2,200 research outputs found
Understanding of BRCA VUS genetic results by breast cancer specialists.
BACKGROUND: Mainstreaming genetic medicine, increased media coverage and clinical trials for BRCA mutation carriers are leading oncologists into more patient discussions about BRCA genetic testing. BRCA variants of uncertain significance (VUS) occur in 10-20% of tests. VUS detection introduces additional uncertainty for patient and potentially clinician. We aimed to explore the ability of breast cancer specialists (BCS) in the UK to correctly respond to a VUS report. METHODS: A survey sent to 800 UK BCS collected demographics data, VUS general knowledge and interpretation and communication based on two genetics reports. A separate survey of UK clinical geneticists collected demographics data, laboratory reporting practice and methods used to clarify VUS pathogenicity including classification systems. RESULTS: Of the 155 BCS (22.5%) who completed the survey, 12% reported no genetics training. Ninety five percent referred patients for BRCA genetic tests, 71% felt unsure about the clinical implications of the test reports presented here. A VUS report from a patient with a positive family history was interpreted and theoretically communicated correctly by 94% but when presented with a different VUS report with no management guidance and negative family history, 39% did not know how to communicate this result to the patient. Geneticists reported multiple VUS classification systems; the most commonly used was word-based in 32%. CONCLUSIONS: A consistent and standardised format to report particularly VUS results across all diagnostic laboratories plus additional training of UK BCS will be necessary for effective mainstreaming of BRCA testing to the oncology clinic
Structure–activity relationships on the odor detectability of homologous carboxylic acids by humans
We measured concentration detection functions for the odor detectability of the homologs: formic, acetic, butyric, hexanoic, and octanoic acids. Subjects (14 ≤ n ≤ 18) comprised young (19–37 years), healthy, nonsmoker, and normosmic participants from both genders. Vapors were delivered by air dilution olfactometry, using a three-alternative forced-choice procedure against carbon-filtered air, and an ascending concentration approach. Delivered concentrations were established by gas chromatography (flame ionization detector) in parallel with testing. Group and individual olfactory functions were modeled by a sigmoid (logistic) equation from which two parameters are calculated: C, the odor detection threshold (ODT) and D, the steepness of the function. Thresholds declined with carbon chain length along formic, acetic, and butyric acid where they reached a minimum (ODTs = 514, 5.2, and 0.26 ppb by volume, respectively). Then, they increased for hexanoic (1.0 ppb) and octanoic (0.86 ppb) acid. Odor thresholds and interindividual differences in olfactory acuity among these young, normosmic participants were lower than traditionally thought and reported. No significant effects of gender on odor detectability were observed. The finding of an optimum molecular size for odor potency along homologs confirms a prediction made by a model of ODTs based on a solvation equation. We discuss the mechanistic implications of this model for the process of olfactory detection
A Size of ~10 Mpc for the Ionized Bubbles at the End of Cosmic Reionization
The first galaxies to appear in the universe at redshifts z>20 created
ionized bubbles in the intergalactic medium of neutral hydrogen left over from
the Big-Bang. It is thought that the ionized bubbles grew with time, surrounded
clusters of dwarf galaxies and eventually overlapped quickly throughout the
universe over a narrow redshift interval near z~6. This event signaled the end
of the reionization epoch when the universe was a billion years old. Measuring
the hitherto unknown size distribution of the bubbles at their final overlap
phase is a focus of forthcoming observational programs aimed at highly
redshifted 21cm emission from atomic hydrogen. Here we show that the combined
constraints of cosmic variance and causality imply an observed bubble size at
the end of the overlap epoch of ~10 physical Mpc, and a scatter in the observed
redshift of overlap along different lines-of-sight of ~0.15. This scatter is
consistent with observational constraints from recent spectroscopic data on the
farthest known quasars. Our novel result implies that future radio experiments
should be tuned to a characteristic angular scale of ~0.5 degrees and have a
minimum frequency band-width of ~8 MHz for an optimal detection of 21cm flux
fluctuations near the end of reionization.Comment: Accepted for publication in Nature. Press embargo until publishe
Dwarf Galaxy Formation Was Suppressed By Cosmic Reionization
A large number of faint galaxies, born less than a billion years after the
big bang, have recently been discovered. The fluctuations in the distribution
of these galaxies contributed to a scatter in the ionization fraction of cosmic
