224 research outputs found
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Validation of a consumer-grade activity monitor for continuous daily activity monitoring in individuals with multiple sclerosis.
Background:Technological advancements of remote-monitoring used in clinical-care and research require validation of model updates. Objectives:To compare the output of a newer consumer-grade accelerometer to a previous model in people with multiple sclerosis (MS) and to the ActiGraph, a waist-worn device widely used in MS research. Methods:Thirty-one individuals with MS participated in a 7-day validation by the Fitbit Flex (Flex), Fitbit Flex-2 (Flex2) and ActiGraph GT3X. Primary outcome was step count. Valid epochs of 5-min block increments, where there was overlap of ≥1 step/min for both devices were compared and summed to give a daily total for analysis. Results:Bland-Altman plots showed no systematic difference between the Flex and Flex2; mean step-count difference of 25 more steps-per-day more recorded by Flex2 (95% confidence intervals (CI) = 2, 48; p = 0.04),interclass correlation coefficient (ICC) = 1.00. Compared to the ActiGraph, Flex2 (and Flex) tended to record more steps (808 steps-per-day more than the ActiGraph (95% CI= -2380, 765; p < 0.01), although the ICC was high (0.98) indicating that the devices were likely measuring the same kind of activity. Conclusions:Steps from Flex and Flex2 can be used interchangeably. Differences in total step count between ActiGraph and Flex devices can make cross-device comparisons of numerical step-counts challenging particularly for faster walkers
Trkalian fields: ray transforms and mini-twistors
We study X-ray and Divergent beam transforms of Trkalian fields and their
relation with Radon transform. We make use of four basic mathematical methods
of tomography due to Grangeat, Smith, Tuy and Gelfand-Goncharov for an integral
geometric view on them. We also make use of direct approaches which provide a
faster but restricted view of the geometry of these transforms. These reduce to
well known geometric integral transforms on a sphere of the Radon or the
spherical Curl transform in Moses eigenbasis, which are members of an analytic
family of integral operators. We also discuss their inversion. The X-ray (also
Divergent beam) transform of a Trkalian field is Trkalian. Also the Trkalian
subclass of X-ray transforms yields Trkalian fields in the physical space. The
Riesz potential of a Trkalian field is proportional to the field. Hence, the
spherical mean of the X-ray (also Divergent beam) transform of a Trkalian field
over all lines passing through a point yields the field at this point. The
pivotal point is the simplification of an intricate quantity: Hilbert transform
of the derivative of Radon transform for a Trkalian field in the Moses basis.
We also define the X-ray transform of the Riesz potential (of order 2) and
Biot-Savart integrals. Then, we discuss a mini-twistor respresentation,
presenting a mini-twistor solution for the Trkalian fields equation. This is
based on a time-harmonic reduction of wave equation to Helmholtz equation. A
Trkalian field is given in terms of a null vector in C3 with an arbitrary
function and an exponential factor resulting from this reduction.Comment: 37 pages, http://dx.doi.org/10.1063/1.482610
String Theory and Water Waves
We uncover a remarkable role that an infinite hierarchy of non-linear
differential equations plays in organizing and connecting certain {hat c}<1
string theories non-perturbatively. We are able to embed the type 0A and 0B
(A,A) minimal string theories into this single framework. The string theories
arise as special limits of a rich system of equations underpinned by an
integrable system known as the dispersive water wave hierarchy. We observe that
there are several other string-like limits of the system, and conjecture that
some of them are type IIA and IIB (A,D) minimal string backgrounds. We explain
how these and several string-like special points arise and are connected. In
some cases, the framework endows the theories with a non-perturbative
definition for the first time. Notably, we discover that the Painleve IV
equation plays a key role in organizing the string theory physics, joining its
siblings, Painleve I and II, whose roles have previously been identified in
this minimal string context.Comment: 49 pages, 4 figure
Silent progression in disease activity-free relapsing multiple sclerosis.
ObjectiveRates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.MethodsDisability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.ResultsRelapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).InterpretationLong-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666
Unimodality Problems in Ehrhart Theory
Ehrhart theory is the study of sequences recording the number of integer
points in non-negative integral dilates of rational polytopes. For a given
lattice polytope, this sequence is encoded in a finite vector called the
Ehrhart -vector. Ehrhart -vectors have connections to many areas of
mathematics, including commutative algebra and enumerative combinatorics. In
this survey we discuss what is known about unimodality for Ehrhart
-vectors and highlight open questions and problems.Comment: Published in Recent Trends in Combinatorics, Beveridge, A., et al.
(eds), Springer, 2016, pp 687-711, doi 10.1007/978-3-319-24298-9_27. This
version updated October 2017 to correct an error in the original versio
The Smoking Paradox in the Development of Psoriatic Arthritis among Psoriasis Patients – A Population-Based Study
Objectives: Smoking is strongly associated with an increased risk of psoriatic arthritis (PsA) in the general population, but not among psoriasis patients. We sought to clarify the possible methodologic mechanisms behind this paradox.
Methods: Using 1995-2015 data from The Health Improvement Network, we performed survival analysis to examine the association between smoking and incident PsA in the general population and among psoriasis patients. We clarified the paradox using mediation analysis and conducted bias sensitivity analyses to evaluate the potential impact of index event bias and quantify its magnitude from uncontrolled/unmeasured confounders.
Results: Of 6.65 million subjects without PsA at baseline, 225,213 participants had psoriasis and 7,057 developed incident PsA. Smoking was associated with an increased risk of PsA in the general population (RR, 1.27; 95% CI, 1.19-1.36), but with a decreased risk among psoriasis patients (RR 0.91; 95% CI, 0.85-0.99). Mediation analysis showed that the effect of smoking on the risk of PsA was mediated almost entirely through its effect on psoriasis. Bias sensitivity analyses indicated that even when the relation of uncontrolled confounders to either smoking or PsA was modest (both RRs = ~1.50), it could reverse the biased estimate of effect of smoking among psoriasis patients (RR=0.9).
