Abstract
We present JWST Early Release Science coronagraphic observations of the super-Jupiter exoplanet, HIP 65426b, with the Near-Infrared Camera (NIRCam) from 2 to 5
μ
m, and with the Mid-Infrared ...Instrument (MIRI) from 11 to 16
μ
m. At a separation of ∼0.″82 (87
−
31
+
108
au), HIP 65426b is clearly detected in all seven of our observational filters, representing the first images of an exoplanet to be obtained by JWST, and the first-ever direct detection of an exoplanet beyond 5
μ
m. These observations demonstrate that JWST is exceeding its nominal predicted performance by up to a factor of 10, depending on separation and subtraction method, with measured 5
σ
contrast limits of ∼1 × 10
−5
and ∼2 × 10
−4
at 1″ for NIRCam at 4.4
μ
m and MIRI at 11.3
μ
m, respectively. These contrast limits provide sensitivity to sub-Jupiter companions with masses as low as 0.3
M
Jup
beyond separations of ∼100 au. Together with existing ground-based near-infrared data, the JWST photometry are fit well by a
BT-SETTL
atmospheric model from 1 to 16
μ
m, and they span ∼97% of HIP 65426b's luminous range. Independent of the choice of model atmosphere, we measure an empirical bolometric luminosity that is tightly constrained between
log
L
bol
/
L
⊙
= −4.31 and −4.14, which in turn provides a robust mass constraint of 7.1 ± 1.2
M
Jup
. In totality, these observations confirm that JWST presents a powerful and exciting opportunity to characterize the population of exoplanets amenable to high-contrast imaging in greater detail.
Purpose: To evaluate pregabalin (PGB), 150 mg/day, and PGB, 600 mg/day, as an add‐on treatment for patients with refractory partial seizures concurrently treated with one to three anticonvulsants ...(AEDs).
Methods: An international (13 countries), multicenter (45 centers), 12‐week, double‐blind, randomized study in which patients with partial seizures received placebo (n = 96); PGB, 150 mg/day (n = 99); or PGB, 600 mg/day (n = 92); given 3 times a day (t.i.d.). The primary efficacy criterion was reduction in seizure frequency during treatment as compared with baseline, as measured by RRatio, the symmetrical percentage change in seizure rates determined from daily seizure diaries. The RRatio between the 8‐week baseline (pretreatment phase) and the 12‐week treatment period were compared between each of the PGB groups and the placebo group by using an analysis of variance analysis of the intent‐to‐treat population.
Results: PGB, 150 mg/day and 600 mg/day, were both significantly more effective than placebo in reducing the RRatio –11.5 (p = 0.0007) and –31.4 (p ≤ 0.0001), respectively, vs. 0.9. These RRatio values correspond to seizure‐frequency reductions from baseline of –1.8, 20.6, and 47.8% for placebo, 150 mg/day, and 600 mg/day, respectively. PGB efficacy was significantly dose related (p ≤ 0.0001). Secondary efficacy variables corroborated the findings of the primary analysis. Significantly more patients were responders (≥50% reduction in seizure frequency) in the PGB, 600 mg/day (43.5%), group than in the placebo group (6.2%) (p ≤ 0.001). PGB was well tolerated. Dose‐related, treatment‐emergent adverse events (≥10%), mostly mild or moderate in intensity, were somnolence, dizziness, ataxia, diplopia, and weight gain. The withdrawal rate due to adverse events was 10% of patients at 150 mg/day and 18.5% of patients at 600 mg/day, compared with 6.2% of patients receiving placebo.
Conclusions: PGB, 150 mg/day and 600 mg/day, is highly effective and well‐tolerated add‐on therapy in patients with partial seizures.
The quantitative relationship of incident cardiovascular disease (CVD) to lifetime cumulative risk factor exposure is not well understood.
Using CARDIA (Coronary Artery Risk Development in Young ...Adults) study data, we examined the quantitative associations of cumulative exposure over time to multiple, simultaneously operating risk factors with CVD incidence and the incidence of its components.
Regression models were developed quantifying the influence of the time course and severity of multiple CVD risk factors, operating simultaneously, on risk of incident CVD. The outcomes were incident CVD and the incidence of its components: coronary heart disease, stroke, and congestive heart failure.
Our study included 4,958 asymptomatic adults enrolled in CARDIA from 1985 to 1986 (ages 18 to 30 years) who were followed for 30 years. Risk of incident CVD depends on the time course and severity of a series of independent risk factors, the impact of which is mediated by their effects on individual CVD components after age 40 years. Cumulative exposure (AUC vs time) to low-density lipoprotein cholesterol and triglycerides was independently associated with risk of incident CVD. Of the blood pressure variables, areas under the mean arterial pressure vs time curve and the pulse pressure vs time curve were strongly and independently associated with incident CVD risk.
The quantitative description of the link between risk factors and CVD informs the construction of individualized CVD mitigation strategies, design of primary prevention trials, and assessment of public health impact of risk factor-based interventions.
Display omitted
Previous studies have identified subdomains of the 22-item Sino-Nasal Outcome Test (SNOT-22), reflecting distinct and largely independent categories of chronic rhinosinusitis (CRS) symptoms. However, ...no study has validated the subdomain structure of the SNOT-22. This study aims to validate the existence of underlying symptom subdomains of the SNOT-22 using confirmatory factor analysis (CFA) and to develop a subdomain model that practitioners and researchers can use to describe CRS symptomatology.
A total of 800 patients with CRS were included into this cross-sectional study (400 CRS patients from Boston, MA, and 400 CRS patients from Reno, NV). Their SNOT-22 responses were analyzed using exploratory factor analysis (EFA) to determine the number of symptom subdomains. A CFA was performed to develop a validated measurement model for the underlying SNOT-22 subdomains along with various tests of validity and goodness of fit.
