Therapeutic glucocorticoids have been widely used in rheumatic diseases since they became available over 60 years ago. Despite the advent of more specific biologic therapies, a notable proportion of ...individuals with chronic rheumatic diseases continue to be treated with these drugs. Glucocorticoids are powerful, broad-spectrum anti-inflammatory agents, but their use is complicated by an equally broad range of adverse effects. The specific cellular mechanisms by which glucocorticoids have their therapeutic action have been difficult to identify, and attempts to develop more selective drugs on the basis of the action of glucocorticoids have proven difficult. The actions of glucocorticoids seem to be highly cell-type and context dependent. Despite emerging data on the effect of tissue-specific manipulation of glucocorticoid receptors in mouse models of inflammation, the cell types and intracellular targets of glucocorticoids in rheumatic diseases have not been fully identified. Although showing some signs of decline, the use of systemic glucocorticoids in rheumatology is likely to continue to be widespread, and careful consideration is required by rheumatologists to balance the beneficial effects and deleterious effects of these agents.
Cachexia is the involuntary loss of muscle and adipose tissue that strongly affects mortality and treatment efficacy in patients with cancer or chronic inflammatory disease. Currently, no specific ...treatments or interventions are available for patients developing this disorder. Given the well-documented involvement of pro-inflammatory cytokines in muscle and fat metabolism in physiological responses and in the pathophysiology of chronic inflammatory disease and cancer, considerable interest has revolved around their role in mediating cachexia. This has been supported by association studies that report increased levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in some, but not all, cancers and in chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis (RA). In addition, preclinical studies including animal disease models have provided a substantial body of evidence implicating a causal contribution of systemic inflammation to cachexia. The presence of inflammatory cytokines can affect skeletal muscle through several direct mechanisms, relying on activation of the corresponding receptor expressed by muscle, and resulting in inhibition of muscle protein synthesis (MPS), elevation of catabolic activity through the ubiquitin-proteasomal system (UPS) and autophagy, and impairment of myogenesis. Additionally, systemic inflammatory mediators indirectly contribute to muscle wasting through dysregulation of tissue and organ systems, including GCs via the hypothalamus-pituitary-adrenal (HPA) axis, the digestive system leading to anorexia-cachexia, and alterations in liver and adipocyte behavior, which subsequently impact on muscle. Finally, myokines secreted by skeletal muscle itself in response to inflammation have been implicated as autocrine and endocrine mediators of cachexia, as well as potential modulators of this debilitating condition. While inflammation has been shown to play a pivotal role in cachexia development, further understanding how these cytokines contribute to disease progression is required to reveal biomarkers or diagnostic tools to help identify at risk patients, or enable the design of targeted therapies to prevent or delay the progression of cachexia.
Heterostructures are central to the efficient manipulation of charge carriers, excitons and photons for high-performance semiconductor devices. Although these can be formed by stepwise evaporation of ...molecular semiconductors, they are a considerable challenge for polymers owing to re-dissolution of the underlying layers. Here we demonstrate a simple and versatile photocrosslinking methodology based on sterically hindered bis(fluorophenyl azide)s. The photocrosslinking efficiency is high and dominated by alkyl side-chain insertion reactions, which do not degrade semiconductor properties. We demonstrate two new back-infiltrated and contiguous interpenetrating donor-acceptor heterostructures for photovoltaic applications that inherently overcome internal recombination losses by ensuring path continuity to give high carrier-collection efficiency. This provides the appropriate morphology for high-efficiency polymer-based photovoltaics. We also demonstrate photopatternable polymer-based field-effect transistors and light-emitting diodes, and highly efficient separate-confinement-heterostructure light-emitting diodes. These results open the way to the general development of high-performance polymer semiconductor heterostructures that have not previously been thought possible.
Despite the proven evidence of high glycemic index (GI) and glycemic load (GL) diets to increase cardiometabolic risks, knowledge about the meta-evidence for carbohydrate quality within world ...geographic regions is limited. We conducted a meta-analysis to synthesize the evidence of GI/GL studies and carbohydrate quality, gathering additional exposures for carbohydrate, high glycemic carbohydrate, total dietary fiber, and cereal fiber and risks for type 2 diabetes (T2DM), coronary heart disease (CHD), stroke, and mortality, grouped into the US, Europe, and Asia. Secondary aims examined cardiometabolic risks in overweight/obese individuals, by sex, and dose–response dietary variable trends.
