1,291 research outputs found
Prediction of the effect of dapagliflozin on kidney and heart failure outcomes based on short-term changes in multiple risk markers
BACKGROUND: Besides improving glucose control, sodium-glucose co-transporter 2 inhibition with dapagliflozin reduces blood pressure, body weight and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes (T2DM). The parameter response efficacy (PRE) score was developed to predict how short-term drug effects on cardiovascular risk markers translate into long-term changes in clinical outcomes. We applied the PRE score to clinical trials of dapagliflozin to model the effect of the drug on kidney and heart failure (HF) outcomes in patients with T2DM and impaired kidney function. METHODS: The relationships between multiple risk markers and long-term outcome were determined in a background population of patients with T2DM with a multivariable Cox model. These relationships were then applied to short-term changes in risk markers observed in a pooled database of dapagliflozin trials (n = 7) that recruited patients with albuminuria to predict the drug-induced changes to kidney and HF outcomes. RESULTS: A total of 132 and 350 patients had UACR >200 mg/g and >30 mg/g at baseline, respectively, and were selected for analysis. The PRE score predicted a risk change for kidney events of -40.8% [95% confidence interval (CI) -51.7 to -29.4) and -40.4% (95% CI -48.4 to -31.1) with dapagliflozin 10 mg compared with placebo for the UACR >200 mg/g and >30 mg/g subgroups. The predicted change in risk for HF events was -27.3% (95% CI -47.7 to -5.1) and -21.2% (95% CI -35.0 to -7.8), respectively. Simulation analyses showed that even with a smaller albuminuria-lowering effect of dapagliflozin (10% instead of the observed 35% in both groups), the estimated kidney risk reduction was still 26.5 and 26.8%, respectively. CONCLUSIONS: The PRE score predicted clinically meaningful reductions in kidney and HF events associated with dapagliflozin therapy in patients with diabetic kidney disease. These results support a large long-term outcome trial in this population to confirm the benefits of the drug on these endpoints
New Mechanics of Traumatic Brain Injury
The prediction and prevention of traumatic brain injury is a very important
aspect of preventive medical science. This paper proposes a new coupled
loading-rate hypothesis for the traumatic brain injury (TBI), which states that
the main cause of the TBI is an external Euclidean jolt, or SE(3)-jolt, an
impulsive loading that strikes the head in several coupled degrees-of-freedom
simultaneously. To show this, based on the previously defined covariant force
law, we formulate the coupled Newton-Euler dynamics of brain's micro-motions
within the cerebrospinal fluid and derive from it the coupled SE(3)-jolt
dynamics. The SE(3)-jolt is a cause of the TBI in two forms of brain's rapid
discontinuous deformations: translational dislocations and rotational
disclinations. Brain's dislocations and disclinations, caused by the
SE(3)-jolt, are described using the Cosserat multipolar viscoelastic continuum
brain model.
Keywords: Traumatic brain injuries, coupled loading-rate hypothesis,
Euclidean jolt, coupled Newton-Euler dynamics, brain's dislocations and
disclinationsComment: 18 pages, 1 figure, Late
LAPAROSCOPICALLY ASSISTED ANORECTOPLASTY AND THE USE OF THE BIPOLAR DEVICE TO SEAL THE RECTAL URINARY FISTULA
Silver hake tracks changes in Northwest Atlantic circulation
Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Communications 2 (2011): 412, doi:10.1038/ncomms1420.Recent studies documenting shifts in spatial distribution of many organisms in response
to a warming climate highlight the need to understand the mechanisms underlying species
distribution at large spatial scales. Here we present one noteworthy example of remote
oceanographic processes governing the spatial distribution of adult silver hake, Merluccius
bilinearis, a commercially important fish in the Northeast US shelf region. Changes in spatial
distribution of silver hake over the last 40 years are highly correlated with the position of the
Gulf Stream (GS). These changes in distribution are in direct response to local changes in
bottom temperature on the continental shelf that are responding to the same large scale
circulation change affecting the GS path, namely changes in the Atlantic Meridional Overturning
Circulation (AMOC). If AMOC weakens as is suggested by global climate models, silver hake
distribution will remain in a poleward position, the extent to which could be forecast at both
decadal and multidecadal scales.J.A.N. was supported by the NOAA
Fisheries and the Environment program (FATE). T.M.J. and Y.O.K. were supported by the
WHOI Ocean Climate Change Institute and Ocean Life Institute
Estimation of Kinetic Parameters During the Treatment of Steelmaking Slag Expansibility Data
Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli
Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts. Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins. Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets
Spin polarization versus lifetime effects at point contacts between superconducting niobium and normal metals
Point-contact Andreev reflection spectroscopy is used to measure the spin
polarization of metals but analysis of the spectra has encountered a number of
serious challenges, one of which is the difficulty to distinguish the effects
of spin polarization from those of the finite lifetime of Cooper pairs. We have
recently confirmed the polarization-lifetime ambiguity for Nb-Co and Nb-Cu
contacts and suggested to use Fermi surface mismatch, the normal reflection due
to the difference of Fermi wave vectors of the two electrodes, to solve this
dilemma. Here we present further experiments on contacts between
superconducting Nb and the ferromagnets Fe and Ni as well as the noble metals
Ag and Pt that support our previous results. Our data indicate that the Nb -
normal metal interfaces have a transparency of up to about 80 per cent and a
small, if not negligible, spin polarization.Comment: 7 pages, 2 figures, submitted to Proceedings of the 26th Conference
on Low Temperature Physic
Contaminated mouth swabs caused a multi-hospital outbreak of Pseudomonas aeruginosa infection
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