Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

Background: Evidence of the impact of in utero exposure to anti-tumor necrosis factor (TNF)-alpha on long-term childhood development is limited. The aim was to assess the impact of in utero exposure to anti-TNF-alpha due to mothers' inflammatory bowel disease (IBD) on longterm postnatal development of exposed children. Methods: We included consecutive children (≥12 months of age) born to mothers with IBD (2007-2016) treated with anti-TNF-alpha during pregnancy in 3 centers in the Czech Republic. A control group was comprised of unexposed children of non-IBD mothers undergoing mandatory checkups at general pediatricians' offices. Data on perinatal period, psychomotor development, vaccination, infections, antibiotics, and allergy were collected by treating pediatricians using a predefined questionnaire. Results: Seventy-two exposed and 69 unexposed children were included (median age, 35 and 50 months, respectively). Exposed children had growth and psychomotor development similar to controls. There was no significant difference in infectious complications within the first year of life (23.9% vs 17.4%; P = 0.36) or during the whole follow-up between exposed infants and controls (P = 0.32). Concomitant immunosuppressants during pregnancy and anti-TNF-alpha levels in cord blood were not associated with elevated infection rate within the first year of life (P > 0.05). Over 95% of exposed children had adequate serologic response to vaccination, except for haemophilus and mumps vaccines. Clinically manifested allergy was similar between the groups (P = 0.98). Conclusions: Anti-TNF-alpha exposure in utero does not seem to have a negative impact on postnatal development of children with regard to infectious complications, allergy, growth, or psychomotor development when compared with unexposed children of non-IBD women.

Biodegradable nanofibers are extensively employed in different areas of biology and medicine, particularly in tissue engineering. The electrospun polycaprolactone (PCL) nanofibers are attracting growing interest due to their good mechanical properties and a low-cost structure similar to the extracellular matrix. However, the unmodified PCL nanofibers exhibit an inert surface, hindering cell adhesion and negatively affecting their further fate. The employment of PCL nanofibrous scaffolds for wound healing requires a certain modification of the PCL surface. In this work, the morphology of PCL nanofibers is optimized by the careful tuning of electrospinning parameters. It is shown that the modification of the PCL nanofibers with the COOH plasma polymers and the subsequent binding of NH2 groups of protein molecules is a rather simple and technologically accessible procedure allowing the adhesion, early spreading, and growth of human fibroblasts to be boosted. The behavior of fibroblasts on the modified PCL surface was found to be very different when compared to the previously studied cultivation of mesenchymal stem cells on the PCL nanofibrous meshes. It is demonstrated by X-ray photoelectron spectroscopy (XPS) that the freeze–thawed platelet-rich plasma (PRP) immobilization can be performed via covalent and non-covalent bonding and that it does not affect biological activity. The covalently bound components of PRP considerably reduce the fibroblast apoptosis and increase the cell proliferation in comparison to the unmodified PCL nanofibers or the PCL nanofibers with non-covalent bonding of PRP. The reported research findings reveal the potential of PCL matrices for application in tissue engineering, while the plasma modification with COOH groups and their subsequent covalent binding with proteins expand this potential even further. The use of such matrices with covalently immobilized PRP for wound healing leads to prolonged biological activity of the immobilized molecules and protects these biomolecules from the aggressive media of the wound.

Abstract:The scaffolds made of polycaprolactone (PCL) are actively employed in different areas of biology and medicine, especially in tissue engineering. However, the usage of unmodified PCL is significantly restricted by the hydrophobicity of its surface, due to the fact that its inert surface hinders the adhesion of cells and the cell interactions on PCL surface. In this work, the surface of PCL nanofibers is modified by Ar/CO 2 /C 2 H 4 plasma depositing active COOH groups in the amount of 0.57 at % that were later used for the immobilization of platelet-rich plasma (PRP). The modification of PCL nanofibers significantly enhances the viability and proliferation (by hundred times) of human mesenchymal stem cells, and decreases apoptotic cell death to a normal level. According to X-ray photoelectron spectroscopy (XPS), after immobilization of PRP, up to 10.7 at % of nitrogen was incorporated into the nanofibers surface confirming the grafting of proteins. Active proliferation and sustaining the cell viability on nanofibers with immobilized PRP led to an average number of cells of 258 ± 12.9 and 364 ± 34.5 for nanofibers with ionic and covalent bonding of PRP, respectively. Hence, our new method for the modification of PCL nanofibers with PRP opens new possibilities for its application in tissue engineering.

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In somatotroph pituitary tumours, somatostatin analogue (SSA) therapy outcomes vary throughout the studies. We performed an analysis of cohort of patients with acromegaly from the Czech registry to identify new prognostic and predictive factors. Clinical data of patients were collected, and complex immunohistochemical assessment of tumour samples was performed (SSTR1‐5, dopamine D2 receptor, E‐cadherin, AIP). The study included 110 patients. In 31, SSA treatment outcome was evaluated. Sparsely granulated tumours (SGST) differed from the other subtypes in expression of SSTR2A, SSTR3, SSTR5 and E‐cadherin and occurred more often in young. No other clinical differences were observed. Trouillas grading system showed association with age, tumour size and SSTR2A expression. Factors significantly associated with SSA treatment outcome included age, IGF1 levels, tumour size and expression of E‐cadherin and SSTR2A. In the group of SGST, poor SSA response was observed in younger patients with larger tumours, lower levels of SSTR2A and higher Ki67. We observed no relationship with expression of other proteins including AIP. No predictive value of E‐cadherin was observed when tumour subtype was considered. Multiple additional factors apart from SSTR2A expression can predict treatment outcome in patients with acromegaly.

Biodegradable composite nanofibers were electrospun from poly(ε-caprolactone) (PCL) and poly(ethylene oxide) (PEO) mixtures dissolved in acetic and formic acids. The variation of PCL:PEO concentration in the polymer blend, from 5:95 to 75:25, revealed the tunability of the hydrolytic stability and mechanical properties of the nanofibrous mats. The degradation rate of PCL/PEO nanofibers can be increased compared to pure PCL, and the mechanical properties can be improved compared to pure PEO. Although PCL and PEO have been previously reported as immiscible, the electrospinning into nanofibers having restricted dimensions (250–450 nm) led to a microscopically mixed PCL/PEO blend. However, the hydrolytic stability and tensile tests revealed the segregation of PCL into few-nanometers-thin fibrils in the PEO matrix of each nanofiber. A synergy phenomenon of increased stiffness appeared for the high concentration of PCL in PCL/PEO nanofibrous mats. The pure PCL and PEO mats had a Young’s modulus of about 12 MPa, but the mats made of high concentration PCL in PCL/PEO solution exhibited 2.5-fold higher values. The increase in the PEO content led to faster degradation of mats in water and up to a 20-fold decrease in the nanofibers’ ductility. The surface of the PCL/PEO nanofibers was functionalized by an amine plasma polymer thin film that is known to increase the hydrophilicity and attach proteins efficiently to the surface. The combination of different PCL/PEO blends and amine plasma polymer coating enabled us to tune the surface functionality, the hydrolytic stability, and the mechanical properties of biodegradable nanofibrous mats.

Taken together, human RBCs express low but significant amounts of PrP(C) /cell, which makes them, due to high RBC numbers, major contributors to the pool of cell-associated PrP(C) in blood. Previous reports utilizing MoAb 3F4 may have underestimated the amount of PrP(C) in RBCs. Likewise, screening tests for the presence of the abnormal prion protein in blood may be difficult if the abnormal protein is modified similar to RBC PrP(C).