806 research outputs found
All nonadherence is equal but is some more equal than others? Tuberculosis in the digital era
Adherence to treatment for tuberculosis (TB) has been a concern for many decades, resulting in the World Health Organization's recommendation of the direct observation of treatment in the 1990s. Recent advances in digital adherence technologies (DATs) have renewed discussion on how to best address nonadherence, as well as offering important information on dose-by-dose adherence patterns and their variability between countries and settings. Previous studies have largely focussed on percentage thresholds to delineate sufficient adherence, but this is misleading and limited, given the complex and dynamic nature of adherence over the treatment course. Instead, we apply a standardised taxonomy – as adopted by the international adherence community – to dose-by-dose medication-taking data, which divides missed doses into 1) late/noninitiation (starting treatment later than expected/not starting), 2) discontinuation (ending treatment early), and 3) suboptimal implementation (intermittent missed doses). Using this taxonomy, we can consider the implications of different forms of nonadherence for intervention and regimen design. For example, can treatment regimens be adapted to increase the “forgiveness” of common patterns of suboptimal implementation to protect against treatment failure and the development of drug resistance? Is it reasonable to treat all missed doses of treatment as equally problematic and equally common when deploying DATs? Can DAT data be used to indicate the patients that need enhanced levels of support during their treatment course? Critically, we pinpoint key areas where knowledge regarding treatment adherence is sparse and impeding scientific progress
Effects of Supersymmetric Threshold Corrections on High-Scale Flavor Textures
Integration of superpartners out of the spectrum induces potentially large
contributions to Yukawa couplings. These corrections, the supersymmetric
threshold corrections, therefore influence the CKM matrix prediction in a
non-trivial way. We study effects of threshold corrections on high-scale flavor
structures specified at the gauge coupling unification scale in supersymmetry.
In our analysis, we first consider high-scale Yukawa textures which qualify
phenomenologically viable at tree level, and find that they get completely
disqualified after incorporating the threshold corrections. Next, we consider
Yukawa couplings, such as those with five texture zeroes, which are incapable
of explaining flavor-changing proceses. Incorporation of threshold corrections,
however, makes them phenomenologically viable textures. Therefore,
supersymmetric threshold corrections are found to leave observable impact on
Yukawa couplings of quarks, and any confrontation of high-scale textures with
experiments at the weak scale must take into account such corrections.Comment: 25 pages, submitted to JHE
Brief Report: AIP Mutation in Pituitary Adenomas in the 18th Century and Today
From New England Journal of Medicine, Volume 364, issue 1, p.43-50. Copyright © (2011) Massachusetts Medical Society. Reprinted with permission.Gigantism results when a growth hormone–secreting pituitary adenoma is present
before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of
an Irish patient who lived from 1761 to 1783,1-3 he noted an enlarged pituitary
fossa. We extracted DNA from the patient’s teeth and identified a germline mutation
in the aryl hydrocarbon–interacting protein gene (AIP). Four contemporary
Northern Irish families who presented with gigantism, acromegaly, or prolactinoma
have the same mutation and haplotype associated with the mutated gene. Using
coalescent theory, we infer that these persons share a common ancestor who lived
about 57 to 66 generations earlier
An Electron Fixed Target Experiment to Search for a New Vector Boson A' Decaying to e+e-
We describe an experiment to search for a new vector boson A' with weak
coupling alpha' > 6 x 10^{-8} alpha to electrons (alpha=e^2/4pi) in the mass
range 65 MeV < m_A' < 550 MeV. New vector bosons with such small couplings
arise naturally from a small kinetic mixing of the "dark photon" A' with the
photon -- one of the very few ways in which new forces can couple to the
Standard Model -- and have received considerable attention as an explanation of
various dark matter related anomalies. A' bosons are produced by radiation off
an electron beam, and could appear as narrow resonances with small production
cross-section in the trident e+e- spectrum. We summarize the experimental
approach described in a proposal submitted to Jefferson Laboratory's PAC35,
PR-10-009. This experiment, the A' Experiment (APEX), uses the electron beam of
the Continuous Electron Beam Accelerator Facility at Jefferson Laboratory
(CEBAF) at energies of ~1-4 GeV incident on 0.5-10% radiation length Tungsten
wire mesh targets, and measures the resulting e+e- pairs to search for the A'
using the High Resolution Spectrometer and the septum magnet in Hall A. With a
~1 month run, APEX will achieve very good sensitivity because the statistics of
e+e- pairs will be ~10,000 times larger in the explored mass range than any
previous search for the A' boson. These statistics and the excellent mass
resolution of the spectrometers allow sensitivity to alpha'/alpha one to three
orders of magnitude below current limits, in a region of parameter space of
great theoretical and phenomenological interest. Similar experiments could also
