Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors ...of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.
A stochastic magnetic boundary, produced by an applied edge resonant magnetic perturbation, is used to suppress most large edge-localized modes (ELMs) in high confinement (H-mode) plasmas. The ...resulting H mode displays rapid, small oscillations with a bursty character modulated by a coherent 130 Hz envelope. The H mode transport barrier and core confinement are unaffected by the stochastic boundary, despite a threefold drop in the toroidal rotation. These results demonstrate that stochastic boundaries are compatible with H modes and may be attractive for ELM control in next-step fusion tokamaks.
Ischaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin ...receptor antagonist, reduced the occurrence of new DUs by 48%. The present study (RAPIDS-2, for 'RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis') was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc.
This double-blind, placebo-controlled trial conducted at 41 centres in Europe and North America randomised 188 patients with SSc with at least 1 active DU ('cardinal ulcer') to bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 20 weeks (n=98) or matching placebo (n=90; total 24 weeks). The two primary end points were the number of new DUs and the time to healing of the cardinal ulcer. Secondary end points included pain, disability and safety.
Over 24 weeks, bosentan treatment was associated with a 30% reduction in the number of new DUs compared with placebo (mean ± standard error: 1.9±0.2 vs 2.7±0.3 new ulcers; p=0.04). This effect was greater in patients who entered the trial with more DUs. There was no difference between treatments in healing rate of the cardinal ulcer or secondary end points of pain and disability. Peripheral oedema and elevated aminotransferases were associated with bosentan treatment.
Bosentan treatment reduced the occurrence of new DUs in patients with SSc but had no effect on DU healing. Bosentan was well tolerated and may be a useful adjunct in the management of patients with SSc with recurrent DUs.
Direct evidence of zonal flow (ZF) predator-prey oscillations and the synergistic roles of ZF- and equilibrium E×B flow shear in triggering the low- to high-confinement (L- to H-mode) transition in ...the DIII-D tokamak is presented. Periodic turbulence suppression is first observed in a narrow layer at and just inside the separatrix when the shearing rate transiently exceeds the turbulence decorrelation rate. The final transition to H mode with sustained turbulence and transport reduction is controlled by equilibrium E×B shear due to the increasing ion pressure gradient.
Serial studies have demonstrated that induction therapy with FLAM flavopiridol (alvocidib) 50 mg/m(2) days 1-3, cytarabine 667 mg/m(2)/day continuous infusion days 6-8, and mitoxantrone (FLAM) 40 ...mg/m(2) day 9 yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011-July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18-70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m(2)/day continuous infusion days 1-7 and daunorubicin 90 mg/m(2) days 1-3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m(2)/day continuous infusion days 1-5 and daunorubicin 45 mg/m(2) days 1-2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/-5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.
Objective
To estimate risks of major congenital anomaly (MCA) among children of mothers prescribed antidepressants during early pregnancy or diagnosed with depression but without antidepressant ...prescriptions.
Design
Population‐based cohort study.
Setting
Linked UK maternal–child primary care records.
Population
A total of 349 127 singletons liveborn between 1990 and 2009.
Methods
Odds ratios adjusted for maternal sociodemographics and comorbidities (aORs) were calculated for MCAs, comparing women with first‐trimester selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) and women with diagnosed but unmedicated depression, or women without diagnosed depression.
Main outcome measures
Fourteen system‐specific MCA groups classified according to the European Surveillance of Congenital Anomalies and five specific heart anomaly groups.
Results
Absolute risks of MCA were 2.7% (95% confidence interval, 95% CI, 2.6–2.8%) in children of mothers without diagnosed depression, 2.8% (95% CI 2.5–3.2%) in children of mothers with unmedicated depression, and 2.7% (95% CI 2.2–3.2%) and 3.1% (95% CI 2.2–4.1%) in children of mothers with SSRIs or TCAs, respectively. Compared with women without depression, MCA overall was not associated with unmedicated depression (aOR 1.07, 95% CI 0.96–1.18), SSRIs (aOR 1.01, 95% CI 0.88–1.17), or TCAs (aOR 1.09, 95% CI 0.87–1.38). Paroxetine was associated with increased heart anomalies (absolute risk 1.4% in the exposed group compared with 0.8% in women without depression; aOR 1.78, 95% CI 1.09–2.88), which decreased marginally when compared with women with diagnosed but unmedicated depression (aOR 1.67, 95% CI 1.00–2.80).
