In this study, investigators compared genome sequencing with cytogenetic analysis in 263 patients with acute myeloid leukemia or myelodysplastic syndromes. Prospective sequencing detected new genetic ...information that was not revealed by cytogenetic analysis in nearly 25% of the patients, which altered the risk category for most of these patients.
Objectives This study sought to evaluate the safety and efficacy of the CoreValve transcatheter heart valve (THV) for the treatment of severe aortic stenosis in patients at extreme risk for surgery. ...Background Untreated severe aortic stenosis is a progressive disease with a poor prognosis. Transcatheter aortic valve replacement (TAVR) with a self-expanding bioprosthesis is a potentially effective therapy. Methods We performed a prospective, multicenter, nonrandomized investigation evaluating the safety and efficacy of self-expanding TAVR in patients with symptomatic severe aortic stenosis with prohibitive risks for surgery. The primary endpoint was a composite of all-cause mortality or major stroke at 12 months, which was compared with a pre-specified objective performance goal (OPG). Results A total of 41 sites in the United States recruited 506 patients, of whom 489 underwent attempted treatment with the CoreValve THV. The rate of all-cause mortality or major stroke at 12 months was 26.0% (upper 2-sided 95% confidence bound: 29.9%) versus 43.0% with the OPG (p < 0.0001). Individual 30-day and 12-month events included all-cause mortality (8.4% and 24.3%, respectively) and major stroke (2.3% and 4.3%, respectively). Procedural events at 30 days included life-threatening/disabling bleeding (12.7%), major vascular complications (8.2%), and need for permanent pacemaker placement (21.6%). The frequency of moderate or severe paravalvular aortic regurgitation was lower 12 months after self-expanding TAVR (4.2%) than at discharge (10.7%; p = 0.004 for paired analysis). Conclusions TAVR with a self-expanding bioprosthesis was safe and effective in patients with symptomatic severe aortic stenosis at prohibitive risk for surgical valve replacement. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902 )
Transcatheter aortic-valve replacement with a new self-expanding prosthesis was compared with surgical aortic-valve replacement in patients with aortic stenosis who were at high surgical risk. The ...rate of death from any cause at 1 year was lower in the TAVR group.
Aortic stenosis is a debilitating disease in elderly persons that carries a dismal prognosis after symptom onset.
1
Although surgical aortic-valve replacement remains the standard treatment for aortic stenosis,
2
many patients are not suitable candidates for surgical replacement owing to an increased risk of death during surgery.
3
,
4
Transcatheter aortic-valve replacement (TAVR) with a balloon-expandable device improves survival, as compared with medical therapy, in patients with severe aortic stenosis who cannot undergo surgery.
5
Balloon-expandable TAVR and surgical aortic-valve replacement are associated with similar survival rates at 1 year among patients considered to be at high surgical risk, although the frequency of . . .
The CoreValve U.S. Pivotal High Risk Trial was the first randomized trial to show superior 1-year mortality of transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve ...replacement (SAVR) among high operative mortality–risk patients.
The authors sought to compare TAVR to SAVR for mid-term 5-year outcomes of safety, performance, and durability.
Surgical high-risk patients were randomized (1:1) to TAVR with the self-expanding bioprosthesis or SAVR. VARC-1 (Valve Academic Research Consortium I) definitions were applied. Severe hemodynamic structural valve deterioration was defined as a mean gradient ≥40 mm Hg or a change in gradient ≥20 mm Hg or new severe aortic regurgitation. Five-year follow-up was planned.
A total of 797 patients were randomized at 45 U.S. centers, of whom 750 underwent an attempted implant (TAVR = 391, SAVR = 359). The overall mean age was 83 years, and the STS score was 7.4%. All-cause mortality rates at 5 years were 55.3% for TAVR and 55.4% for SAVR. Subgroup analysis showed no differences in mortality. Major stroke rates were 12.3% for TAVR and 13.2% for SAVR. Mean aortic valve gradients were 7.1 ± 3.6 mm Hg for TAVR and 10.9 ± 5.7 mm Hg for SAVR. No clinically significant valve thrombosis was observed. Freedom from severe SVD was 99.2% for TAVR and 98.3% for SAVR (p = 0.32), and freedom from valve reintervention was 97.0% for TAVR and 98.9% for SAVR (p = 0.04). A permanent pacemaker was implanted in 33.0% of TAVR and 19.8% of SAVR patients at 5 years.
