Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

A Development of New Material for 4D Printing and the Material Properties Comparison between the Conventional and Stereolithography Polymerised NVCL Hydrogels

The term 4D printing refers to the idea that the shape or properties of a printed object can be changed when an external stimulus is applied. In this contribution, a temperature-responsive polymer Poly (N-vinyl caprolactam) (PNVCL), which is normally prepared via radical free polymerization, was used to justify the 4D printing concept. As a result, by using a Stereolithography (SLA) 3D printer, 4D prints were successfully prepared. These prints were able to demonstrate intelligent and reversible expansion/shrinkage behaviour as the temperature increases and decreases. Additionally, in order to examine the differences in chemical structure, thermal properties, mechanical properties, and swelling behaviours of the photopolymerised and printed parts, a series of characterisation tests, including Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), goniometry, tensile test, gel fraction measurement and pulsatile swelling study were performed on this study. In conclusion, the differences between polymerisation methods are significant; despite their chemical structures and thermal properties being similar, there were significant differences with regard to tensile properties, swellability and wettability of samples. The implications of conducting this study are remarkable, not only in providing a new way of preparing NVCL, but also in demonstrating the possibility of using 4D printed NVCL for practical applications

Lower Critical Solution Temperature Tuning and Swelling Behaviours of NVCL-Based Hydrogels for Potential 4D Printing Applications

The phase transitions of poly (N-vinyl caprolactam) (PNVCL) hydrogels are currently under investigation as possible materials for biomedical applications thanks to their thermosensitive properties. This study aims to use the photopolymerisation process to simulate the 4D printing process. NVCL-based polymers with different thermal properties and swellability were prepared to explore the possibility of synthetic hydrogels being used for 4D printing. In this contribution, the thermal behaviours of novel photopolymerised NVCL-based hydrogels were analysed. The lower critical solution temperature (LCST) of the physically crosslinked gels was detected using differential scanning calorimetry (DSC), ultraviolet (UV) spectroscopy, and cloud point measurement. The chemical structure of the xerogels was characterised by means of Fourier transform infrared spectroscopy (FTIR). Pulsatile swelling studies indicated that the hydrogels had thermo-reversible properties. As a result, the effect of varying the macromolecular monomer concentration was apparent. The phase transition temperature is increased when different concentrations of hydrophilic monomers are incorporated. The transition temperature of the hydrogels may allow for excellent flexibility in tailoring transition for specific applications, while the swelling and deswelling behaviour of the gels is strongly temperature- and monomer feed ratio-dependent

Synthesis and Characterisation of Hydrogels Based on Poly (N-Vinylcaprolactam) with Diethylene Glycol Diacrylate

Poly (N-vinylcaprolactam) is a polymer that is biocompatible, water-soluble, thermally sensitive, non-toxic, and nonionic. In this study, the preparation of hydrogels based on Poly (N-vinylcaprolactam) with diethylene glycol diacrylate is presented. The N-Vinylcaprolactam-based hydrogels are synthesised by using a photopolymerisation technique using diethylene glycol diacrylate as a crosslinking agent, and Diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide as a photoinitiator. The structure of the polymers is investigated via Attenuated Total Reflectance–Fourier Transform Infrared Spectroscopy. The polymers are further characterised using differential scanning calorimetry and swelling analysis. This study is conducted to determine the characteristics of P (N-vinylcaprolactam) with diethylene glycol diacrylate, including the addition of Vinylacetate or N-Vinylpyrrolidone, and to examine the effects on the phase transition. Although various methods of free-radical polymerisation have synthesised the homopolymer, this is the first study to report the synthesis of Poly (N-vinylcaprolactam) with diethylene glycol diacrylate by using free-radical photopolymerisation, using Diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide to initiate the reaction. FTIR analysis shows that the NVCL-based copolymers are successfully polymerised through UV photopolymerisation. DSC analysis indicates that increasing the concentration of crosslinker results in a decrease in the glass transition temperature. Swelling analysis displays that the lower the concentration of crosslinker present in the hydrogel, the quicker the hydrogels reach their maximum swelling ratio

Modulation of the Lower Critical Solution Temperature of Thermoresponsive Poly(<i>N</i>-vinylcaprolactam) Utilizing Hydrophilic and Hydrophobic Monomers