Conclusions: In this large cohort representative of the UK general population, smoking was positively associated with PsA risk in the general population, but negatively associated among psoriasis patients. Conditioning on a causal intermediate variable (psoriasis) can reverse the association between smoking and PsA, explaining the smoking paradox for the risk of PsA among psoriasis patients
VaxCelerate II: Rapid development of a self-assembling vaccine for Lassa fever
Development of effective vaccines against emerging infectious diseases (EID) can take as much or more than a decade to progress from pathogen isolation/identification to clinical approval. As a result, conventional approaches fail to produce field-ready vaccines before the EID has spread extensively. Lassa is a prototypical emerging infectious disease endemic to West Africa for which no successful vaccine is available. We established the VaxCelerate Consortium to address the need for more rapid vaccine development by creating a platform capable of generating and pre-clinically testing a new vaccine against specific pathogen targets in less than 120 d. A self-assembling vaccine is at the core of the approach. It consists of a fusion protein composed of the immunostimulatory Mycobacterium tuberculosis heat shock protein 70 (MtbHSP70) and the biotin binding protein, avidin. Mixing the resulting protein (MAV) with biotinylated pathogen-specific immunogenic peptides yields a self-assembled vaccine (SAV). To meet the time constraint imposed on this project, we used a distributed R&D model involving experts in the fields of protein engineering and production, bioinformatics, peptide synthesis/design and GMP/GLP manufacturing and testing standards. SAV immunogenicity was first tested using H1N1 influenza specific peptides and the entire VaxCelerate process was then tested in a mock live-fire exercise targeting Lassa fever virus. We demonstrated that the Lassa fever vaccine induced significantly increased class II peptide specific interferon-γ CD4+ T cell responses in HLA-DR3 transgenic mice compared to peptide or MAV alone controls. We thereby demonstrated that our SAV in combination with a distributed development model may facilitate accelerated regulatory review by using an identical design for each vaccine and by applying safety and efficacy assessment tools that are more relevant to human vaccine responses than current animal models
Structural characterization of anti-inflammatory Immunoglobulin G Fc proteins
Immunoglobulin G (IgG) is a central mediator of host defense due to its ability to recognize and eliminate pathogens. The recognition and effector responses are encoded on distinct regions of IgGs. The diversity of the antigen recognition Fab domains accounts for IgG’s ability to bind with high specificity to essentially any antigen. Recent studies have indicated that the Fc effector domain also displays considerable heterogeneity, accounting for its complex effector functions of inflammation, modulation and immune suppression. Therapeutic anti-tumor antibodies, for example, require the pro-inflammatory properties of the IgG Fc to eliminate tumor cells, while the anti-inflammatory activity of Intravenous Immunoglobulin G (IVIG) requires specific Fc glycans for activity. In particular, the anti-inflammatory activity of IVIG is ascribed to a small population of IgGs in which the Asn297-linked complex N-glycans attached to each Fc C_H2 domain include terminal α2,6-linked sialic acids. We used chemoenzymatic glycoengineering to prepare fully di-sialylated IgG Fc and solved its crystal structure. Comparison of the structures of asialylated Fc, sialylated Fc, and F241A Fc, a mutant that displays increased glycan sialylation, suggests that increased conformational flexibility of the C_H2 domain is associated with the switch from pro- to anti-inflammatory activity of the Fc
A Novel Laser Vaccine Adjuvant Increases the Motility of Antigen Presenting Cells
Background
Development of a potent vaccine adjuvant without introduction of any side effects remains an unmet challenge in the field of the vaccine research.
Methodology/Principal Findings
We found that laser at a specific setting increased the motility of antigen presenting cells (APCs) and immune responses, with few local or systemic side effects. This laser vaccine adjuvant (LVA) effect was induced by brief illumination of a small area of the skin or muscle with a nondestructive, 532 nm green laser prior to intradermal (i.d.) or intramuscular (i.m.) administration of vaccines at the site of laser illumination. The pre-illumination accelerated the motility of APCs as shown by intravital confocal microscopy, leading to sufficient antigen (Ag)-uptake at the site of vaccine injection and transportation of the Ag-captured APCs to the draining lymph nodes. As a result, the number of Ag+ dendritic cells (DCs) in draining lymph nodes was significantly higher in both the 1° and 2° draining lymph nodes in the presence than in the absence of LVA. Laser-mediated increases in the motility and lymphatic transportation of APCs augmented significantly humoral immune responses directed against a model vaccine ovalbumin (OVA) or influenza vaccine i.d. injected in both primary and booster vaccinations as compared to the vaccine itself. Strikingly, when the laser was delivered by a hair-like diffusing optical fiber into muscle, laser illumination greatly boosted not only humoral but also cell-mediated immune responses provoked by i.m. immunization with OVA relative to OVA alone.
Conclusion/Significance
The results demonstrate the ability of this safe LVA to augment both humoral and cell-mediated immune responses. In comparison with all current vaccine adjuvants that are either chemical compounds or biological agents, LVA is novel in both its form and mechanism; it is risk-free and has distinct advantages over traditional vaccine adjuvants.National Institutes of Health (U.S.) (grant AI070785)National Institutes of Health (U.S.) (grant RC1 DA028378)Bill & Melinda Gates Foundation (Grand Challenges Explorations grant # 53273)Boston BioCom (Firm) (Sponsored Research agreement grant #2008A25652
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