Rapid single nucleotide polymorphism detection for personalized medicine applications using planar waveguide fluorescence sensors

Journal ArticlePersonalized medicine is an emerging field in which clinical diagnostics information about a patient's genotype or phenotype is used to optimize his/her pharmacotherapy. This article evaluates whether planar waveguide fluorescent sensors are suitable for determining such information from patient testing in point-of-care (POC) settings. The model system was Long QT Syndrome, a congenital disease associated with single nucleotide polymorphisms (SNPs) in genes encoding for cardiac ion channels. Three different SNP assay formats were examined: DNA/DNA hybridization, DNA/PNA hybridization (PNA: "peptide nucleic acid"), and single base extension (SBEX). Although DNA/DNA hybridization produced a strong intensity-time response for both wildtype and SNP analytes in a 5-min assay at 32?C, their hybridization rates differed by only 32.7%, which was insufficient for clinical decision-making. Much better differentiation of the two rates was observed at 53?C, where the wildtype's hybridization rate was two-thirds of its maximum value, while that of the SNP was essentially zero. Such all-or-nothing resolution would be adequate for clinical decision-making; however, the elevated temperature and precise temperature control would be hard to achieve in a POC setting. Results from DNA/PNA hybridization studies were more promising. Nearly 20-fold discrimination between wildtype and SNP hybridization rates was observed in a 5-min assay at 30?C, although the low ionic strength conditions required necessitated a de-salting step between sample preparation and SNP detection. SBEX was the most promising of the three, determining the absolute identity of the suspected polymorphism in a 5-min assay at 40?C

Spin-orbit torque induced dipole skyrmion motion at room temperature

We demonstrate deterministic control of dipole-field-stabilized skyrmions by means of spin-orbit torques arising from heavy transition-metal seed layers. Experiments are performed on amorphous Fe/Gd multilayers that are patterned into wires and exhibit stripe domains and dipole skyrmions at room temperature. We show that while the domain walls and skyrmions are achiral on average due to lack of Dzyaloshinskii-Moriya interactions, the N\'eel-like closure domain walls at each surface are chiral and can couple to spin-orbit torques. The current-induced domain evolutions are reported for different magnetic phases, including disordered stripe domains, coexisting stripes and dipole skyrmions and a closed packed dipole skyrmion lattice. The magnetic textures exhibit motion under current excitations with a current density ~10^8 A/m2. By comparing the motion resulting from magnetic spin textures in Fe/Gd films with different heavy transition-metal interfaces, we confirm spin currents can be used to manipulate achiral dipole skyrmions via spin-orbit torques.Comment: 23 pages, 8 figure

All metrics have curvature tensors characterised by its invariants as a limit: the \epsilon-property

We prove a generalisation of the $\epsilon$-property, namely that for any dimension and signature, a metric which is not characterised by its polynomial scalar curvature invariants, there is a frame such that the components of the curvature tensors can be arbitrary close to a certain "background". This "background" is defined by its curvature tensors: it is characterised by its curvature tensors and has the same polynomial curvature invariants as the original metric.Comment: 6 page

Using DHS to Identify Sites for HIV Prevention Trials

Recruiting high-risk, HIV-negative participants is challenging for HIV prevention trials. This study aimed to 1) identify and characterize subsets of high-risk women based on responses to demographic and psychosocial questions from the AIDS Indicator Survey (AIS) and 2) develop a rapid, inexpensive tool for site identification. We developed a latent class model (LCM), hypothesizing that AIS respondents could be grouped by responses to psychosocial indicators, and that these latent classes would vary by HIV status, socio-demographic, and other indicators. We tested our model on women respondents from the Tanzania 2003 AIS Survey, and replicated it in several other populations.  LCM produced four classes of women who significantly varied by psychosocial indicators and HIV status. Geographic differences in HIV prevalence and class composition were observed. Our approach has the potential to provide a more systematic, inexpensive and rapid strategy to identify HIV prevention trial sites

Using preliminary data and prospective power analyses for mid-stream revision of projected group and subgroup sizes in pragmatic patient-centered outcomes research