This study shows similar mid-term survival and stroke rates in high-risk patients following TAVR or SAVR. Severe structural valve deterioration and valve reinterventions were uncommon. (Safety and Efficacy Study of the Medtronic CoreValve® System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902)
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Summary Background Partial blockade of voltage-gated sodium channels is neuroprotective in experimental models of inflammatory demyelinating disease. In this phase 2 trial, we aimed to assess whether ...the sodium-channel blocker lamotrigine is also neuroprotective in patients with secondary progressive multiple sclerosis. Methods Patients with secondary progressive multiple sclerosis who attended the National Hospital for Neurology and Neurosurgery or the Royal Free Hospital, London, UK, were eligible for inclusion in this double-blind, parallel-group trial. Patients were randomly assigned via a website by minimisation to receive lamotrigine (target dose 400 mg/day) or placebo for 2 years. Treating physicians, evaluating physicians, and patients were masked to treatment allocation. The primary outcome was the rate of change of partial (central) cerebral volume over 24 months. All patients who were randomly assigned were included in the primary analysis. This trial is registered with ClinicalTrials.gov , NCT00257855. Findings 120 patients were randomly assigned to treatment (87 women and 33 men): 61 to lamotrigine and 59 to placebo. 108 patients were analysed for the primary endpoint: 52 in the lamotrigine group and 56 in the placebo group. The mean change in partial (central) cerebral volume per year was −3·18 mL (SD −1·25) in the lamotrigine group and −2·48 mL (−0·97) in the placebo group (difference −0·71 mL, 95% CI −2·56 to 1·15; p=0·40). However, in an exploratory modelling analysis, lamotrigine treatment seemed to be associated with greater partial (central) cerebral volume loss than was placebo in the first year (p=0·04), and volume increased partially after treatment stopped (p=0·04). Lamotrigine treatment reduced the deterioration of the timed 25-foot walk (p=0·02) but did not affect other secondary clinical outcome measures. Rash and dose-related deterioration of gait and balance were experienced more by patients in the lamotrigine group than the placebo group. Interpretation The effect of lamotrigine on cerebral volume of patients with secondary progressive multiple sclerosis did not differ from that of placebo over 24 months, but lamotrigine seemed to cause early volume loss that reversed partially on discontinuation of treatment. Future trials of neuroprotection in multiple sclerosis should include investigation of complex early volume changes in different compartments of the CNS, effects unrelated to neurodegeneration, and targeting of earlier and more inflammatory disease. Funding Multiple Sclerosis Society of Great Britain and Northern Ireland.
Iliofemoral arterial disease can preclude transfemoral (TF) transcatheter aortic valve replacement (TF-TAVR). Transthoracic access by direct aortic or a transapical approach imparts a greater risk of ...complications and death than TF access. We hypothesized that subclavian/axillary arterial (SCA) access offers equivalent risks and outcomes as TF access.
The outcomes of 202 patients from the CoreValve (Medtronic, Minneapolis, MN) United States Pivotal Trial Program treated with SCA access were propensity matched with patients treated with TF access and analyzed.
Matching was successful, with no significant baseline differences in the SCA group and the TF group, except the SCA group had more past or present smokers (79.2% vs 61.4%, p < 0.001) and fewer patients with anemia requiring transfusion (18.5% vs 27.5%, p = 0.04). SCA patients experienced a significantly longer time from enrollment to procedure (8.6 ± 19.1 vs 5.3 ± 6.3 days; p = 0.02), likely the result of case planning. Significant differences in procedural outcomes include less post-TAVR balloon dilation (17.9% vs 26.7%, p = 0.03) and more general anesthesia (99.0% vs 89.6%, p < 0.001) for the SCA accesses. There were no differences in procedure time (57.8 ± 45.3 vs 57.5 ± 32.1 min, p = 0.94) or Valve Academic Research Consortium I–defined procedure success between groups (p = 0.89). Event rates at 30 days or 1 year were similar, with a trend toward fewer pacemakers with SCA accesses.
Major morbidity and mortality rates SCA-TAVR are equivalent to TF-TAVR. The SCA should be the preferred secondary access site for TAVR because it offers procedural and clinical outcomes comparable to TF-TAVR and applies to most patients who are not TF candidates.
The Great Barrier Reef (GBR) provides a globally significant demonstration of the effectiveness of large-scale networks of marine reserves in contributing to integrated, adaptive management. ...Comprehensive review of available evidence shows major, rapid benefits of no-take areas for targeted fish and sharks, in both reef and nonreef habitats, with potential benefits for fisheries as well as biodiversity conservation. Large, mobile species like sharks benefit less than smaller, site-attached fish. Critically, reserves also appear to benefit overall ecosystem health and resilience: outbreaks of coral-eating, crown-of-thorns starfish appear less frequent on no-take reefs, which consequently have higher abundance of coral, the very foundation of reef ecosystems. Effective marine reserves require regular review of compliance: fish abundances in no-entry zones suggest that even no-take zones may be significantly depleted due to poaching. Spatial analyses comparing zoning with seabed biodiversity or dugong distributions illustrate significant benefits from application of best-practice conservation principles in data-poor situations. Increases in the marine reserve network in 2004 affected fishers, but preliminary economic analysis suggests considerable net benefits, in terms of protecting environmental and tourism values. Relative to the revenue generated by reef tourism, current expenditure on protection is minor. Recent implementation of an Outlook Report provides regular, formal review of environmental condition and management and links to policy responses, key aspects of adaptive management. Given the major threat posed by climate change, the expanded network of marine reserves provides a critical and cost-effective contribution to enhancing the resilience of the Great Barrier Reef.
