Lifetime Predictions for High-Density Polyethylene under Creep: Experiments and Modeling.

Observations are reported in uniaxial tensile tests with various strain rates, tensile relaxation tests with various strains, and tensile creep tests with various stresses on high-density polyethylene (HDPE) at room temperature. Constitutive equations are developed for the viscoelastoplastic response of semicrystalline polymers. The model involves seven material parameters. Four of them are found by fitting observations in relaxation tests, while the others are determined by matching experimental creep curves. The predictive ability of the model is confirmed by comparing observations in independent short- and medium-term creep tests (with the duration up to several days) with the results of numerical analysis. The governing relations are applied to evaluate the lifetime of HDPE under creep conditions. An advantage of the proposed approach is that it predicts the stress-time-to-failure diagrams with account for the creep endurance limit.

Swelling of Thermo-Responsive Gels in Aqueous Solutions of Salts: A Predictive Model.

The equilibrium degree of swelling of thermo-responsive (TR) gels is strongly affected by the presence of ions in an aqueous solution. This phenomenon plays an important role in (i) the synthesis of multi-stimuli-responsive gels for soft robotics, where extraordinary strength and toughness are reached by soaking of a gel in solutions of multivalent ions, and (ii) the preparation of hybrid gels with interpenetrating networks formed by covalently cross-linked synthetic chains and ionically cross-linked biopolymer chains. A model is developed for equilibrium swelling of a TR gel in aqueous solutions of salts at various temperatures T below and above the critical temperature at which collapse of the gel occurs. An advantage of the model is that it involves a a small (compared with conventional relations) number of material constants and allows the critical temperature to be determined explicitly. Its ability (i) to describe equilibrium swelling diagrams on poly(N-isopropylacrylamide) gels in aqueous solutions of mono- and multivalent salts and (ii) to predict the influence of volume fraction of salt on the critical temperature is confirmed by comparison of observations with results of numerical simulation.

Fungal quinones: diversity, producers, and applications of quinones from Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium.

Quinones represent an important group of highly structurally diverse, mainly polyketide-derived secondary metabolites widely distributed among filamentous fungi. Many quinones have been reported to have important biological functions such as inhibition of bacteria or repression of the immune response in insects. Other quinones, such as ubiquinones are known to be essential molecules in cellular respiration, and many quinones are known to protect their producing organisms from exposure to sunlight. Most recently, quinones have also attracted a lot of industrial interest since their electron-donating and -accepting properties make them good candidates as electrolytes in redox flow batteries, like their often highly conjugated double bond systems make them attractive as pigments. On an industrial level, quinones are mainly synthesized from raw components in coal tar. However, the possibility of producing quinones by fungal cultivation has great prospects since fungi can often be grown in industrially scaled bioreactors, producing valuable metabolites on cheap substrates. In order to give a better overview of the secondary metabolite quinones produced by and shared between various fungi, mainly belonging to the genera Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium, this review categorizes quinones into families such as emodins, fumigatins, sorbicillinoids, yanuthones, and xanthomegnins, depending on structural similarities and information about the biosynthetic pathway from which they are derived, whenever applicable. The production of these quinone families is compared between the different genera, based on recently revised taxonomy. KEY POINTS: • Quinones represent an important group of secondary metabolites widely distributed in important fungal genera such as Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium. • Quinones are of industrial interest and can be used in pharmacology, as colorants and pigments, and as electrolytes in redox flow batteries. • Quinones are grouped into families and compared between genera according to the revised taxonomy.

Thermo-Mechanical Behavior of Poly(ether ether ketone): Experiments and Modeling.

Observations are reported on poly(ether ether ketone) (PEEK) in uniaxial tensile tests, relaxation tests and creep tests with various stresses in a wide interval of temperatures ranging from room temperature to 180 °C. Constitutive equations are developed for the thermo-mechanical behavior of PEEK under uniaxial deformation. Adjustable parameters in the governing equations are found by matching the experimental data. Good agreement is demonstrated between the observations and results of numerical simulation. It is shown that the activation energies for the elastoplastic, viscoelastic and viscoelastoplastic responses adopt similar values at temperatures above the glass transition point.

Associations of loneliness and social isolation with physical and mental health among adolescents and young adults.