hydrogen on scales of tens of Mpc, as observed along the lines of sight to the
earliest known quasars. Theoretical simulations predict that the formation of
dwarf galaxies should have been suppressed after cosmic hydrogen was reionized,
leading to a drop in the cosmic star formation rate. Here we present evidence
for this suppression. We show that the post-reionization galaxies which
produced most of the ionizing radiation at a redshift z~5.5, must have had a
mass in excess of ~10^{10.6+/-0.4} solar masses or else the aforementioned
scatter would have been smaller than observed. This limiting mass is two orders
of magnitude larger than the galaxy mass that is thought to have dominated the
reionization of cosmic hydrogen (~10^8 solar masses). We predict that future
surveys with space-based infrared telescopes will detect a population of
smaller galaxies that reionized the Universe at an earlier time, prior to the
epoch of dwarf galaxy suppression.Comment: 19 pages, 3 figures. Accepted for publication in Nature; press
embargo until publishe
Adding many Baumgartner clubs
I define a homogeneous ℵ2–c.c. proper product forcing for adding many clubs of ω1 with finite conditions. I use this forcing to build models of b(ω1)=ℵ2, together with d(ω1) and 2ℵ0 large and with very strong failures of club guessing at ω1
Gamma-Ray Background from Structure Formation in the Intergalactic Medium
The universe is filled with a diffuse and isotropic extragalactic background
of gamma-ray radiation, containing roughly equal energy flux per decade in
photon energy between 3 MeV-100 GeV. The origin of this background is one of
the unsolved puzzles in cosmology. Less than a quarter of the gamma-ray flux
can be attributed to unresolved discrete sources, but the remainder appears to
constitute a truly diffuse background whose origin has hitherto been
mysterious. Here we show that the shock waves induced by gravity during the
formation of large-scale structure in the intergalactic medium, produce a
population of highly-relativistic electrons with a maximum Lorentz factor above
10^7. These electrons scatter a small fraction of the microwave background
photons in the present-day universe up to gamma-ray energies, thereby providing
the gamma-ray background. The predicted diffuse flux agrees with the observed
background over more than four decades in photon energy, and implies a mean
cosmological density of baryons which is consistent with Big-Bang
nucleosynthesis.Comment: 7 pages, 1 figure. Accepted for publication in Nature. (Press embargo
until published.
Mechanical Systems with Symmetry, Variational Principles, and Integration Algorithms
This paper studies variational principles for mechanical systems with symmetry and their applications to integration algorithms. We recall some general features of how to reduce variational principles in the presence of a symmetry group along with general features of integration algorithms for mechanical systems. Then we describe some integration algorithms based directly on variational principles using a
discretization technique of Veselov. The general idea for these variational integrators is to directly discretize Hamilton’s principle rather than the equations of motion in a way that preserves the original systems invariants, notably the symplectic form and, via a discrete version of Noether’s theorem, the momentum map. The resulting mechanical integrators are second-order accurate, implicit, symplectic-momentum algorithms. We apply these integrators to the rigid body and the double spherical pendulum to show that the techniques are competitive with existing integrators
Cosmic Hydrogen Was Significantly Neutral a Billion Years After the Big Bang
The ionization fraction of cosmic hydrogen, left over from the big bang,
provides crucial fossil evidence for when the first stars and quasar black
holes formed in the infant universe. Spectra of the two most distant quasars
known show nearly complete absorption of photons with wavelengths shorter than
the Ly-alpha transition of neutral hydrogen, indicating that hydrogen in the
intergalactic medium (IGM) had not been completely ionized at a redshift z~6.3,
about a billion years after the big bang. Here we show that the radii of
influence of ionizing radiation from these quasars imply that the surrounding
IGM had a neutral hydrogen fraction of tens of percent prior to the quasar
activity, much higher than previous lower limits of ~0.1%. When combined with
the recent inference of a large cumulative optical depth to electron scattering
after cosmological recombination from the WMAP data, our result suggests the
existence of a second peak in the mean ionization history, potentially due to
an early formation episode of the first stars.Comment: 14 Pages, 2 Figures. Accepted for publication in Nature. Press
embargo until publishe
Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes
<p>Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.</p>
<p>Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.</p>
<p>Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.</p>
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