Evaluation of cortical bone perfusion using dynamic contrast enhanced ultrashort echo time imaging: a feasibility study.

Background:Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been used to study perfusion in a wide variety of soft tissues including the bone marrow. Study of perfusion in hard tissues such as cortical bone has been much more limited because of the lack of detectable MR signal from them using conventional pulse sequences. However, two-dimensional (2D) ultrashort echo time (UTE) sequences detect signal from cortical bone and allow fast imaging of this tissue. In addition, adiabatic 2D inversion recovery UTE (IR-UTE) sequences can provide excellent signal suppression of soft tissues, such as muscle and marrow, and allow cortical bone to be seen with high contrast and reduced artefacts. We aimed to assess the feasibility of using 2D UTE and 2D IR-UTE sequences to perform DCE-MRI in the cortical bone of rabbits and human volunteers. Methods:Cortical bone perfusion was studied in rabbits (n=12) and human volunteers (n=3) using 2D UTE and 2D IR-UTE sequences on a clinical 3T scanner. Dynamic data with an in-plane resolution of ~0.5×0.5 mm2, single slice thickness of 3 mm for rabbits and 10 mm for human volunteers, and temporal resolution of 23 s for 2D UTE imaging of rabbits, 28 s for 2D UTE imaging of human volunteers, and 60 s for 2D IR-UTE imaging of both the rabbits and human volunteers were acquired before and after the injection of a Gd contrast agent (Gd-BOPTA: Multihance; Bracco Imaging SpA, Milan, Italy). The dose was 0.06 mmol/kg for rabbits and 0.2 mmol/kg for human subjects. Kinetic analyses based on the Brix model, as well as simple calculations of maximum enhancement (ME) and enhancement slope (ES), were performed. Results:The 12 rabbits showed a mean Ktrans of 0.36±0.07 min-1, Kep of 8.42±3.17 min-1, ME of 28.30±6.83, ES of 0.35±0.18 for the femur with the 2D UTE sequence, and a mean Ktrans of 0.45±0.10 min-1, Kep of 9.80±0.50 min-1, ME of 48.84±12.12, and ES of 0.69±0.27 for the femur with the 2D IR-UTE sequence. Lower ME and ES values were observed in the tibial midshaft of healthy human volunteers compared to rabbits. Conclusions:These results show that 2D UTE and 2D IR-UTE sequences are capable of detecting dynamic contrast enhancement in cortical bone in both rabbits and healthy human volunteers. Clinical studies with these techniques are likely to be feasible

S6 kinase localizes to the presynaptic active zone and functions with PDK1 to control synapse development

S6 kinase localizes to the active zone in a Brp-dependent manner and collaborates with presynaptic PDK1 to modulate neuronal cell size, bouton size, active zone number, and neurotransmitter release

Molecular mechanisms that enhance synapse stability despite persistent disruption of the spectrin/ankyrin/microtubule cytoskeleton

Neuromuscular junctions crippled by a disrupted microtubule cytoskeleton are rescued by stress-induced activation of MAPK-JNK-Fos signaling

The effect of Z-group modification on the RAFT polymerization of N-vinylpyrrolidone controlled by "switchable" N-pyridyl-functional dithiocarbamates

This is an accepted manuscript of an article published by Royal Society of Chemistry in the Polymer Chemistry on 24/08/2015, available online: https://doi.org/10.1039/C5PY01021G The accepted version of the publication may differ from the final published version.The ability of a RAFT agent to control the polymerization of a monomer is dictated by the structures of both the monomer and the RAFT agent. In this paper, the polymerization of N-vinylpyrrolidone was examined with a series of cyanomethyl N-aryl-N-pyridyldithiocarbamates [(4-R′Ph)N(py)C(S)SCH2CN] varying in the substituent (R′) at the 4-position on the phenyl ring. The polymerization of N-vinylpyrrolidone was best controlled when R′ was methoxy; one of the least active RAFT agents in the series. The preservation of RAFT agent functionality was demonstrated by chain extension experiments with further N-vinylpyrrolidone. Again best control again was found for the RAFT agent with R′ = MeOPh. The utility of this RAFT agent was also proved with the preparation of poly(N-isopropylacrylamide)-block-poly(N-vinylpyrrolidone).The authors gratefully acknowledge the Australian Government for award of an Australian Postgraduate Award to S.J.S., the CSIRO Manufacturing Flagship and the School of Science and Technology at the University of New England for project funding.Published versio

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

Background: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. Methods: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Findings: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. Interpretation: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Funding: Novo Nordisk

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Chain transfer kinetics of acid/base switchable n-aryl- n-pyridyl dithiocarbamate RAFT agents in methyl acrylate, n-vinylcarbazole and vinyl acetate polymerization

This is an accepted manuscript of an article published by American Chemistry Society in Macromolecules on 14/05/2012, available online: https://doi.org/10.1021/ma300616g ©American Chemical Society. The accepted version of the publication may differ from the final published version.The structures of the "Z" and "R" substituents of a RAFT agent (Z-C(S)S-R) determine a RAFT agent's ability to control radical polymerization. In this paper we report new acid/base switchable N-aryl-N-pyridyl dithiocarbamates (R = -CH 2CN, Z = -N(Py)(Ar)) which vary in substituent at the 4-position of the aryl ring and the use of these to control molecular weight and dispersity. In their protonated form, the new RAFT agents are more effective in controlling polymerization of the more activated monomer, methyl acrylate (MA), whereas in their neutral form they provide more effective control of the polymerization of less activated monomers, N-vinyl carbazole (NVC) and vinyl acetate (VAc). For each polymerization, the apparent chain transfer coefficient (C trapp) shows a good correlation with Hammett parameters. Dithiocarbamates with more electron-withdrawing aryl ring substituents have the higher C trapp. This demonstrates the influence of polar effects on C trapp and supports the hypothesis that the activity of these RAFT agents is determined by the availability of the lone pair of the dithiocarbamate nitrogen.The authors gratefully acknowledge the Capability Development Fund of CSIRO Materials Science and Engineering for financial support.Published versio