AIMS: The present study investigates whether loneliness and social isolation are associated with poor physical and mental health among adolescents and young adults, and whether age and gender play a role in the associations of loneliness and social isolation with mental and physical health. METHODS: This study used cross-sectional self-report data from the 2017 Danish Health and Morbidity Surveys titled 'How are you?' (N = 19,890, M = 22.6 years). RESULTS: Logistic regression analyses showed that loneliness and social isolation were independently associated with poor physical and mental health. Loneliness was associated with increased odds of asthma, migraine, osteoarthritis, rheumatoid arthritis, hypertension, slipped disc/back pain, tinnitus, long-term mental illness, depressive symptomatology, anxiety symptomatology and alcohol problems. Social isolation was associated with decreased odds of having migraine, osteoarthritis and alcohol problems, and an increased risk of long-term mental illness and depressive symptomatology. Small age and gender differences were detected. CONCLUSIONS: In adolescents and young adults, loneliness and social isolation were associated with poor mental health and loneliness with poor physical health. These findings highlight the need for targeted prevention and intervention initiatives to alleviate loneliness and social isolation.

Modulation of the volume phase transition temperature of thermo-responsive gels.

Thermo-responsive (TR) gels swell substantially below their volume phase transition temperature Tc and shrink above this temperature. Applications of TR gels in controlled drug delivery and their use as biosensors and temperature-triggered soft actuators require fine tuning of Tc. As the critical temperature is independent of the preparation conditions and molar fractions of monomers and cross-linkers, it is modulated by incorporation of (neutral or ionic) monomers and polymer chains into pre-gel solutions for TR gels. A model is developed for the mechanical response and equilibrium swelling of TR gels. Analytical formulas are derived for the effect of molar fraction of comonomers on the volume phase transition temperature Tc in copolymer gels and gels with semi-interpenetrating networks. Adjustable parameters are found by fitting equilibrium swelling diagrams on poly(N,N-diethylacrylamide) gels. Good agreement is demonstrated between predictions of the model and experimental data.

Tension-compression asymmetry in the mechanical response of hydrogels.

Two factors play the key role in application of hydrogels as biomedical implants (for example, for replacement of damaged intervertebral discs and repair of spinal cord injuries): their stiffness and strength (measured in tensile tests) and mechanical integrity (estimated under uniaxial compression). Observations show a pronounced difference between the responses of hydrogels under tension and compression (the Young's moduli can differ by two orders of magnitude), which is conventionally referred to as the tension-compression asymmetry (TCA). A constitutive model is developed for the mechanical behavior of hydrogels, where TCA is described within the viscoplasticity theory (plastic flow is treated as sliding of junctions between chains with respect to their reference positions). The governing equations involve five material constants with transparent physical meaning. These quantities are found by fitting stress-strain diagrams under tension and compression on a number of pristine and nanocomposite hydrogels with various kinds of chemical and physical bonds between chains. Good agreement is demonstrated between the experimental data and results of simulation. The influence of volume fraction of nanoparticles, concentration of cross-links, and topology of a polymer network on material parameters is analyzed numerically.

Levels of Intestinal Inflammation and Fibrosis in Resection Specimens after Preoperative Anti-Tumor Necrosis Factor Alpha Treatment in Patients with Crohn's Disease: A Comparative Pilot Study.

BACKGROUND: Strictures are a common complication in Crohn's disease (CD), found in more than 50% of patients. They are characterized by the excessive deposition of extracellular proteins in the tissue as a result of the chronic inflammatory process. The effect of anti-tumor necrosis factor alpha (TNF-α) therapy on the development of fibrosis is not yet fully understood. AIM: To investigate whether the degree of intestinal inflammation and fibrosis is correlated with preoperative anti-TNF-α) therapy on the development of fibrosis is not yet fully understood. METHODS: This unblinded, prospective, single tertiary center, pilot cohort study included all adult patients with CD who underwent elective, laparoscopic, or open intestinal resection. Preoperative investigations included measurement of blood TNF-α) therapy on the development of fibrosis is not yet fully understood. RESULTS: Histopathological specimens from 10 patients with CD who underwent ileocecal or ileocolic resections were retrieved. Four of those patients were on anti-TNF-α) therapy on the development of fibrosis is not yet fully understood. α) therapy on the development of fibrosis is not yet fully understood. α) therapy on the development of fibrosis is not yet fully understood. p=0.01). Anti-TNF-α) therapy on the development of fibrosis is not yet fully understood. α) therapy on the development of fibrosis is not yet fully understood. α) therapy on the development of fibrosis is not yet fully understood. CONCLUSIONS: Patients who underwent preoperative anti-TNF-α treatment had a higher fibrosis score than controls.α) therapy on the development of fibrosis is not yet fully understood.