Pragmatic clinical trials are commonly used in patient-centered outcomes research to assess heterogeneity of treatment effects. Patient-Centered Outcomes Research Institute (PCORI) methodology standards for assessing heterogeneity of treatment effects are extremely rigorous, but their implementation in real-world settings can be difficult. Predicting recruitment effectiveness and subgroup characteristics is often challenging and may require mid-stream revision of projected group and subgroup sizes. Yet, little real-world data are available to demonstrate methodologically valid approaches to address situations where such revisions are necessary. These data were used for mid-stream revision of group and subgroup sizes in the Management of Diabetes in Everyday Life (MODEL) clinical trial. The planned number of randomized participants retained over the one-year study period was reduced from 800 to 581 due to recruitment difficulties among potential participants residing in rural areas. Prospective power analyses are based on the revised target of 581 participants retained and the proportions of 167 participants with various key baseline characteristics, who had been randomized in MODEL by January 2018, as reported to the Patient Center Outcomes Research Institute (PCORI) and the MODEL Data Safety and Monitoring Committee. Power calculations are based on two-sided t-tests with type-I error rates of 0.05 and the assumption that effect sizes will range from small (standardized difference = 0.36) to medium (= 0.50). The primary outcome variables are how many days in the previous week participants 1) ate healthy meals, 2) participated in at least 30 minutes of physical activity, and 3) took medications as prescribed. The POWER procedure of SAS 9.4 was used for all analyses. These data, along with the approach, can assist statisticians as they plan future pragmatic clinical trials evaluating heterogeneity of treatment effects. These data can help inform investigators, conducting patient-centered outcomes research, as they define subgroups for either confirmatory analyses for testing heterogeneity of treatment effects or for exploratory analyses where estimation of confidence bounds may be useful for generating future hypotheses. (This work was supported through a Patient-Centered Outcomes Research Institute (PCORI) Project Program Award (SC15-1503-28336), www.ClinicalTrials.gov and Identifier: NCT02957513 [1].

Sculpting the Extra Dimensions: Inflation from Codimension-2 Brane Back-reaction

We construct an inflationary model in 6D supergravity that is based on explicit time-dependent solutions to the full higher-dimensional field equations, back-reacting to the presence of a 4D inflaton rolling on a space-filling codimension-2 source brane. Fluxes in the bulk stabilize all moduli except the `breathing' modulus (that is generically present in higher-dimensional supergravities). Back-reaction to the inflaton roll causes the 4D Einstein-frame on-brane geometry to expand, a(t) ~ t^p, as well as exciting the breathing mode and causing the two off-brane dimensions to expand, r(t) ~ t^q. The model evades the general no-go theorems precluding 4D de Sitter solutions, since adjustments to the brane-localized inflaton potential allow the power p to be dialed to be arbitrarily large, with the 4D geometry becoming de Sitter in the limit p -> infinity (in which case q = 0). Slow-roll solutions give accelerated expansion with p large but finite, and q = 1/2. Because the extra dimensions expand during inflation, the present-day 6D gravity scale can be much smaller than it was when primordial fluctuations were generated - potentially allowing TeV gravity now to be consistent with the much higher gravity scale required at horizon-exit for observable primordial gravity waves. Because p >> q, the 4 on-brane dimensions expand more quickly than the 2 off-brane ones, providing a framework for understanding why the observed four dimensions are presently so much larger than the internal two. If uplifted to a 10D framework with 4 dimensions stabilized, the 6D evolution described here could describe how two of the six extra dimensions evolve to become much larger than the others, as a consequence of the enormous expansion of the 4 large dimensions we can see.Comment: 27 pages + appendices, 2 figure

Supersymmetric codimension-two branes in six-dimensional gauged supergravity

We consider the six-dimensional Salam-Sezgin supergravity in the presence of codimension-2 branes. In the case that the branes carry only tension, we provide a way to supersymmetrise them by adding appropriate localised Fayet-Iliopoulos terms and localised corrections to the Chern-Simons term and modifying accordingly the fermionic supersymmetry transformations. The resulting brane action has N=1 supersymmetry (SUSY). We find the axisymmetric vacua of the system and show that one has unwarped background solutions with "football"-shaped extra dimensions which always respect N=1 SUSY for any value of the equal brane tensions, in contrast with the non-supersymmetric brane action background. Finally, we generically find multiple zero modes of the gravitino in this background and discuss how one could obtain a single chiral zero mode present in the low energy spectrum.Comment: 21 pages, no figures, A sign error in the gauge potential at the lower brane corrected and its consequent effect discusse

Chronology Protection in Galileon Models and Massive Gravity

Galileon models are a class of effective field theories that have recently received much attention. They arise in the decoupling limit of theories of massive gravity, and in some cases they have been treated in their own right as scalar field theories with a specific nonlinearly realized global symmetry (Galilean transformation). It is well known that in the presence of a source, these Galileon theories admit superluminal propagating solutions, implying that as quantum field theories they must admit a different notion of causality than standard local Lorentz invariant theories. We show that in these theories it is easy to construct closed timelike curves (CTCs) within the {\it naive} regime of validity of the effective field theory. However, on closer inspection we see that the CTCs could never arise since the Galileon inevitably becomes infinitely strongly coupled at the onset of the formation of a CTC. This implies an infinite amount of backreaction, first on the background for the Galileon field, signaling the break down of the effective field theory, and subsequently on the spacetime geometry, forbidding the formation of the CTC. Furthermore the background solution required to create CTCs becomes unstable with an arbitrarily fast decay time. Thus Galileon theories satisfy a direct analogue of Hawking's chronology protection conjecture.Comment: 34 pages, no figure