Conclusions
Overall MCA risk did not increase with maternal depression or with antidepressant prescriptions. Paroxetine was associated with increases of heart anomalies, although this could represent a chance finding from a large number of comparisons undertaken.
Psychosocial interventions for adolescent mental health problems are effective, but evidence on their longer-term outcomes is scarce, especially in low-resource settings. We report on the 12-month ...sustained effectiveness and costs of scaling up a lay counselor-delivered, transdiagnostic problem-solving intervention for common adolescent mental health problems in low-income schools in New Delhi, India.
Participants in the original trial were 250 school-going adolescents (mean M age = 15.61 years, standard deviation SD = 1.68), including 174 (69.6%) who identified as male. Participants were recruited from 6 government schools over a period of 4 months (August 20 to December 14, 2018) and were selected on the basis of elevated mental health symptoms and distress/functional impairment. A 2-arm, randomized controlled trial design was used to examine the effectiveness of a lay counselor-delivered, problem-solving intervention (4 to 5 sessions over 3 weeks) with supporting printed booklets (intervention arm) in comparison with problem solving delivered via printed booklets alone (control arm), at the original endpoints of 6 and 12 weeks. The protocol was modified, as per the recommendation of the Trial Steering Committee, to include a post hoc extension of the follow-up period to 12 months. Primary outcomes were adolescent-reported psychosocial problems (Youth Top Problems YTP) and mental health symptoms (Strengths and Difficulties Questionnaire SDQ Total Difficulties scale). Other self-reported outcomes included SDQ subscales, perceived stress, well-being, and remission. The sustained effects of the intervention were estimated at the 12-month endpoint and over 12 months (the latter assumed a constant effect across 3 follow-up points) using a linear mixed model for repeated measures and involving complete case analysis. Sensitivity analyses examined the effect of missing data using multiple imputations. Costs were estimated for delivering the intervention during the trial and from modeling a scale-up scenario, using a retrospective ingredients approach. Out of the 250 original trial participants, 176 (70.4%) adolescents participated in the 12-month follow-up assessment. One adverse event was identified during follow-up and deemed unrelated to the intervention. Evidence was found for intervention effects on both SDQ Total Difficulties and YTP at 12 months (YTP: adjusted mean difference AMD = -0.75, 95% confidence interval CI = -1.47, -0.03, p = 0.04; SDQ Total Difficulties: AMD = -1.73, 95% CI = -3.47, 0.02, p = 0.05), with stronger effects over 12 months (YTP: AMD = -0.98, 95% CI = -1.51, -0.45, p < 0.001; SDQ Total Difficulties: AMD = -1.23, 95% CI = -2.37, -0.09; p = 0.03). There was also evidence for intervention effects on internalizing symptoms, impairment, perceived stress, and well-being over 12 months. The intervention effect was stable for most outcomes on sensitivity analyses adjusting for missing data; however, for SDQ Total Difficulties and impairment, the effect was slightly attenuated. The per-student cost of delivering the intervention during the trial was $3 United States dollars (USD; or $158 USD per case) and for scaling up the intervention in the modeled scenario was $4 USD (or $23 USD per case). The scaling up cost accounted for 0.4% of the per-student school budget in New Delhi. The main limitations of the study's methodology were the lack of sample size calculations powered for 12-month follow-up and the absence of cost-effectiveness analyses using the primary outcomes.
In this study, we observed that a lay counselor-delivered, brief transdiagnostic problem-solving intervention had sustained effects on psychosocial problems and mental health symptoms over the 12-month follow-up period. Scaling up this resource-efficient intervention is an affordable policy goal for improving adolescents' access to mental health care in low-resource settings. The findings need to be interpreted with caution, as this study was a post hoc extension, and thus, the sample size calculations did not take into account the relatively high attrition rate observed during the long-term follow-up.
ClinicalTrials.gov NCT03630471.