Recent interest in astrocyte activation states has raised the fundamental question of how these cells, normally essential for synapse and neuronal maintenance, become pathogenic. Here, we show that ...activation of the unfolded protein response (UPR), specifically phosphorylated protein kinase R-like endoplasmic reticulum (ER) kinase (PERK-P) signaling—a pathway that is widely dysregulated in neurodegenerative diseases—generates a distinct reactivity state in astrocytes that alters the astrocytic secretome, leading to loss of synaptogenic function in vitro. Further, we establish that the same PERK-P-dependent astrocyte reactivity state is harmful to neurons in vivo in mice with prion neurodegeneration. Critically, targeting this signaling exclusively in astrocytes during prion disease is alone sufficient to prevent neuronal loss and significantly prolongs survival. Thus, the astrocyte reactivity state resulting from UPR over-activation is a distinct pathogenic mechanism that can by itself be effectively targeted for neuroprotection.
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•PERK-eIF2α signaling in astrocytes generates a distinct “UPR”-reactivity state•UPR-reactive astrocytes have an altered secretome, with reduced synaptogenic factors•UPR-reactive astrocytes fail to support synaptogenesis in vitro•Targeting the astrocytic UPR prevents synapse and neuronal loss in prion-diseased mice
Dysregulation of UPR signaling in neurons is a key mediator of neurodegeneration. Smith et al. show that UPR dysregulation in astrocytes impairs their ability to support synapses; modulating astrocytic UPR signaling prevents neuronal loss and increases survival in prion-diseased mice.
Abstract
We report ALMA detections of C
ii
and a dust continuum in Az9, a multiply imaged galaxy behind the Frontier Field cluster MACS J0717.5+3745. The bright C
ii
emission line provides a ...spectroscopic redshift of
z
= 4.274. This strongly lensed (
μ
= 7 ± 1) galaxy has an intrinsic stellar mass of only 2 × 10
9
M
⊙
and a total star formation rate of 26
M
⊙
yr
−1
(∼80% of which is dust-obscured). Using public magnification maps, we reconstruct the C
ii
emission in the source plane to reveal a stable, rotation-dominated disk with
V
/
σ
= 5.3, which is >2× higher than predicted from simulations for similarly high-redshift, low-mass galaxies. In the source plane, the C
ii
disk has a half-light radius of 1.8 kpc and, along with the dust, is spatially offset from the peak of the stellar light by 1.4 kpc. Az9 is not deficient in C
ii
;
L
C
II
/
L
IR
= 0.0027, consistent with local and high-redshift normal star-forming galaxies. While dust-obscured star formation is expected to dominate in higher-mass galaxies, such a large reservoir of dust and gas in a lower-mass disk galaxy 1.4 Gyr after the Big Bang challenges our picture of early galaxy evolution. Furthermore, the prevalence of such low-mass dusty galaxies has important implications for the selection of the highest-redshift dropout galaxies with JWST. As one of the lowest stellar mass galaxies at
z
> 4 to be detected in a dust continuum and C
ii
, Az9 is an excellent laboratory in which to study early dust enrichment in the interstellar medium.
Reconstructing the growth and decay of palaeo-ice sheets is critical to understanding mechanisms of global climate change and associated sea-level fluctuations in the past, present and future. The ...significance of palaeo-ice sheets is further underlined by the broad range of disciplines concerned with reconstructing their behaviour, many of which have undergone a rapid expansion since the 1980s. In particular, there has been a major increase in the size and qualitative diversity of empirical data used to reconstruct and date ice sheets, and major improvements in our ability to simulate their dynamics in numerical ice sheet models. These developments have made it increasingly necessary to forge interdisciplinary links between sub-disciplines and to link numerical modelling with observations and dating of proxy records. The aim of this paper is to evaluate recent developments in the methods used to reconstruct ice sheets and outline some key challenges that remain, with an emphasis on how future work might integrate terrestrial and marine evidence together with numerical modelling. Our focus is on pan-ice sheet reconstructions of the last deglaciation, but regional case studies are used to illustrate methodological achievements, challenges and opportunities. Whilst various disciplines have made important progress in our understanding of ice-sheet dynamics, it is clear that data-model integration remains under-used, and that uncertainties remain poorly quantified in both empirically-based and numerical ice-sheet reconstructions. The representation of past climate will continue to be the largest source of uncertainty for numerical modelling. As such, palaeo-observations are critical to constrain and validate modelling. State-of-the-art numerical models will continue to improve both in model resolution and in the breadth of inclusion of relevant processes, thereby enabling more accurate and more direct comparison with the increasing range of palaeo-observations. Thus, the capability is developing to use all relevant palaeo-records to more strongly constrain deglacial (and to a lesser extent pre-LGM) ice sheet evolution. In working towards that goal, the accurate representation of uncertainties is required for both constraint data and model outputs. Close cooperation between modelling and data-gathering communities is essential to ensure this capability is realised and continues to progress.
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•Disciplines concerned with reconstructing ice sheets have rapidly expanded.•The size and qualitative diversity of empirical datasets has increased.•Our ability to simulate their dynamics in numerical ice sheet models has improved.•Data-model integration remains under-used and uncertainties remain poorly quantified.•Close cooperation between modelling and data-gathering communities is essential.
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