Mothers vary in duration of breastfeeding. These individual differences are related to a variety of demographic and individual maternal factors including maternal hormones, mood and early ...experiences. However, little is known about the role of genetic factors. We studied single‐nucleotide polymorphisms (SNPs) in the OXT peptide gene (rs2740210; rs4813627) and the OXT receptor gene (OXTR rs237885) in two samples of mothers from the Maternal adversity, Vulnerability and Neurodevelopment study (MAVAN), a multicenter (Hamilton and Montreal, Canada) study following mothers and their children from pregnancy until 7 years of age. Data from the Hamilton site was the primary sample (n = 201) and data from Montreal was the replication sample (n = 151). Breastfeeding duration, maternal mood (measured by the CES‐D scale) and early life adversity (measured by the CTQ scale) were established during 12 months postpartum. In our primary sample, polymorphisms in OXT rs2740210, but not the other SNPs, interacted with early life adversity to predict variation in breastfeeding duration (overall F8,125 = 2.361, P = 0.021; interaction effect b = −8.12, t = −2.3, P = 0.023) and depression (overall F8,118 = 5.751, P ≤ 0.001; interaction effect b = 6.06, t = 3.13, P = 0.002). A moderated mediation model showed that higher levels of depression mediated the inverse relation of high levels of early life adversity to breastfeeding duration, but only in women possessing the CC genotype effect a′ = −3.3401, 95% confidence interval (CI) = −7.9466 to −0.0015 of the OXT SNP and not in women with the AA/AC genotype (a′ = −1.2942, ns). The latter findings (moderated mediation model) were replicated in our Montreal sample (a′ = −0.277, 95% CI = −0.7987 to −0.0348 for CC; a′ = −0.1820, ns for AA/AC).
Depression mediates the inverse relation of early adversity to breastfeeding duration, but only in women with the CC genotype of OXT rs2740210.
Amivantamab plus carboplatin–pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced ...non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial.
A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab–lazertinib–chemotherapy, chemotherapy, or amivantamab–chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab–lazertinib–chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion.
All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively. Consistent PFS results were seen by investigator assessment (HR 0.41 and 0.38 for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab–chemotherapy had lower rates of hematologic AEs than amivantamab–lazertinib–chemotherapy.
Amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab–lazertinib–chemotherapy regimen.
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•Amivantamab–chemotherapy improved PFS and intracranial PFS versus chemotherapy.•Amivantamab–lazertinib–chemotherapy improved PFS and intracranial PFS versus chemotherapy.•Predominant AEs in the amivantamab-containing arms were hematologic, EGFR, and MET related.•MARIPOSA-2 is the first study to demonstrate improved PFS versus chemotherapy after disease progression on osimertinib.
The objectives of this study were to compare the survival of sarcoid patients with pulmonary fibrosis with that of the general population and to determine the causes of death and the incidence of ...evolutive complications. This retrospective cohort included 142 sarcoid patients in radiographic stage IV (74 males; mean ± SD age 48.1 ± 12 yrs). Their survival was compared with that of the general French population, matched for the year and age at diagnosis of stage IV disease, sex and length of follow-up. Expected survival probabilities were calculated year-by-year on the basis of probabilities provided by official demographic data for France. Survival curves were based on the Kaplan-Meier method and compared using the log-rank test. During the follow-up period (7.1 ± 4.8 yrs), pulmonary hypertension (PH) was observed in 29.7% of cases and aspergilloma in 11.3%. Long-term oxygen therapy was required in 12%. Survival was 84.1% at 10 yrs, which was worse than for the general population (p = 0.013). 16 (11.3%) patients died from the following causes: refractory PH (n = 5), chronic respiratory insufficiency (n = 4), acute respiratory insufficiency (n = 2), haemoptysis due to aspergilloma (n = 1), heart sarcoidosis (n = 1), nocardiosis (n = 1) and unknown causes (n = 2). Survival is significantly decreased in stage IV patients. 75% of fatalities are directly attributable to respiratory causes.
