Rheumatoid arthritis is a common complex genetic disease, and, despite a significant genetic element, no gene other than HLA-DRB1 has been clearly demonstrated to be involved in the disease. However, ...this association accounts for less than half the overall genetic susceptibility. Investigation of other candidate genes, in particular those that reside within the major histocompatibility complex, are hampered by the presence of strong linkage disequilibrium and problems with study design.
Patients with coeliac disease (CD) commonly report a variety of adverse symptoms to gluten, but descriptions of the symptomatic response in the literature may have been confounded by the presence of ...food components such as fermentable carbohydrates (FODMAPs) causing symptoms of irritable bowel syndrome independent of gluten. In recent unmasked and masked low FODMAP gluten challenge studies in small groups of treated CD patients, nausea and vomiting were shown to be the key symptoms associated with serum interleukin (IL)-2 release. Our objective was to utilise a large and diverse cohort of people with CD undertaking a standardised gluten food challenge to characterise the demographic, genetic and clinical factors influencing the severity and timing of acute gluten reactions and IL-2 production.
A total of 295 adults treated for CD were observed for 6 h after an unmasked food challenge consisting of 10 g vital wheat gluten (low in FODMAPs) in 100 ml water. Assessments included patient-reported outcomes, serum IL-2 and adverse events. Responses were analysed according to patient characteristics, HLA-DQ genotype, duodenal histology and response to a second gluten challenge.
Peak symptom severity was at 3 h (median severity 5/10). Peak IL-2 was at 4 h (median 4 pg/ml, range undetectable to 1028 pg/ml). Older age, older age at diagnosis, HLA-DQ2.5 positivity and homozygosity for HLA-DQB1*02 were each significantly associated with IL-2 elevations after gluten. Patients positive for HLA-DQ2.5, DQ8, DQ2.2 or DQ7 showed elevated IL-2 after gluten. Patient factors were not significantly associated with severity of digestive symptoms, but symptoms were correlated to one another and serum IL-2. Gluten challenge after 5 months caused more vomiting and higher IL-2 levels, but responses correlated with the first.
Gluten-induced symptoms and cytokine release is common in adults with treated CD. Age, genetics and previous response to gluten predict these acute reactions to gluten challenge. Structured symptom assessment and serum IL-2 after standardised gluten challenge may inform on patient diagnosis, the role of gluten in symptomatology and the need for adjunctive treatment.
ClinicalTrials.gov , NCT03644069 Registered 21 May 2018.
Winter roads play a vital role in linking communities and building economies in the northern high latitudes. With these regions warming 2–3 times faster than the global average, climate change ...threatens the long-term viability of these important seasonal transport routes. We examine how climate change will impact the world’s busiest heavy-haul winter road—the Tibbitt to Contwoyto Winter Road (TCWR) in northern Canada. The FLake freshwater lake model is used to project ice thickness for a lake at the start of the TCWR—first using observational climate data, and second using modeled future climate scenarios corresponding to varying rates of warming ranging from 1.5° to 4°C above preindustrial temperatures. Our results suggest that 2°C warming could be a tipping point for the viability of the TCWR, requiring at best costly adaptation and at worst alternative forms of transportation. Containing warming to the more ambitious temperature target of 1.5°C pledged at the 2016 Paris Agreement may be the only way to keep the TCWR viable—albeit with a shortened annual operational season relative to present. More widely, we show that higher regional winter warming across much of the rest of Arctic North America threatens the long-term viability of winter roads at a continental scale. This underlines the importance of continued global efforts to curb greenhouse gas emissions to avoid many long-term and irreversible impacts of climate change.
Single microring resonators have been used in applications such as wavelength multicasting and microwave photonics, but the dependence of the free spectral range with ring radius imposes a trade-off ...between the required GHz optical channel spacing, footprint and power consumption. We demonstrate four-channel all-optical wavelength multicasting using only 1 mW of control power, with converted channel spacing of 40-60 GHz. Our device is based on a compact embedded microring design fabricated on a scalable SOI platform. The coexistence of close resonance spacing and high finesse (205) in a compact footprint is possible due to enhanced quality factors (30,000) resulting from the embedded configuration and the coupling-strength dependence of resonance spacing, instead of ring size. In addition, we discuss the possibility of achieving continuously mode splitting from a single-notch resonance up to 40 GHz.
Given a protein's amino acid sequence, the protein structure prediction problem is to find a three dimensional structure that has the native energy level. For many decades, it has been one of the ...most challenging problems in computational biology. A simplified version of the problem is to find an on-lattice self-avoiding walk that minimizes the interaction energy among the amino acids. Local search methods have been preferably used in solving the protein structure prediction problem for their efficiency in finding very good solutions quickly. However, they suffer mainly from two problems: re-visitation and stagnancy.
In this paper, we present an efficient local search algorithm that deals with these two problems. During search, we select the best candidate at each iteration, but store the unexplored second best candidates in a set of elite conformations, and explore them whenever the search faces stagnation. Moreover, we propose a new non-isomorphic encoding for the protein conformations to store the conformations and to check similarity when applied with a memory based search. This new encoding helps eliminate conformations that are equivalent under rotation and translation, and thus results in better prevention of re-visitation.
On standard benchmark proteins, our algorithm significantly outperforms the state-of-the art approaches for Hydrophobic-Polar energy models and Face Centered Cubic Lattice.
Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether ...MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.
In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.
MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.
The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.
There is unequivocal evidence that the combination of an inhaled corticosteroid (ICS) -- i.e. glucocorticoid -- and an inhaled long-acting beta(2)-adrenoceptor agonist (LABA) is superior to each ...component administered as a monotherapy alone in the clinical management of asthma. Moreover, Calverley and colleagues (Lancet 2003, 361: 449-456; N Engl J Med 2007, 356: 775-789) reporting for the 'TRial of Inhaled STeroids ANd long-acting beta(2)-agonists (TRISTAN)' and 'TOwards a Revolution in COPD Health (TORCH)' international study groups also demonstrated the superior efficacy of LABA/ICS combination therapies over ICS alone in the clinical management of chronic obstructive pulmonary disease. This finding has been independently confirmed indicating that the therapeutic benefit of LABA/ICS combination therapies is not restricted to asthma and may be extended to other chronic inflammatory diseases of the airways. Despite the unquestionable benefit of LABA/ICS combination therapies, there is a vast gap in our understanding of how these two drugs given together deliver superior clinical efficacy. In this article, we review the history of LABA/ICS combination therapies and critically evaluate how these two classes of drugs might interact at the biochemical level to suppress pro-inflammatory responses. Understanding the molecular basis of this fundamental clinical observation is a Holy Grail of current respiratory diseases research as it could permit the rational exploitation of this effect with the development of new 'optimized' LABA/ICS combination therapies.
We demonstrate an integrated photonic platform comprising a refractive index (RI) sensor based on Photonic Molecule (PM) that effectively mitigates the influence of environmental perturbations using ...a differential measurement scheme while providing high quality-factor (Q) resonances. The RI sensor consists of a partially unclad microdisk resonator coupled to an external clad microring resonator fabricated on silicon-on-insulator (SOI) platform. We report a RI sensitivity of 24 nm/RIU, achieving a limit of detection (LOD) of 1.7 × 10 −3 refractive index units (RIU) with improved stability for an operation range of 0.15 RIU in a compact footprint of 40 × 40 µm 2 , representing an important solution for real-life applications in which measurement conditions are not easily controllable.
. Hollingsworth KG, Hodgson T, MacGowan GA, Blamire AM, Newton JL (Institute of Cellular Medicine, Campus for Ageing and Vitality; Institute of Genetic Medicine; and Institute for Ageing and Health, ...Campus for Ageing and Vitality; Newcastle University, Newcastle, UK). Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging. J Intern Med 2012; 271: 264–270.
Objectives. Impaired cardiac function has been confirmed in patients with chronic fatigue syndrome (CFS). Magnetic resonance cardiac tagging is a novel technique that assesses myocardial wall function in vivo. We hypothesized that patients with CFS may have impaired development and release of myocardial torsion and strain.
Methods. Cardiac morphology and function were assessed using magnetic resonance imaging and cardiac tagging methodology in 12 CFS patients (Fukuda) and 10 matched controls.
Results. Compared to controls, the CFS group had substantially reduced left ventricular mass (reduced by 23%), end‐diastolic volume (30%), stroke volume (29%) and cardiac output (25%). Residual torsion at 150% of the end‐systolic time was found to be significantly higher in the patients with CFS (5.3 ± 1.6°) compared to the control group (1.7 ± 0.7°, P = 0.0001). End‐diastolic volume index correlated negatively with both torsion‐to‐endocardial‐strain ratio (TSR) (r = −0.65, P = 0.02) and the residual torsion at 150% end‐systolic time (r = −0.76, P = 0.004), so decreased end‐diastolic volume is associated with raised TSR and torsion persisting longer into diastole. Reduced end‐diastolic volume index also correlated significantly with increased radial thickening (r = −0.65, P = 0.03) and impaired diastolic function represented by the ratio of early to late ventricular filling velocity (E/A ratio, r = 0.71, P = 0.009) and early filling percentage (r = 0.73, P = 0.008).
Conclusion. Patients with CFS have markedly reduced cardiac mass and blood pool volumes, particularly end‐diastolic volume: this results in significant impairments in stroke volume and cardiac output compared to controls. The CFS group appeared to have a delay in the release of torsion.
This study aimed to determine the prevalence of hand and wrist osteoarthritis in former elite cricket and rugby union players, by sport and playing position, and to define the prevalence of severe ...hand injury, and its association with hand osteoarthritis.
Cross-sectional.
Data from cross-sectional studies of former elite male cricket and rugby players were used to determine the prevalence of hand pain, physician-diagnosed osteoarthritis, and previous severe injury. Multivariable logistic regression was used to determine the association of previous injury with pain and osteoarthritis.
Data from 200 cricketers and 229 rugby players were available. Complete case analysis resulted in 127 cricketers and 140 rugby players. Hand pain was more prevalent amongst cricketers (19.7%) than rugby players (10.0%). The prevalence did not differ between cricket and rugby players for hand osteoarthritis (2.4% and 3.6%), wrist osteoarthritis (1.6% and 2.1%), or previous severe hand injury (36.2% and 31.4%). No significant association between previous hand injury and pain or osteoarthritis was identified in either sport.
Former elite cricketers reported more hand pain than rugby players. No significant association was found between self-reported severe injury and hand osteoarthritis in either cohort, potentially indicating that risk factors aside from injury may be more prominent in the development of hand osteoarthritis.
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