EFA demonstrated 4 distinct factors reflecting: sleep, nasal, otologic/facial pain, and emotional symptoms (Cronbach's alpha, >0.7; Bartlett's test of sphericity, p < 0.001; Kaiser-Meyer-Olkin >0.90), independent of geographic locale. The corresponding CFA measurement model demonstrated excellent measures of fit (root mean square error of approximation, <0.06; standardized root mean square residual, <0.08; comparative fit index, >0.95; Tucker-Lewis index, >0.95) and measures of construct validity (heterotrait-monotrait HTMT ratio, <0.85; composite reliability, >0.7), again independent of geographic locale.
The use of the 4-subdomain structure for SNOT-22 (reflecting sleep, nasal, otologic/facial pain, and emotional symptoms of CRS) was validated as the most appropriate to calculate SNOT-22 subdomain scores for patients from different geographic regions using CFA.
The Arctic climate is changing. Permafrost is warming, hydrological processes are changing and biological and social systems are also evolving in response to these changing conditions. Knowing how ...the structure and function of arctic terrestrial ecosystems are responding to recent and persistent climate change is paramount to understanding the future state of the Earth system and how humans will need to adapt. Our holistic review presents a broad array of evidence that illustrates convincingly; the Arctic is undergoing a system-wide response to an altered climatic state. New extreme and seasonal surface climatic conditions are being experienced, a range of biophysical states and processes influenced by the threshold and phase change of freezing point are being altered, hydrological and biogeochemical cycles are shifting, and more regularly human sub-systems are being affected. Importantly, the patterns, magnitude and mechanisms of change have sometimes been unpredictable or difficult to isolate due to compounding factors. In almost every discipline represented, we show how the biocomplexity of the Arctic system has highlighted and challenged a paucity of integrated scientific knowledge, the lack of sustained observational and experimental time series, and the technical and logistic constraints of researching the Arctic environment. This study supports ongoing efforts to strengthen the interdisciplinarity of arctic system science and improve the coupling of large scale experimental manipulation with sustained time series observations by incorporating and integrating novel technologies, remote sensing and modeling. PUBLICATION ABSTRACT
The ERBB family of type 1 receptor tyrosine kinases and their ligands have crucial functions during mammopoiesis, but the signaling networks that ultimately regulate ERBB activity in the breast have ...remained elusive. Here, we show that mice with Cre-lox mediated deletions of both Erbb4 alleles within the developing mammary gland (Erbb4(Flox/Flox)Wap-Cre) fail to accumulate lobuloalveoli or successfully engage lactation at parturition owing, in part, to impaired epithelial proliferation. Analysis of the mammary differentiation factor STAT5 by immunohistochemistry and western blot revealed a complete ablation of STAT5 activation in Erbb4(Flox/Flox)Wap-Cre mammary epithelium at parturition. Consistent with disrupted STAT5 function, Erbb4(Flox/Flox)Wap-Cre mammary glands at parturition failed to express the mammary epithelial differentiation marker NPT2B. Defects in epithelial functional differentiation at parturition were accompanied by a profound reduction in expression of the STAT5-regulated milk genes casein beta and whey acidic protein. We propose that ERBB4 functions as an essential mediator of STAT5 signaling, and that loss of STAT5 activity contributes to the impaired functional differentiation of mammary glands observed in mice containing conditional Erbb4 deletions.
Huntington's disease (HD) is characterized by the accumulation of a pathogenic protein, Huntingtin (Htt), that contains an abnormal polyglutamine expansion. Here, we report that a pathogenic fragment ...of Htt (Httex1p) can be modified either by small ubiquitin-like modifier (SUMO)-1 or by ubiquitin on identical lysine residues. In cultured cells, SUMOylation stabilizes Httex1p, reduces its ability to form aggregates, and promotes its capacity to repress transcription. In a Drosophila model of HD, SUMOylation of Httex1p exacerbates neurodegeneration, whereas ubiquitination of Httex1p abrogates neurodegeneration. Lysine mutations that prevent both SUMOylation and ubiquitination of Httex1p reduce HD pathology, indicating that the contribution of SUMOylation to HD pathology extends beyond preventing Htt ubiquitination and degradation.
Decorporation of intravenously injected monomeric241Am and^{237+239}{\rm Pu}$by the administration of 30 μmole Zn-diethylenetriaminepentaacetic acid (DTPA)/kg each day beginning 2 weeks after ...radionuclide injection was compared in beagles entered into the experiment when 3 months (juveniles), 1.9 years (young adults), or 10 years (mature adults) old and studied for about 5 months. DTPA therapy was most effective in the juvenile dogs and least effective in the mature adults. Retention of241Am in the liver decreased from a pretreatment value for adults of about 50% of the injected activity to about 10% in the mature adults and less than 1% in the young adults at 140 days of treatment, while the liver retention of juveniles decreased from pretreatment values of about 16% to undetectable levels by 28 days of treatment. Plutonium retention in the liver decreased from adult pretreatment levels of about 30% of the injected activity (corrected for radioactive decay) to near 10% in the mature adults and 6% in the young adults at 140 days of treatment, while juvenile liver retention decreased from pretreatment values near 15% to undetectable levels by 56 days of treatment. Nonliver Am retention (mainly skeleton) decreased in mature adults from pretreatment values of about 45% of the injected activity to near 25%, in young adults from 35 to 20%, and in juveniles from roughly 70 to 9% by 140 days of DTPA administration. Nonliver Pu retention decreased from pretreatment values of about 50% of the injected activity (corrected for radioactive decay) for mature and young adults to about 30% by 140 days and from 75 to 16% in juveniles over the same period.
PDF