Equilibrium swelling of thermo-responsive copolymer microgels.

Thermo-responsive (TR) hydrogels with a lower critical solution temperature swell strongly at temperatures below their volume phase transition temperature T c and collapse above T c. Biomedical application of these materials requires tuning the critical temperature in a rather wide interval. A facile method for modulation of T c is to polymerize the basic monomers with hydrophilic or hydrophobic comonomers. Although the effectiveness of this method has been confirmed by experimental data, molar fractions of comonomers necessary for fine tuning of T c in macroscopic gels and microgels are unknown. A simple model is developed for the equilibrium swelling of TR copolymer gels. Its adjustable parameters are found by fitting swelling diagrams on several macro- and microgels with N-isopropylacrylamide as a basic monomer. Good agreement is demonstrated between the experimental swelling curves and results of numerical analysis. An explicit expression is derived for the volume phase transition temperature as a function of molar fraction of comonomers. The ability of this relation to predict the critical temperature is confirmed by comparison with observations.

The effect of saccharides on equilibrium swelling of thermo-responsive gels.

Mechanical and optical properties of thermo-responsive (TR) gels change drastically at their volume phase transition temperature. As the critical temperature is strongly affected by the presence of small amounts of additives in aqueous solutions, TR gels can be employed as sensors for detection and recognition of multiple analytes (from specific ions to hazardous biochemicals to pathogenic proteins) and actuators for biomedical applications. A simplified mean-field model is developed for equilibrium swelling of TR gels in aqueous solutions of additives. Its advantage is that the model involves a relatively small (compared with the conventional approaches) number of material constants and accounts for changes in the thermo-mechanical response at transition from the swollen to collapsed state. The ability of the model to describe experimental swelling diagrams and to predict the influence of additives on the equilibrium degree of swelling and the volume phase transition temperature of TR gels is confirmed by comparison of observations on poly(N-isopropylacrylamide) gel in aqueous solutions of saccharides (glucose, sucrose and galactose) with results of numerical analysis.

Closing the loop for PET, PE and PP waste from households: Influence of material properties and product design for plastic recycling.

Recycling of plastic is an important step towards circular economy. However, plastic from household waste (HHW) is a heterogeneous and contaminated resource, leading to recycled plastic with reduced quality, limiting the potential for closed-loop recycling. In addition to regulatory requirements for the chemical composition of recycled plastic, reduced physical and mechanical properties may limit the potential for closed-loop recycling. Consequently, this study analyses the thermal degradation, processability and mechanical properties of a range of reprocessed PET, PE and PP samples from source-separated plastic in HHW. On this basis, the potential for closed-loop recycling is evaluated. The study demonstrated that PET, PE and PP recycling represent different challenges. Potential degradation of the PET polymer can be reversed in a decontamination process, making PET waste well-suited for closed-loop, multiple times recycling, even when the degree of heterogeneity in the waste is high. The processability of different kinds of PE and PP packaging types varied considerably, especially for PP. Consequently, current recycling of mixed PP waste and even separate recycling of individual PP waste packaging types, will not technically facilitate recycling into new packaging products. This highlights the importance of PE and PP waste homogeneity when sent to reprocessing. Such homogeneity may be achieved through additional plastic sorting and regulatory harmonisation of product design, accounting for polymer properties and recyclability. Degradation of PP during recycling was shown to be substantial, representing another important limitation for PP recycling, necessary to address in the future.

Double-network gels with dynamic bonds under multi-cycle deformation.