40-prospective observational studies from 4-Medline bibliographical databases (Ovid, PubMed, EBSCOhost, CINAHL) were search up to November 2019. Random-effects hazard ratios (HR) and 95% confidence intervals (CI) for highest vs. lowest categories and continuous form combined were reported. Heterogeneity (I2>50%) was frequent in US GI/GL studies due to differing study characteristics. Increased risks ((HRGI,T2DM,US=1.14;CI:1.06,1.21), HRGL,T2DM,US=1.02 (1.01, 1.03)), HRGI,T2DM,Asia=1.25;1.02,1.53), and HRGL,T2DM,Asia=1.37 (1.17, 1.60)) were associated with cardiometabolic diseases. GI/GL in overweight/obese females had the strongest magnitude of risks in US-and Asian studies. Total dietary fiber (HRT2DM,US = 0.92;0.88,0.96) and cereal fiber (HRT2DM,US = 0.83;0.77,0.90) decreased risk of developing T2DM. Among females, we found protective dose–response risks for total dietary fiber (HR5g-total-dietary-fiber,T2DM,US = 0.94;0.92,0.97), but cereal fiber showed better ability to lower T2DM risk (HR5g-cereal-fiber,T2DM,US = 0.67;0.60,0.74). Total dietary-and cereal fibers' dose–response effects were nullified by GL, but not so for cereal fiber with GI.
Overweight/obese females could shift their carbohydrate intake for higher cereal fiber to decrease T2DM risk, but higher GL may cancel-out this effect.
•High Glycemic index & glycemic load increased risk of type 2 diabetes in US studies.•High glycemic load increased risk of coronary heart disease in European female studies.•Glycemic index and glycemic load had the highest risks in overweight/obese persons.•Dietary and cereal fibers were protective against type 2 diabetes in US studies.•Cereal fiber dose–response was protective against type 2 diabetes in US studies.
Background. In community-dwelling older adults, global cognitive function predicts longitudinal gait speed decline. Few prospective studies have evaluated whether specific executive cognitive ...deficits in aging may account for gait slowing over time. Methods. Multiple cognitive tasks were administered at baseline in 909 participants in the Health, Aging, and Body Composition Study Cognitive Vitality Substudy (mean age 75.2 ± 2.8 years, 50.6% women, 48.4% black). Usual gait speed (m/s) over 20 minutes was assessed at baseline and over a 5-year follow-up. Results. Poorer performance in each cognitive task was cross-sectionally associated with slower gait independent of demographic and health characteristics. In longitudinal analyses, each 1 SD poorer performance in global function, verbal memory, and executive function was associated with 0.003–0.004 m/s greater gait speed decline per year (p =.03–.05) after adjustment for baseline gait speed, demographic, and health characteristics. Conclusions. In this well-functioning cohort, several cognitive tasks were associated with gait speed cross-sectionally and predicted longitudinal gait speed decline. These data are consistent with a shared pathology underlying cognitive and motor declines but do not suggest that specific executive cognitive deficits account for slowing of usual gait in aging.
Anaphylaxis has been defined as a ‘severe, life‐threatening generalized or systemic hypersensitivity reaction’. However, data indicate that the vast majority of food‐triggered anaphylactic reactions ...are not life‐threatening. Nonetheless, severe life‐threatening reactions do occur and are unpredictable. We discuss the concepts surrounding perceptions of severe, life‐threatening allergic reactions to food by different stakeholders, with particular reference to the inclusion of clinical severity as a factor in allergy and allergen risk management. We review the evidence regarding factors that might be used to identify those at most risk of severe allergic reactions to food, and the consequences of misinformation in this regard. For example, a significant proportion of food‐allergic children also have asthma, yet almost none will experience a fatal food‐allergic reaction; asthma is not, in itself, a strong predictor for fatal anaphylaxis. The relationship between dose of allergen exposure and symptom severity is unclear. While dose appears to be a risk factor in at least a subgroup of patients, studies report that individuals with prior anaphylaxis do not have a lower eliciting dose than those reporting previous mild reactions. It is therefore important to consider severity and sensitivity as separate factors, as a highly sensitive individual will not necessarily experience severe symptoms during an allergic reaction. We identify the knowledge gaps that need to be addressed to improve our ability to better identify those most at risk of severe food‐induced allergic reactions.