Four-dimensional printing is primarily based on the concept of 3D printing technology. However, it requires additional stimulus and stimulus-responsive materials. Poly-N-vinylcaprolactam is a temperature-sensitive polymer. Unique characteristics of poly-N-vinylcaprolactam -based hydrogels offer the possibility of employing them in 4D printing. The main aim of this study is to alter the phase transition temperature of poly-N-vinylcaprolactam hydrogels. This research focuses primarily on incorporating two additional monomers with poly-N-vinylcaprolactam: Vinylacetate and N-vinylpyrrolidone. This work contributes to this growing area of research by altering (increasing and decreasing) the lower critical solution temperature of N-vinylcaprolactam through photopolymerisation. Poly-N-vinylcaprolactam exhibits a lower critical solution temperature close to the physiological temperature range of 34–37 °C. The copolymers were analysed using various characterisation techniques, such as FTIR, DSC, and UV-spectrometry. The main findings show that the inclusion of N-vinylpyrrolidone into poly-N-vinylcaprolactam increased the lower critical solution temperature above the physiological temperature. By incorporating vinylacetate, the lower critical solution temperature dropped to 21 °C, allowing for potential self-assembly of 4D-printed objects at room temperature. In this case, altering the lower critical solution temperature of the material can potentially permit the transformation of the 4D-printed object at a particular temperature

Synthesis and characterisation of hydrogels based on poly (N-Vinylcaprolactam) with diethylene glycol diacrylate

Poly (N-vinylcaprolactam) is a polymer that is biocompatible, water-soluble, thermally sensitive, non-toxic, and nonionic. In this study, the preparation of hydrogels based on Poly (N-vinylcaprolactam) with diethylene glycol diacrylate is presented. The N-Vinylcaprolactam-based hydrogels are synthesised by using a photopolymerisation technique using diethylene glycol diacrylate as a crosslinking agent, and Diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide as a photoinitiator. The structure of the polymers is investigated via Attenuated Total Reflectance–Fourier Transform Infrared Spectroscopy. The polymers are further characterised using differential scanning calorimetry and swelling analysis. This study is conducted to determine the characteristics of P (N-vinylcaprolactam) with diethylene glycol diacrylate, including the addition of Vinylacetate or N-Vinylpyrrolidone, and to examine the effects on the phase transition. Although various methods of free-radical polymerisation have synthesised the homopolymer, this is the first study to report the synthesis of Poly (N-vinylcaprolactam) with diethylene glycol diacrylate by using free-radical photopolymerisation, using Diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide to initiate the reaction. FTIR analysis shows that the NVCL-based copolymers are successfully polymerised through UV photopolymerisation. DSC analysis indicates that increasing the concentration of crosslinker results in a decrease in the glass transition temperature. Swelling analysis displays that the lower the concentration of crosslinker present in the hydrogel, the quicker the hydrogels reach their maximum swelling ratio. </p

Evaluation of Crohn's disease activity:initial validation of a magnetic resonance enterography global score (MEGS) against faecal calprotectin

To develop an MRI enterography global score (MEGS) of Crohn's disease (CD) activity compared with a reference standard of faecal calprotectin (fC), C-reactive protein (CRP) and Harvey-Bradshaw index (HBI)

Modulation of the lower critical solution temperature of thermoresponsive poly(N-vinylcaprolactam) utilizing hydrophilic and hydrophobic monomers

 Four-dimensional printing is primarily based on the concept of 3D printing technology. However, it requires additional stimulus and stimulus-responsive materials. Poly-N-vinylcaprolactam is a temperature-sensitive polymer. Unique characteristics of poly-N-vinylcaprolactam -based hydrogels offer the possibility of employing them in 4D printing. The main aim of this study is to alter the phase transition temperature of poly-N-vinylcaprolactam hydrogels. This research focuses primarily on incorporating two additional monomers with poly-N-vinylcaprolactam: Vinylacetate and N-vinylpyrrolidone. This work contributes to this growing area of research by altering (increasing and decreasing) the lower critical solution temperature of N-vinylcaprolactam through photopolymerisation. Poly-N-vinylcaprolactam exhibits a lower critical solution temperature close to the physiological temperature range of 34–37 ◦C. The copolymers were analysed using various characterisation techniques, such as FTIR, DSC, and UV-spectrometry. The main findings show that the inclusion of N-vinylpyrrolidone into poly-N-vinylcaprolactam increased the lower critical solution temperature above the physiological temperature. By incorporating vinylacetate, the lower critical solution temperature dropped to 21 ◦C, allowing for potential self-assembly of 4D-printed objects at room temperature. In this case, altering the lower critical solution temperature of the material can potentially permit the transformation of the 4D-printed object at a particular temperature. </p

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

: Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including seven recurrent variants in 30 individuals) and six individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function of the Drosophila orthologs, U2af50 and Prp19, led to lethality, abnormal mushroom body (MB) patterning, and social deficits, differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50 deficient flies. Upon re-analysis of negative clinical exomes followed by data sharing, we further identified six NDD patients carrying RBFOX1 missense variants which, by in vitro testing, showed loss of function. Our study implicates three splicing factors as NDD causative genes and establishes a genetic network with hierarchy underlying human brain development and function