Application of double-network (DN) gels with dynamic bonds as implants for repair of damaged and degenerate cartilage tissue and their use as synthetic non-degradable scaffolds for growth, proliferation and differentiation of stem cells requires understanding of the mechanical behavior of these materials under cyclic deformation. A constitutive model is developed for the viscoelastic and viscoplastic responses of DN gels with covalent and non-covalent junctions under multi-cycle loading. Viscoelasticity is treated as breakage and reformation of temporary junctions driven by thermal fluctuations. Viscoplasticity is thought of as sliding of permanent junctions with respect to their initial positions in the polymer network. Adjustable parameters in the governing equations are found by fitting observations in tensile loading-unloading tests with various maximum strains and multi-cycle tests with monotonically increasing maximum elongation ratios per cycle on two DN gels with physical junctions formed due to hydrogen bonds and ionic complexation. Numerical analysis demonstrates the ability of the model not only to describe observations correctly, but also to predict the mechanical response in multi-cycle tests with sophisticated deformation programs. Quantitative and qualitative effects of metal-coordination bonds on the mechanical behavior of supramolecular gels are revealed by simulation.

RET fusions in a small subset of advanced colorectal cancers at risk of being neglected.

Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results: RET fusions were more frequent in older patients (median age of 66 versus 60 years, P = 0.052), with ECOG PS 1-2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P = 0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

A simplified model for equilibrium and transient swelling of thermo-responsive gels.

A simplified model is developed for the elastic response of thermo-responsive gels subjected to swelling under an arbitrary deformation with finite strains. The constitutive equations involve five adjustable parameters that are determined by fitting observations in equilibrium water uptake tests and T-jump transient tests on thin gel disks. Two scenarios for water release under heating are revealed by means of numerical simulation. When the final temperature in a T-jump test is below the volume-phase transition temperature, deswelling is characterized by smooth distribution of water molecules and small tensile stresses. When the final temperature exceeds the critical temperature, a gel disk is split into three regions (central part with a high concentration of water molecules and two domains near the boundaries with low water content) separated by sharp interfaces, whose propagation is accompanied by development of large (comparable with the elastic modulus) tensile stresses.

Comparing effects of insulin analogues and human insulin on nocturnal glycaemia in hypoglycaemia-prone people with Type 1 diabetes.

AIMS: To assess the difference between analogue and human insulin with regard to nocturnal glucose profiles and risk of hypoglycaemia in people with recurrent severe hypoglycaemia. METHODS: A total of 72 people [46 men, mean ± sd age 54 ± 12 years, mean ± sd HbA1c 65 ± 12 mmol/mol (8.1 ± 1.1%), mean ± sd duration of diabetes 30 ± 14 years], who participated in a 2-year randomized, crossover trial of basal-bolus therapy with insulin detemir/insulin aspart or human NPH insulin/human regular insulin (the HypoAna trial) were studied for 2 nights during each treatment. Venous blood was drawn hourly during sleep. Primary endpoints were nocturnal glucose profiles and occurrence of hypoglycaemia (blood glucose ≤ 3.9 mmol/l). RESULTS: During insulin analogue treatment, the mean nocturnal plasma glucose level was significantly higher than during treatment with human insulin (10.6 vs 8.1 mmol/l). The fasting plasma glucose level was similar between the treatments. Nocturnal hypoglycaemia was registered during 41/101 nights (41%) in the human insulin arm and 19/117 nights (16%) in the insulin analogue arm, corresponding to a hazard ratio of 0.26 (95% CI 0.14 to 0.45; P < 0.0001) with insulin analogue. CONCLUSIONS: Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens as compared to conventional recording of hypoglycaemia.

Swelling of glucose-responsive gels functionalized with boronic acid.

A model is developed for the elastic response of a glucose-sensitive gel functionalized with boronic acid under swelling in aqueous solutions of glucose with various pH. A gel is treated as a three-phase medium composed of a solid phase (partially ionized polymer network), solvent (water), and solute (mobile glucose molecules and ions). Constitutive equations are derived by means of the free energy imbalance inequality for three-dimensional deformation with finite strains. Numerical analysis demonstrates the ability of the model to describe the effects of pH, molar fraction of glucose, and concentration of functional groups on equilibrium water uptake diagrams under unconstrained and constrained swelling.

Clinical use of the co-formulation of insulin degludec and insulin aspart.

AIMS: To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. METHODS: Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. RESULTS: In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. CONCLUSIONS: IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins.

Effect of insulin analogues on frequency of non-severe hypoglycaemia in patients with type 1 diabetes prone to severe hypoglycaemia: The HypoAna trial.