Contracts are being granted, but protections are lagging
Interest in mining the deep seabed is not new; however, recent technological advances and increasing global demand for metals and rare-earth ...elements may make it economically viable in the near future (
1
). Since 2001, the International Seabed Authority (ISA) has granted 26 contracts (18 in the last 4 years) to explore for minerals on the deep seabed, encompassing ∼1 million km
2
in the Pacific, Atlantic, and Indian Oceans in areas beyond national jurisdiction (
2
). However, as fragile habitat structures and extremely slow recovery rates leave diverse deep-sea communities vulnerable to physical disturbances such as those caused by mining (
3
), the current regulatory framework could be improved. We offer recommendations to support the application of a precautionary approach when the ISA meets later this July.
Carbohydrate and protein dietary proportions have been debated as to whether higher or lower levels are optimal for diabetes metabolic control.
The objective of this study was to investigate the ...associations, interactions, and mediational relationships between a polygenic risk score (PRS), carbohydrate and protein intake, and physical activity level on type 2 diabetes (T2DM) by genetic ancestry, in European Americans and African Americans. A secondary objective examined the biological pathways associated with the PRS-linked genes and their relationships to dietary intake.
We performed a cross-sectional study in 9,393 participants: 83.3% European Americans and 16.7% African Americans from 7-NHLBI Care studies obtained from the database of Genotypes and Phenotypes. The main outcome was T2DM. Carbohydrate and protein intake derived from food frequency questionnaires were calculated as percent calories. Data were analyzed using multivariable generalized estimation equation models to derive odds ratios (OR) and 95% confidence intervals (CI). Ancestry-specific PRSs were constructed using joint-effects Summary Best Linear Unbiased Estimation in the train dataset and replicated in the test dataset. Mediation analysis was performed using VanderWeele's method.
The PRS in the highest tertile was associated with higher risk of T2DM in European Americans (OR = 1.25;CI = 1.03-1.51) and African Americans (OR = 1.54;1.14-2.09). High carbohydrate and low protein intake had lower risks of T2DM when combined with the PRS after adjusting for covariates. In African Americans, high physical activity combined with the high PRS and high protein diet was associated with a 28% lower incidence of T2DM when compared to low physical activity. In mediational models in African Americans, the PRS-T2DM association was mediated by protein intake in the highest tertile by 55%. The top PRS tertile had the highest magnitude of risks with metabolic factors that were significantly associated with T2DM, especially in European Americans. We found metabolic pathways associated with the PRS-linked genes that were related to insulin/IGF and ketogenesis/ketolysis that can be activated by moderate physical activity and intermittent fasting for better T2DM control.
Clinicians may want to consider diets with a higher portion of carbohydrates than protein, especially when the burden of high-risk alleles is great in patients with T2DM. In addition, clinicians and other medical professionals may want to emphasize the addition of physical activity as part of treatment regimen especially for African Americans. Given the metabolic pathways we identified, moderate physical activity and intermittent fasting should be explored. Researchers may want to consider longitudinal or randomized clinical trials to determine the predictive ability of different dietary patterns to inhibit T2DM in the presence of obesity and an elevated PRS.
Poly(dimethylsiloxane) (PDMS) microchannels are commonly used microfluidic structures that have a wide variety of biological testing applications, including the simulation of blood vessels to study ...the mechanics of vascular disease. In these studies in particular, the deformation of the channel due to the pressure inside is a critical parameter. We describe a method for using fluorescence microscopy to quantify the deformation of such channels under pressure driven flow. Additionally, the relationship between wall thickness and channel deformation is investigated. PDMS microchannels of varying top wall thickness were created using a soft lithography process. A solution of fluorescent dye is pumped through the channels at constant volume flow rates and illuminated. Pressure and fluorescence intensity are measured at five positions along the length of the channel. Fluorescence measurements are then used to determine deformation, using the linear relationship of dye layer thickness and intensity. A linear relationship between pressure and microchannel deformation is measured. Pressure drops and deformations closely correspond to values predicted by the model in most cases. Additionally, measured pressure drops are found to be up to 35% less than the pressure drop in a rigid-walled channel, and channel wall thickness is found to have an increasing effect as the channel wall thickness decreases.
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