Abstract
Calibration and validation of satellite‐derived ice sheet albedo data require high‐quality, in situ measurements commonly acquired by up and down facing pyranometers mounted on automated ...weather stations (AWS). However, direct comparison between ground and satellite‐derived albedo can only be justified when the measured surface is homogeneous at the length‐scale of both satellite pixel and in situ footprint. Here we use digital imagery acquired by an unmanned aerial vehicle to evaluate point‐to‐pixel albedo comparisons across the western, ablating margin of the Greenland Ice Sheet. Our results reveal that in situ measurements overestimate albedo by up to 0.10 at the end of the melt season because the ground footprints of AWS‐mounted pyranometers are insufficient to capture the spatial heterogeneity of the ice surface as it progressively ablates and darkens. Statistical analysis of 21 AWS across the entire Greenland Ice Sheet reveals that almost half suffer from this bias, including some AWS located within the wet snow zone.
Key Points
We test the validity of direct comparison between satellite‐derived albedo and in situ, AWS‐based, measurements over the Greenland Ice Sheet
In situ measurements across the ablation zone have too small a footprint to sample the full heterogeneity of surface ice as it melts
Improved confidence in satellite measurements may be achieved by judicious selection of in situ measurements for validation/calibration
Plain Language Summary
Ground measurements of reflectivity, such as those made by automated weather stations, are often used to determine the accuracy of satellite measurements. But the footprints of the instruments mounted on automated weather stations are usually much smaller than the pixel of the satellite image, meaning that comparison between the two is only justified when the surface is relatively uniform. We use high resolution imagery collected by a UAV to demonstrate that the surface of the Greenland Ice Sheet is often not uniform at the scale of both the weather station and satellite pixel due to the presence of impurities, surface water and crevasses. This means that a point measurement of reflectivity might not capture the full variability of the surface, resulting in discrepancies when compared to satellite image pixels. Furthermore, weather stations are usually located on safe areas of flat, bare ice or snow, so they usually overestimate reflectivity in comparison to the satellite pixel. We argue that if unrepresentative ground measurements are removed from satellite comparison exercises then the uncertainty in satellite products could be reduced. Hence, the long‐term decline in Greenland Ice Sheet reflectivity between 2000 and 2012 might be more significant than previously thought.
Supraglacial lakes represent an ephemeral storage buffer for meltwater runoff and lead to significant, yet short-lived, episodes of ice-flow acceleration by decanting large meltwater and energy ...fluxes into the ice sheet's hydrological system. Here, a methodology for calculating lake volume is used to quantify storage and drainage across Russell Glacier, West Greenland, between 2002 and 2012. Using 502 MODIS scenes, water volume at ~200 seasonally occurring lakes was derived using a depth-reflectance relationship, which was independently calibrated and field validated against lake bathymetry. The inland expansion of lakes is strongly correlated with air temperature: during the record melt years of 2010 and 2012, lakes formed and drained earlier, attaining their maximum volume 38 and 20 days earlier than the 11 yr mean, as well as occupying a greater area and forming at higher elevations (> 1800 m) than previously. Despite occupying under 2% of the study area, lakes delay the transmission of up to 7-13% of the bulk meltwater discharged. Although the results are subject to an observational bias caused by periods of cloud cover, we estimate that across Russell Glacier, 28% of supraglacial lakes drain rapidly (< 4 days). Clustering of such events in space and time suggests a synoptic trigger mechanism. Further, we find no evidence to support a unifying critical size or depth-dependent drainage threshold.
We present detailed records of lake discharge, ice motion and passive seismicity capturing the behaviour and processes preceding, during and following the rapid drainage of a 4 km super(2) ...supraglacial lake through 1.1-km-thick ice on the western margin of the Greenland Ice Sheet. Peak discharge of 3300 m super(3) s super(-1) coincident with maximal rates of vertical uplift indicates that surface water accessed the ice-bed interface causing widespread hydraulic separation and enhanced basal motion. The differential motion of four global positioning system (GPS) receivers located around the lake record the opening and closure of the fractures through which the lake drained. We hypothesise that the majority of discharge occurred through a 3-km-long fracture with a peak width averaged across its wetted length of 0.4 m. We argue that the fracture's kilometre-scale length allowed rapid discharge to be achieved by combining reasonable water velocities with sub-metre fracture widths. These observations add to the currently limited knowledge of in situ supraglacial lake drainage events, which rapidly deliver large volumes of water to the ice-bed interface.
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