AIM: Insulin analogues reduce the risk of hypoglycaemia compared with human insulin in patients with type 1 diabetes (T1D) and minor hypoglycaemia problems. The HypoAna trial showed that, in patients with recurrent severe hypoglycaemia, treatment based on insulin analogues reduces the risk of severe hypoglycaemia. The present study aims to assess whether this also applies to non-severe hypoglycaemia events during the day and at night. METHODS: This 2-year investigator-initiated multicentre, prospective, randomized, open, blinded endpoint (PROBE) trial involved patients with T1D and at least two episodes of severe hypoglycaemia during the previous year. Using a balanced crossover design, patients were randomized to basal-bolus therapy based on analogue (detemir/aspart) or human (NPH/regular) insulins. A total of 114 participants were included. Endpoints were the number of severe hypoglycaemic events and non-severe events, including documented symptomatic and asymptomatic episodes occurring during the day and at night (ClinicalTrials.gov number: NCT00346996). RESULTS: Analogue-based treatment resulted in a 6% (2-10%; P=0.0025) overall relative risk reduction of non-severe hypoglycaemia. This was due to a 39% (32-46%; P<0.0001) reduction of non-severe nocturnal hypoglycaemia, seen for both symptomatic (48% [36-57%]; P<0.0001) and asymptomatic (28% [14-39%]; P=0.0004) nocturnal hypoglycaemia episodes. No clinically significant differences in hypoglycaemia occurrence were observed between the insulin regimens during the day. The time needed to treat one patient with insulin analogues to avoid one episode (TNT1) of non-severe nocturnal hypoglycaemia was approximately 3 months. CONCLUSION: In T1D patients prone to severe hypoglycaemia, treatment with analogue insulin reduced the risk of non-severe nocturnal hypoglycaemia compared with human insulin.

Short-term effects of liraglutide on kidney function and vasoactive hormones in type 2 diabetes: a randomized clinical trial.

AIMS: To investigate the effects of a single dose of 1.2 mg liraglutide, a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist, on key renal variables in patients with type 2 diabetes. METHODS: The study was a placebo-controlled, double-blind, crossover trial in 11 male patients with type 2 diabetes. Measurements included (51) Cr-EDTA plasma clearance estimated glomerular filtration rate (GFR) and MRI-based renal blood flow (RBF), tissue perfusion and oxygenation. RESULTS: Liraglutide had no effect on GFR [95% confidence interval (CI) -6.8 to 3.6 ml/min/1.73 m(2) ] or on RBF (95% CI -39 to 30 ml/min) and did not change local renal blood perfusion or oxygenation. The fractional excretion of lithium increased by 14% (p = 0.01) and sodium clearance tended to increase (p = 0.06). Liraglutide increased diastolic and systolic blood pressure (3 and 6 mm Hg) and heart rate (2 beats per min; all p < 0.05). Angiotensin II (ANG II) concentration decreased by 21% (p = 0.02), but there were no effects on other renin-angiotensin system components, atrial natriuretic peptides (ANPs), methanephrines or excretion of catecholamines. CONCLUSIONS: Short-term liraglutide treatment did not affect renal haemodynamics but decreased the proximal tubular sodium reabsorption. Blood pressure increased with short-term as opposed to long-term treatment. Catecholamine levels were unchanged and the results did not support a GLP-1-ANP axis. ANG II levels decreased, which may contribute to renal protection by GLP-1 receptor agonists.

What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC).

BACKGROUND: Mammary analogue secretory carcinoma (MASC) is a recently described pathologic entity. We report the case of a patient with an initial diagnosis of salivary acinic cell carcinoma later reclassified as MASC after next-generation sequencing revealed an ETV6-NTRK3 fusion. PATIENTS AND METHODS: This alteration was targeted with the pan-Trk inhibitor entrectinib (Ignyta), which possesses potent in vitro activity against cell lines containing various NTRK1/2/3 fusions. RESULTS: A dramatic and durable response was achieved with entrectinib in this patient, followed by acquired resistance that correlated with the appearance of a novel NTRK3 G623R mutation. Structural modeling predicts that this alteration sterically interferes with drug binding, correlating to decreased sensitivity to drug inhibition observed in cell-based assays. CONCLUSIONS: This first report of clinical activity with TrkC inhibition and the development of acquired resistance in an NTRK3-rearranged cancer emphasize the utility of comprehensive molecular profiling and targeted therapy for rare malignancies (NCT02097810).