1,172 research outputs found
The trade-off between impartiality and freedom in the 21st Century Cures Act
This is the final version. Available from the University of Pittsburgh via the DOI in this record.âŻRandomized controlled trials test new drugs using various debiasing devices to prevent participants
from manipulating the trials. But participants often dislike controls, arguing that they impose a
paternalist constraint on their legitimate preferences. The 21st Century Cures Act, passed by US
Congress in 2016, encourages the Food and Drug Administration to use alternative testing methods,
incorporating participantsâ preferences, for regulatory purposes. We discuss, from a historical
perspective, the trade-off between trial impartiality and participantsâ freedom. We argue that the only
way out is considering which methods improve upon the performance of conventional trials in
keeping dangerous or inefficacious compounds out of pharmaceutical marketsMinisterio de Ciencia e InnovaciĂł
DetecciĂłn inmunohistoquĂmica del virus de Epstein-Barr en pacientes con linfoma
El virus de Epstein-Barr es un gammaherpes virus que infecta principalmente a linfocitos B permaneciendo en un estado de latencia en el interior del mismo, pudiendo tambiĂ©n infectar a linfocitos T y cĂ©lulas epiteliales. La persistencia de la infecciĂłn viral inmortaliza a los linfocitos y favorece el desarrollo de procesos linfoproliferativos malignos como linfomas. Si bien se conoce que la relaciĂłn entre la infecciĂłn crĂłnica del virus y el desarrollo de linfoma, varĂa de acuerdo al tipo histolĂłgico, se incrementa en pacientes inmunocomprometidos y de edad avanzada, la evidencia cientĂfica indica no sĂłlo la importancia de este virus como agente infeccioso asociado con la etiologĂa de esta neoplasia, sino tambiĂ©n como un marcador asociado a respuesta refractaria y peor supervivencia. El objetivo de este estudio observacional descriptivo, fue detectar la presencia del Epstein-Barr virus por tĂ©cnicas de inmunohistoquĂmica empleando anticuerpos monoclonales anti antĂgeno viral proteĂna latente de membrana en 86 pacientes con linfoma. La positividad para proteĂna en el total de pacientes con linfoma fue del 44%, correspondiendo el 20% a pacientes con linfoma de Hodgkin y el 24% a pacientes con linfoma no Hodgkin. La detecciĂłn del virus en estas enfermedades, contribuye al manejo clĂnico de las mismas ya que el virus no sĂłlo tiene un rol etiolĂłgico, sino ademĂĄs es un marcador pronĂłstico importante, incluso de interĂ©s terapĂ©utico
Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast
Acknowledgments We thank Rebecca Shapiro for creating CaLC1819, CaLC1855 and CaLC1875, Gillian Milne for help with EM, Aaron Mitchell for generously providing the transposon insertion mutant library, Jesus Pla for generously providing the hog1 hst7 mutant, and Cathy Collins for technical assistance.Peer reviewedPublisher PD
Bilateral macular hole formation secondary to sclopetaria caused by shockwaves transmitted by a posterior vector: case report
<p>Abstract</p> <p>Background</p> <p>Sclopetaria is a rare ophthalmic finding in trauma</p> <p>Case Presentation</p> <p>This is a report of a patient who developed macular holes from sclopetaria induced by indirect trauma. A 22-year-old male, suffered a gunshot wound that passed behind his eyes, resulting in bilateral macular hole formation</p> <p>Conclusion</p> <p>To our knowledge, this is the first reported case in which trauma posterior to the globes caused bilateral macular hole formation</p
Pharmacological Targeting of Native CatSper Channels Reveals a Required Role in Maintenance of Sperm Hyperactivation
The four sperm-specific CatSper ion channel proteins are required for hyperactivated motility and male fertility, and for Ca2+ entry evoked by alkaline depolarization. In the absence of external Ca2+, Na+ carries current through CatSper channels in voltage-clamped sperm. Here we show that CatSper channel activity can be monitored optically with the [Na+]i-reporting probe SBFI in populations of intact sperm. Removal of external Ca2+ increases SBFI signals in wild-type but not CatSper2-null sperm. The rate of the indicated rise of [Na+]i is greater for sperm alkalinized with NH4Cl than for sperm acidified with propionic acid, reflecting the alkaline-promoted signature property of CatSper currents. In contrast, the [Na+]i rise is slowed by candidate CatSper blocker HC-056456 (IC50 âŒ3 ”M). HC-056456 similarly slows the rise of [Ca2+]i that is evoked by alkaline depolarization and reported by fura-2. HC-056456 also selectively and reversibly decreased CatSper currents recorded from patch-clamped sperm. HC-056456 does not prevent activation of motility by HCO3â but does prevent the development of hyperactivated motility by capacitating incubations, thus producing a phenocopy of the CatSper-null sperm. When applied to hyperactivated sperm, HC-056456 causes a rapid, reversible loss of flagellar waveform asymmetry, similar to the loss that occurs when Ca2+ entry through the CatSper channel is terminated by removal of external Ca2+. Thus, open CatSper channels and entry of external Ca2+ through them sustains hyperactivated motility. These results indicate that pharmacological targeting of the CatSper channel may impose a selective late-stage block to fertility, and that high-throughput screening with an optical reporter of CatSper channel activity may identify additional selective blockers with potential for male-directed contraception
The Hubble Constant
I review the current state of determinations of the Hubble constant, which
gives the length scale of the Universe by relating the expansion velocity of
objects to their distance. There are two broad categories of measurements. The
first uses individual astrophysical objects which have some property that
allows their intrinsic luminosity or size to be determined, or allows the
determination of their distance by geometric means. The second category
comprises the use of all-sky cosmic microwave background, or correlations
between large samples of galaxies, to determine information about the geometry
of the Universe and hence the Hubble constant, typically in a combination with
other cosmological parameters. Many, but not all, object-based measurements
give values of around 72-74km/s/Mpc , with typical errors of 2-3km/s/Mpc.
This is in mild discrepancy with CMB-based measurements, in particular those
from the Planck satellite, which give values of 67-68km/s/Mpc and typical
errors of 1-2km/s/Mpc. The size of the remaining systematics indicate that
accuracy rather than precision is the remaining problem in a good determination
of the Hubble constant. Whether a discrepancy exists, and whether new physics
is needed to resolve it, depends on details of the systematics of the
object-based methods, and also on the assumptions about other cosmological
parameters and which datasets are combined in the case of the all-sky methods.Comment: Extensively revised and updated since the 2007 version: accepted by
Living Reviews in Relativity as a major (2014) update of LRR 10, 4, 200
A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.
We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 Ă 10â»ÂčÂČ) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 Ă 10â»ÂčÂč) on 19q12 maps to CCNE1 and rs11892031 (P = 1 Ă 10â»â·) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 Ă 10â»ÂčÂč) and a tag SNP for NAT2 acetylation status (P = 4 Ă 10â»ÂčÂč), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis
f(R) theories
Over the past decade, f(R) theories have been extensively studied as one of
the simplest modifications to General Relativity. In this article we review
various applications of f(R) theories to cosmology and gravity - such as
inflation, dark energy, local gravity constraints, cosmological perturbations,
and spherically symmetric solutions in weak and strong gravitational
backgrounds. We present a number of ways to distinguish those theories from
General Relativity observationally and experimentally. We also discuss the
extension to other modified gravity theories such as Brans-Dicke theory and
Gauss-Bonnet gravity, and address models that can satisfy both cosmological and
local gravity constraints.Comment: 156 pages, 14 figures, Invited review article in Living Reviews in
Relativity, Published version, Comments are welcom
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