be performed at other facilities, such as the Mainz Microtron.Comment: 19 pages, 12 figures, 2 table
The relationship between spasticity in young children (18 months of age) with cerebral palsy and their gross motor function development
<p>Abstract</p> <p>Background</p> <p>It is thought that spasticity has an influence on the development of functional motor abilities among children with cerebral palsy (CP). The extent to which spasticity is associated with the change in motor abilities in young children with CP has not been established. The objective of this study is to evaluate the relationship of initial spasticity in young children with CP and their gross motor function development over one year.</p> <p>Methods</p> <p>Fifty children with CP aged 18 months, GMFCS-levels I-V participated in a longitudinal observational study. Change in gross motor functioning (GMFM-66) was measured over one year. The level of spasticity measured at the first assessment was determined with the Modified Tardieu Scale in three muscle groups of the lower extremity (adductor muscles, the hamstrings and the m. gastrocnemius). The Spasticity Total Score per child was calculated with a maximum score of 12 points.</p> <p>Results</p> <p>Spearman's Rho Correlation (-0.28) revealed a statistically significant relationship (p < 0.05) of small strength between the Spasticity Total Score and the change score of the GMFM-66.</p> <p>Conclusion</p> <p>Our findings indicate that when measured over one year, spasticity is marginally related to gross motor function development in infants with CP. The initial level of spasticity is only one of the many child, environmental and family factors that determines gross motor development of a young child with CP.</p
RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord
ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients
Four Generations: SUSY and SUSY Breaking
We revisit four generations within the context of supersymmetry. We compute
the perturbativity limits for the fourth generation Yukawa couplings and show
that if the masses of the fourth generation lie within reasonable limits of
their present experimental lower bounds, it is possible to have perturbativity
only up to scales around 1000 TeV. Such low scales are ideally suited to
incorporate gauge mediated supersymmetry breaking, where the mediation scale
can be as low as 10-20 TeV. The minimal messenger model, however, is highly
constrained. While lack of electroweak symmetry breaking rules out a large part
of the parameter space, a small region exists, where the fourth generation stau
is tachyonic. General gauge mediation with its broader set of boundary
conditions is better suited to accommodate the fourth generation.Comment: 27 pages, 5 figure
Magnetism, FeS colloids, and Origins of Life
A number of features of living systems: reversible interactions and weak
bonds underlying motor-dynamics; gel-sol transitions; cellular connected
fractal organization; asymmetry in interactions and organization; quantum
coherent phenomena; to name some, can have a natural accounting via
interactions, which we therefore seek to incorporate by expanding the horizons
of `chemistry-only' approaches to the origins of life. It is suggested that the
magnetic 'face' of the minerals from the inorganic world, recognized to have
played a pivotal role in initiating Life, may throw light on some of these
issues. A magnetic environment in the form of rocks in the Hadean Ocean could
have enabled the accretion and therefore an ordered confinement of
super-paramagnetic colloids within a structured phase. A moderate H-field can
help magnetic nano-particles to not only overcome thermal fluctuations but also
harness them. Such controlled dynamics brings in the possibility of accessing
quantum effects, which together with frustrations in magnetic ordering and
hysteresis (a natural mechanism for a primitive memory) could throw light on
the birth of biological information which, as Abel argues, requires a
combination of order and complexity. This scenario gains strength from
observations of scale-free framboidal forms of the greigite mineral, with a
magnetic basis of assembly. And greigite's metabolic potential plays a key role
in the mound scenario of Russell and coworkers-an expansion of which is
suggested for including magnetism.Comment: 42 pages, 5 figures, to be published in A.R. Memorial volume, Ed
Krishnaswami Alladi, Springer 201
Formation of Supermassive Black Holes
Evidence shows that massive black holes reside in most local galaxies.
Studies have also established a number of relations between the MBH mass and
properties of the host galaxy such as bulge mass and velocity dispersion. These
results suggest that central MBHs, while much less massive than the host (~
0.1%), are linked to the evolution of galactic structure. In hierarchical
cosmologies, a single big galaxy today can be traced back to the stage when it
was split up in hundreds of smaller components. Did MBH seeds form with the
same efficiency in small proto-galaxies, or did their formation had to await
the buildup of substantial galaxies with deeper potential wells? I briefly
review here some of the physical processes that are conducive to the evolution
of the massive black hole population. I will discuss black hole formation
processes for `seed' black holes that are likely to place at early cosmic
epochs, and possible observational tests of these scenarios.Comment: To appear in The Astronomy and Astrophysics Review. The final
publication is available at http://www.springerlink.co
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