Experimental and Numerical study of a hydrogen fuelled I.C. engine fitted with the hydrogen assisted jet ignition system

The use of hydrogen as an engine fuel poses several challenges as well as opportunities in engine design and control. These challenges are mainly due to hydrogen's high flame temperatures at near stoichiometric mixtures, as well as the reactant volume fraction which can reduce the engine power output significantly. However, the wide flammability limits of hydrogen combustion in air means that a large part of the engine operation regime can be achieved without the use of the engine throttle or exhaust after treatment. This paper presents results of experiments and computations for a research single cylinder pressure boosted hydrogen fuelled internal combustion engine (H2ICE) fitted with the Hydrogen Assisted Jet Ignition system (HAJI) and running extremely lean mixtures

Large emergency-response exercises: qualitative characteristics - a survey

Exercises, drills, or simulations are widely used, by governments, agencies and commercial organizations, to simulate serious incidents and train staff how to respond to them. International cooperation has led to increasingly large-scale exercises, often involving hundreds or even thousands of participants in many locations. The difference between ‘large’ and ‘small’ exercises is more than one of size: (a) Large exercises are more ‘experiential’ and more likely to undermine any model of reality that single organizations may create; (b) they create a ‘play space’ in which organizations and individuals act out their own needs and identifications, and a ritual with strong social implications; (c) group-analytic psychotherapy suggests that the emotions aroused in a large group may be stronger and more difficult to control. Feelings are an unacknowledged major factor in the success or failure of exercises; (d) successful large exercises help improve the nature of trust between individuals and the organizations they represent, changing it from a situational trust to a personal trust; (e) it is more difficult to learn from large exercises or to apply the lessons identified; (f) however, large exercises can help develop organizations and individuals. Exercises (and simulation in general) need to be approached from a broader multidisciplinary direction if their full potential is to be realized

Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding Mode.

With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations

A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066

Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors.This work was funded by the Wellcome Trust Strategic (090340/Z/09/Z) and Pathfinder (107714/Z/15/Z) Awards. The Spring lab acknowledges support from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no [279337/DOS]. In addition, the group research was supported by grants from the Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council, Royal Society and Welcome Trust

Supplementary data for article: Trmčić, M.; Chadbourne, F. L.; Brear, P. M.; Denny, P. W.; Cobb, S. L.; Hodgson, D. R. W. Aqueous Synthesis of N,S-Dialkylthiophosphoramidates: Design, Optimisation and Application to Library Construction and Antileishmanial Testing. Organic and Biomolecular Chemistry 2013, 11 (16), 2660–2675. https://doi.org/10.1039/c3ob27448a

Supplementary material for: [https://doi.org/10.1039/c3ob27448a]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1620]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/2821

The Medicago truncatula Vacuolar iron Transporter-Like proteins VTL4 and VTL8 deliver iron to rhizobium bacteria at different stages of the infection process

The symbiotic relationship between legumes and rhizobium bacteria in root nodules has a high demand for iron, and questions remain regarding which transporters are involved. Here, we characterize two nodule-specific Vacuolar iron Transporter-Like (VTL) proteins in Medicago truncatula. Localization of fluorescent fusion proteins and mutant studies were carried out to correlate with existing RNA-seq data showing differential expression of VTL4 and VTL8 during early and late infection, respectively. The vtl4 insertion lines showed decreased nitrogen fixation capacity associated with more immature nodules and less elongated bacteroids. A mutant line lacking the tandemly-arranged VTL4–VTL8 genes, named 13U, was unable to develop functional nodules and failed to fix nitrogen, which was almost fully restored by expression of VTL8 alone. Using a newly developed lux reporter to monitor iron status of the bacteroids, a moderate decrease in luminescence signal was observed in vtl4 mutant nodules and a strong decrease in 13U nodules. Iron transport capability of VTL4 and VTL8 was shown by yeast complementation. These data indicate that VTL8, the closest homologue of SEN1 in Lotus japonicus, is the main route for delivering iron to symbiotic rhizobia. We propose that a failure in iron protein maturation leads to early senescence of the bacteroids

Incisional hernia following colorectal cancer surgery according to suture technique: Hughes Abdominal Repair Randomized Trial (HART).

BACKGROUND: Incisional hernias cause morbidity and may require further surgery. HART (Hughes Abdominal Repair Trial) assessed the effect of an alternative suture method on the incidence of incisional hernia following colorectal cancer surgery. METHODS: A pragmatic multicentre single-blind RCT allocated patients undergoing midline incision for colorectal cancer to either Hughes closure (double far-near-near-far sutures of 1 nylon suture at 2-cm intervals along the fascia combined with conventional mass closure) or the surgeon's standard closure. The primary outcome was the incidence of incisional hernia at 1 year assessed by clinical examination. An intention-to-treat analysis was performed. RESULTS: Between August 2014 and February 2018, 802 patients were randomized to either Hughes closure (401) or the standard mass closure group (401). At 1 year after surgery, 672 patients (83.7 per cent) were included in the primary outcome analysis; 50 of 339 patients (14.8 per cent) in the Hughes group and 57 of 333 (17.1 per cent) in the standard closure group had incisional hernia (OR 0.84, 95 per cent c.i. 0.55 to 1.27; P = 0.402). At 2 years, 78 patients (28.7 per cent) in the Hughes repair group and 84 (31.8 per cent) in the standard closure group had incisional hernia (OR 0.86, 0.59 to 1.25; P = 0.429). Adverse events were similar in the two groups, apart from the rate of surgical-site infection, which was higher in the Hughes group (13.2 versus 7.7 per cent; OR 1.82, 1.14 to 2.91; P = 0.011). CONCLUSION: The incidence of incisional hernia after colorectal cancer surgery is high. There was no statistical difference in incidence between Hughes closure and mass closure at 1 or 2 years. REGISTRATION NUMBER: ISRCTN25616490 (http://www.controlled-trials.com)

Action to protect the independence and integrity of global health research

Storeng KT, Abimbola S, Balabanova D, et al. Action to protect the independence and integrity of global health research. BMJ GLOBAL HEALTH. 2019;4(3): e001746

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

Determinants of recovery from post-COVID-19 dyspnoea: analysis of UK prospective cohorts of hospitalised COVID-19 patients and community-based controls

Background The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders