Summary
Ulcerative colitis is a chronic inflammatory and debilitating disease requiring lifelong treatment. First‐line therapy for ulcerative colitis is 5‐aminosalicylic acid, which suffers from poor ...patient adherence outside the clinical trial setting.
Formulations to deliver 5‐aminosalicylic acid to the disease activity site, both orally and topically, are often inconvenient and require multiple daily dosing. Such regimens can interfere with normal life and reduce the overall quality of life, negatively impacting on treatment adherence and leading to poorer long‐term outcomes. These include increased morbidity with an elevated risk of symptomatic relapse, possible greater risk of colorectal cancer and higher overall costs of care.
Ulcerative colitis patients cite treatment regimen complexity, tablet quantity and dose frequency as key negative influencers of adherence. Solutions to these issues include addressing patient concerns, simplifying daily regimens and utilizing new formulations such as micropellet and multimatrix oral formulations, rectal gel and once‐daily suppository formulations.
This review examines the prevalence and impact of non‐adherence to 5‐aminosalicylic acid therapy among patients with ulcerative colitis, as well as drug delivery strategies that may enhance dosing regimens to improve patient acceptability, adherence and long‐term clinical outcomes. It is a combination of understanding patient behaviour, recognizing signs of non‐adherent behaviour and utilizing management strategies to change behaviour that will improve patient outcomes.
Linked ContentThis article is linked to Seow et al and Seow papers. To view these articles visit https://doi.org/10.1111/apt.14040 and https://doi.org/10.1111/apt.14093.
Abstract Calcitonin gene related peptide (CGRP) has a key role in migraine and recently CGRP receptor antagonists have demonstrated clinical efficacy in the treatment of migraine. However, it remains ...unclear where the CGRP receptors are located within the CGRP signaling pathway in the human trigeminal system and hence the potential antagonist sites of action remain unknown. Therefore we designed a study to evaluate the localization of CGRP and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein (RAMP) 1 in the human trigeminal ganglion using immunohistochemistry and compare with that of rat. Antibodies against purified CLR and RAMP1 proteins were produced and characterized for this study. Trigeminal ganglia were obtained at autopsy from adult subjects and sections from rat trigeminal ganglia were used to compare the immunostaining pattern. The number of cells expressing CGRP, CLR and RAMP1, respectively, were counted. In addition, the glial cells of trigeminal ganglion, particularly the satellite glial cell, were studied to understand a possible relation. We observed immunoreactivity for CGRP, CLR and RAMP1, in the human trigeminal ganglion: 49% of the neurons expressed CGRP, 37% CLR and 36% RAMP1. Co-localization of CGRP and the receptor components was rarely found. There were no CGRP immunoreactions in the glial cells; however some of the glial cells displayed CLR and RAMP1 immunoreactivity. Similar results were observed in rat trigeminal ganglia. We report that human and rat trigeminal neurons store CGRP, CLR and RAMP1; however, CGRP and CLR/RAMP1 do not co-localize regularly but are found in separate neurons. Glial cells also contain the CGRP receptor components but not CGRP. Our results indicate, for the first time, the possibility of CGRP signaling in the human trigeminal ganglion involving both neurons and satellite glial cells. This suggests a possible site of action for the novel CGRP receptor antagonists in migraine therapy.
The Transiting Exoplanet Survey Satellite (TESS) recently observed 18 transits of the hot Jupiter WASP-4b. The sequence of transits occurred 81.6 11.7 s earlier than had been predicted, based on data ...stretching back to 2007. This is unlikely to be the result of a clock error, because TESS observations of other hot Jupiters (WASP-6b, 18b, and 46b) are compatible with a constant period, ruling out an 81.6 s offset at the 6.4 level. The 1.3 day orbital period of WASP-4b appears to be decreasing at a rate of ms per year. The apparent period change might be caused by tidal orbital decay or apsidal precession, although both interpretations have shortcomings. The gravitational influence of a third body is another possibility, though at present there is minimal evidence for such a body. Further observations are needed to confirm and understand the timing variation.
The discovery of broadly neutralizing antibodies that can neutralize multiple strains or subtypes of a pathogen has renewed interest in the development of broadly protective vaccines. To that end, ...there has been an interest in designing immunofocusing strategies to direct the immune response to specific, conserved regions on antigenic proteins. Modulation of glycosylation is one such immunofocusing strategy; extensive glycosylation is often exploited by pathogens for immune evasion. Masking epitopes on protein immunogens with “self” glycans can also shield the underlying protein surface from humoral immune surveillance. We review recent advances in applying glycosylation as an immunofocusing tool. We also highlight recent interesting work in the HIV‐1 field involving the identification and elicitation of broadly neutralizing antibodies that incorporate glycans into their binding epitopes.
The elicitation of broadly neutralizing antibodies is the goal of many vaccines. Immunofocusing strategies aim to redirect the immune response to conserved epitopes on antigenic proteins. Many pathogens evade immune surveillance by exploiting host‐cell machinery to glycosylate protein surfaces; the addition of glycosylation can similarly be used in vaccine design to shield selected regions of the protein surface from the immune system. Here, we review recent advances in utilizing glycosylation as an immunofocusing tool.
This paper describes a thermodynamic analysis of multivalent interactions, with the goal of clarifying the influence of the linker on the enhancement in avidity due to multivalency. The use of ...multivalency represents a promising approach to inhibit undesired biological interactions, promote desired cellular responses, and control recognition events at surfaces. Several groups have synthesized multivalent ligands that are orders of magnitude more potent than the corresponding monovalent ligands. A better understanding of the theoretical basis for the large enhancements in avidity would help guide the design of more potent synthetic multivalent ligands. In particular, there has been significant controversy regarding the extent to which the loss of conformational entropy of the linker influences the enhancement in avidity due to multivalency. To help clarify this issue, we present the thermodynamic analysis of a heterodivalent ligand-receptor interaction. Our analysis helps reconcile seemingly competing theoretical analyses of multivalent binding. Our results indicate that the dependence of the free energy of multivalent binding on linker length can be weak even if there is a significant decrease in the conformational entropy of the linker on binding. Our results are also consistent with studies demonstrating that the use of flexible linkers represents an effective strategy to design potent multivalent ligands.
Means for temporally regulating gene expression and cellular activity are invaluable for elucidating underlying physiological processes and would have therapeutic implications. Here we report the ...development of a genetically encoded system for remote regulation of gene expression by low-frequency radio waves (RFs) or a magnetic field. Iron oxide nanoparticles are synthesized intracellularly as a GFP-tagged ferritin heavy and light chain fusion. The ferritin nanoparticles associate with a camelid anti-GFP-transient receptor potential vanilloid 1 fusion protein, αGFP-TRPV1, and can transduce noninvasive RF or magnetic fields into channel activation, also showing that TRPV1 can transduce a mechanical stimulus. This, in turn, initiates calcium-dependent transgene expression. In mice with stem cell or viral expression of these genetically encoded components, remote stimulation of insulin transgene expression with RF or a magnet lowers blood glucose. This robust, repeatable method for remote regulation in vivo may ultimately have applications in basic science, technology and therapeutics.
Abstract There has been an increasing interest in understanding how the mechanical properties of the microenvironment influence stem cell fate. We describe studies of the proliferation and ...differentiation of neural stem cells (NSCs) encapsulated within three-dimensional scaffolds – alginate hydrogels – whose elastic moduli were varied over two orders of magnitude. The rate of proliferation of neural stem cells decreased with increase in the modulus of the hydrogels. Moreover, we observed the greatest enhancement in expression of the neuronal marker β-tubulin III within the softest hydrogels, which had an elastic modulus comparable to that of brain tissues. To our knowledge, this work represents the first demonstration of the influence of modulus on NSC differentiation in three-dimensional scaffolds. Three-dimensional scaffolds that control stem cell fate would be broadly useful for applications in regenerative medicine and tissue engineering.
Nutrition risk screening for community-living seniors is of great interest in the health arena. However, to be useful, nutrition risk indices need to be valid and reliable. The following three ...studies describe construct validation, test-retest and inter-rater reliability of SCREEN II.
Study (1) seniors were recruited from the general community and from a geriatrician's clinic to complete a nutritional assessment and SCREEN II. 193 older adults provided medical and nutritional history, 3 days of dietary recall and anthropometric measurements. A dietitian reviewed all information collected and ranked seniors on risk: 1 (low) to 10 (high risk). Receiver operating characteristic curves were completed. An abbreviated SCREEN II was developed through statistical analysis and expert ranking of the 17 items. Studies (2) and (3) seniors were recruited from the community to self-administer (n = 149) or be interviewed (n = 97) using SCREEN II twice within 2 weeks. For self-administration one index was completed via mail. Interviewer administration was completed via telephone with two interviewers. Intra-class correlations were calculated.
(1) Total and abbreviated SCREEN II have increased sensitivity and specificity as compared to SCREEN I in identifying seniors at nutritional risk. (2) Test-retest reliability was adequate (intra-class correlation (ICC) = 0.83). (3) Inter-rater reliability was adequate (ICC = 0.83).
SCREEN II appears to be a valid and reliable tool for the identification of risk for impaired nutritional states in community-living older adults, and is an improvement over SCREEN I.
Context. The NASA mission TESS is currently doing an all-sky survey from space to detect transiting planets around bright stars. As part of the validation process, the most promising planet ...candidates need to be confirmed and characterized using follow-up observations.
Aims. In this article, our aim is to confirm the planetary nature of the transiting planet candidate TOI-674b using spectroscopic and photometric observations.
Methods. We use TESS, Spitzer, ground-based light curves, and HARPS spectrograph radial velocity measurements to establish the physical properties of the transiting exoplanet candidate TOI-674b. We perform a joint fit of the light curves and radial velocity time series to measure the mass, radius, and orbital parameters of the candidate.
Results. We confirm and characterize TOI-674b, a low-density super-Neptune transiting a nearby M dwarf. The host star (TIC 158588995, V = 14.2 mag, J = 10.3 mag) is characterized by its M2V spectral type with M⋆ = 0.420 ± 0.010 Mꙩ, R⋆ = 0.420 ± 0.013 Rꙩ, and T(eff) = 3514 ± 57 K; it is located at a distance d = 46.16 ± 0.03 pc. Combining the available transit light curves plus radial velocity measurements and jointly fitting a circular orbit model, we find an orbital period of 1.977143 ± 3 × 10^(−6) days, a planetary radius of 5.25 ± 0.17 Rꚛ, and a mass of 23.6 ± 3.3 Mꚛ implying a mean density of ρp =0.91 ± 0.15 g/cu. cm. A non-circular orbit model fit delivers similar planetary mass and radius values within the uncertainties. Given the measured planetary radius and mass, TOI-674b is one of the largest and most massive super-Neptune class planets discovered around an M-type star to date. It is found in the Neptunian desert, and is a promising candidate for atmospheric characterization using the James Webb Space Telescope.
PDF