Abstract
The DARWIN observatory is a proposed next-generation experiment to search for particle dark matter and for the neutrinoless double beta decay of
$$^{136}$$
136
Xe. Out of its 50 t total ...natural xenon inventory, 40 t will be the active target of a time projection chamber which thus contains about 3.6 t of
$$^{136}$$
136
Xe. Here, we show that its projected half-life sensitivity is
$$2.4\times {10}^{27}\,{\hbox {year}}$$
2.4
×
10
27
year
, using a fiducial volume of 5 t of natural xenon and 10 year of operation with a background rate of less than 0.2 events/(t
$$\cdot $$
·
year) in the energy region of interest. This sensitivity is based on a detailed Monte Carlo simulation study of the background and event topologies in the large, homogeneous target. DARWIN will be comparable in its science reach to dedicated double beta decay experiments using xenon enriched in
$$^{136}$$
136
Xe.
PSR B0950+08 is a bright nonrecycled pulsar whose single-pulse fluence variability is reportedly large. Based on observations at two widely separated frequencies, 55 MHz (NenuFAR) and 1.4 GHz ...(Westerbork Synthesis Radio Telescope), we review the properties of these single pulses. We conclude that they are more similar to ordinary pulses of radio emission than to a special kind of short and bright giant pulses, observed from only a handful of pulsars. We argue that a temporal variation of the properties of the interstellar medium along the line of sight to this nearby pulsar, namely the fluctuating size of the decorrelation bandwidth of diffractive scintillation makes an important contribution to the observed single-pulse fluence variability. We further present interesting structures in the low-frequency single-pulse spectra that resemble the “sad trombones” seen in fast radio bursts (FRBs); although for PSR B0950+08 the upward frequency drift is also routinely present. We explain these spectral features with radius-to-frequency mapping, similar to the model developed by Wang et al. (2019, ApJ, 876, L15) for FRBs. Finally, we speculate that μs-scale fluence variability of the general pulsar population remains poorly known, and that its further study may bring important clues about the nature of FRBs.
Summary Aim The primary goal of this body of work is to suggest a standardized system for histopathological assessment of experimental surgical instability models of osteoarthritis (OA) in rabbits, ...building on past experience, to achieve comparability of studies from different centres. An additional objective is to review methodologies that have been employed in the past for assessing OA in rabbits with particular reference to the surgical anterior cruciate ligament transection (ACLT) model. Methods A panel of scientists and clinician-scientists with recognized expertise in assessing rabbit models of OA reviewed the literature to provide a critical appraisal of the methods that have been employed to assess both macroscopic and microscopic changes occurring in rabbit joint tissues in experimental OA. In addition, a validation of the proposed histologic histochemical grading system was performed. Results The ACLT variant of the surgical instability model in skeletally mature rabbits is the variation most capable of reproducing the entire range of cartilage, synovial and bone lesions recognized to be associated with OA. These lesions can be semiquantitatively graded using macroscopic and microscopic techniques. Further, as well as cartilage lesions, this ACLT model can produce synovial and bone lesions similar to that of human OA. Conclusions The ACLT variant of the surgical instability model in rabbits is a reproducible and effective model of OA. The cartilage lesions in this model and their response to therapy can be graded according to an adapted histological and histochemical grading system, though also this system is to some extent subjective and, thus, neither objective nor entirely reproducible.
Objective
To evaluate the efficacy of the hands and knees position during the first stage of labour to facilitate the rotation of the fetal head to the occiput anterior position.
Design
Randomised ...controlled trial.
Setting
Geneva University Hospitals, Switzerland.
Population
A total of 439 women with a fetus in the occiput posterior position during the first stage of labour.
Methods
The women in the intervention group were invited to take a hands and knees position for at least for 10 minutes. Women allocated to the control group received the usual care. For both groups, 15 minutes after randomisation, women completed a short questionnaire to report their perceived pain and the comfort of their position.
Main outcome measures
The rotation of the fetal head in occiput anterior position confirmed by ultrasonography 1 hour after randomisation.
Results
One hour after the randomisation, 35 of 203 (17%) fetuses were diagnosed as being in the occiput anterior position in the intervention group compared with 24 of 209 (12%) in the control group. This difference was not statistically significant (relative risk 1.50; 95% CI 0.93–2.43; P = 0.13). The change in the evaluation of comfort between the randomisation and 15 minutes after showed an improvement in 70 and 39 women, no change in 82 and 78 women and a decrease in 56 and 86 women in the intervention and control groups, respectively (P = 0.02).
Conclusions
This study could not demonstrate a benefit of the hands and knees position to correct the occiput posterior position of the fetus during the first stage of labour, but the women reported an increase in their comfort level.
