Correlations were highest between temperament values and tenderness after 21
d. Temperament influences tenderness, although the mechanism is not clear.
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