Tweetable
Hands and knees position does not facilitate rotation into occiput anterior but increases the comfort level of women.
Tweetable
Hands and knees position does not facilitate rotation into occiput anterior but increases the comfort level of women.
Context.
NenuFAR (New extension in Nançay upgrading LOFAR) is a new radio telescope developed and built on the site of the Nançay Radio Observatory. It is designed to observe the largely unexplored ...frequency window from 10 to 85 MHz, offering a high sensitivity across its full bandwidth. NenuFAR has started its “early science” operation in July 2019, with 58% of its final collecting area.
Aims.
Pulsars are one of the major phenomena utilized in the scientific exploitation of this frequency range and represent an important challenge in terms of instrumentation. Designing instrumentation at these frequencies is complicated by the need to compensate for the effects of both the interstellar medium and the ionosphere on the observed signal. We have designed a dedicated backend and developed a complete pulsar observation and data analysis pipeline, which we describe in detail in the present paper, together with first science results illustrating the diversity of the pulsar observing modes.
Methods.
Our real-time pipeline LUPPI (Low frequency Ultimate Pulsar Processing Instrumentation) is able to cope with a high data rate and provide real-time coherent de-dispersion down to the lowest frequencies reached by NenuFAR (10 MHz). The full backend functionality is described, as the available pulsar observing modes (folded, single-pulse, waveform, and dynamic spectrum).
Results.
We also present some of the early science results of NenuFAR on pulsars: the detection of 12 millisecond pulsars (eight of which are detected for the first time below 100 MHz); a high-frequency resolution mapping of the PSR B1919+21 emission profile and a detailed observation of single-pulse substructures from PSR B0809+74 down to 16 MHz; the high rate of giant-pulse emission from the Crab pulsar detected at 68.7 MHz (43 events per minute); and the illustration of the very good timing performance of the instrumentation, which allows us to study dispersion measure variations in great detail.
Oncogenic subtypes in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are used for risk stratification. However, a significant number of BCP-ALL patients are still genetically ...unassigned. Using array-comparative genomic hybridization in a selected BCP-ALL cohort, we characterized a recurrent V(D)J-mediated intragenic deletion of the ERG gene (ERG(del)). A breakpoint-specific PCR assay was designed and used to screen an independent non-selected cohort of 897 children aged 1-17 years treated for BCP-ALL in the EORTC-CLG 58951 trial. ERG(del) was found in 29/897 patients (3.2%) and was mutually exclusive of known classifying genetic lesions, suggesting that it characterized a distinct leukemia entity. ERG(del) was associated with higher age (median 7.0 vs. 4.0 years, P=0.004), aberrant CD2 expression (43.5% vs. 3.7%, P<0.001) and frequent IKZF1 Δ4-7 deletions (37.9% vs. 5.3%, P<0.001). However, ERG(del) patients had a very good outcome, with an 8-year event-free survival (8-y EFS) and an 8-year overall survival of 86.4% and 95.6%, respectively, suggesting that the IKZF1 deletion had no impact on prognosis in this genetic subtype. Accordingly, within patients with an IKZF1 Δ4-7 deletion, those with ERG(del) had a better outcome (8-y EFS: 85.7% vs. 51.3%; hazard ratio: 0.16; 95% confidence interval: 0.02-1.20; P=0.04). These findings have implications for further stratification including IKZF1 status.
Exercising in the heat induces thermoregulatory and other physiological strain that can lead to impairments in endurance exercise capacity. The purpose of this consensus statement is to provide ...up‐to‐date recommendations to optimize performance during sporting activities undertaken in hot ambient conditions. The most important intervention one can adopt to reduce physiological strain and optimize performance is to heat acclimatize. Heat acclimatization should comprise repeated exercise‐heat exposures over 1–2 weeks. In addition, athletes should initiate competition and training in a euhydrated state and minimize dehydration during exercise. Following the development of commercial cooling systems (e.g., cooling vest), athletes can implement cooling strategies to facilitate heat loss or increase heat storage capacity before training or competing in the heat. Moreover, event organizers should plan for large shaded areas, along with cooling and rehydration facilities, and schedule events in accordance with minimizing the health risks of athletes, especially in mass participation events and during the first hot days of the year. Following the recent examples of the 2008 Olympics and the 2014 FIFA World Cup, sport governing bodies should consider allowing additional (or longer) recovery periods between and during events for hydration and body cooling opportunities when competitions are held in the heat.
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