This study investigated the relationship between combat-related traumatic injury (CRTI) and its severity and predicted cardiovascular disease (CVD) risk.
This was an analysis of comparative 10-year ...predicted CVD risk (myocardial infarction, stroke or CVD-death) using the QRISK®3 scoring-system among adults recruited into the Armed Services Trauma Rehabilitation Outcome (ADVANCE) cohort study. Participants with CRTI were compared to uninjured servicemen frequency-matched by age, sex, rank, deployment (Afghanistan 2003-2014) and role. Injury severity was quantified using the New Injury Severity Score (NISS).
One thousand one hundred forty four adult combat veterans were recruited, consisting of 579 injured (161 amputees) and 565 uninjured men of similar age ethnicity and time from deployment/injury. Significant mental illness (8.5% vs 4.4%; p = 0.006) and erectile dysfunction (11.6% vs 5.8%; p < 0.001) was more common, body mass index (28.1 ± 3.9 vs 27.4 ± 3.4 kg/m
; p = 0.001) higher and systolic blood pressure variability (median IQR) (1.7 1.2-3.0 vs 2.1 1.2-3.5 mmHg; p = 0.008) lower among the injured versus uninjured respectively. The relative risk (RR) of predicted CVD (versus the population expected risk) was higher (RR:1.67 IQR 1.16-2.48) among the injured amputees versus the injured non-amputees (RR:1.60 1.13-2.43) and uninjured groups (RR:1.52 1.12-2.34; overall p = 0.015). After adjustment for confounders CRTI, worsening injury severity (higher NISS, blast and traumatic amputation) were independently associated with QRISK®3 scores.
CRTI and its worsening severity were independently associated with increased predicted 10-year CVD risk.
Summary
HIC-Vac is an international network of researchers dedicated to developing human infection challenge studies to accelerate vaccine development against pathogens of high global impact. The ...HIC-Vac Annual Meeting (3rd and 4th November 2022) brought together stakeholders including researchers, ethicists, volunteers, policymakers, industry partners, and funders with a strong representation from low- and middle-income countries. The network enables sharing of research findings, especially in endemic regions. Discussions included pandemic preparedness and the role of human challenge to accelerate vaccine development during outbreak, with industry speakers emphasising the great utility of human challenge in vaccine development. Public consent, engagement, and participation in human challenge studies were addressed, along with the role of embedded social science and empirical studies to uncover social, ethical, and regulatory issues around human infection challenge studies. Study volunteers shared their experiences and motivations for participating in studies. This report summarises completed and ongoing human challenge studies across a variety of pathogens and demographics, and addresses other key issues discussed at the meeting.
The main objective of this work was to gain novel information on the catalytic mechanism of Foot-and-Mouth Disease Virus 3C protease (FMDV 3Cpro) using ensemble and single-molecule fluorescence ...techniques. This was done to aid FMDV 3Cpro inhibitor development. FMDV is the causative agent of foot-and-mouth disease which affects cloven-hoofed animals, such as cattle and sheep, and can cause substantial losses to farmers as well as whole economies. Fluorescence anisotropy (FA) on ensemble level and fluorescence resonance energy transfer (FRET) on single-molecule level were used to probe the interactions of FMDV 3Cpro with its peptide substrates. The main focus of previous work has been on the substrate cleavage specificity of the 3Cpro. Therefore, the FA assays done here - using fluorescein-labelled and unlabelled peptide substrates - gave new insights into the substrate binding specificity of the enzyme. Single-molecule fluorescence experiments, in solution and with surface-immobilised enzyme, were done to probe the interaction of FMDV 3Cpro with FRET-labelled peptide substrates. It was demonstrated that single-molecule sensitivity could be reached, and that the peptide HiLyte488-APAKQLLC(HiLyte647)FDLLKK is a suitable FMDV 3Cpro substrate for single-molecule fluorescence experiments. Single-molecule TIRF (smTIRF) was used to look at the interaction of this FRET peptide with surface-immobilised FMDV 3Cpro, and it was shown that the enzyme retains its biological function after surface attachment. Furthermore, the smTIRF experiments yielded novel and detailed information on the catalytic mechanism of the protease, and the single-molecule data was shown to be consistent with existing ensemble results as well as ensemble fluorescence data obtained here. This work is the first demonstration of single-molecule level experiments on FMDV 3Cpro. A quick and convenient smTIRF protocol was developed, and the experiments done using this protocol yielded novel information on the mechanism of the enzyme. This information will undoubtedly be a step towards more rational FMDV 3Cpro inhibitor design.
The main objective of this work was to gain novel information on the catalytic mechanism of Foot-and-Mouth Disease Virus 3C protease (FMDV 3Cpro) using ensemble and single-molecule fluorescence ...techniques. This was done to aid FMDV 3Cpro inhibitor development. FMDV is the causative agent of foot-and-mouth disease which affects cloven-hoofed animals, such as cattle and sheep, and can cause substantial losses to farmers as well as whole economies. Fluorescence anisotropy (FA) on ensemble level and fluorescence resonance energy transfer (FRET) on single-molecule level were used to probe the interactions of FMDV 3Cpro with its peptide substrates. The main focus of previous work has been on the substrate cleavage specificity of the 3Cpro. Therefore, the FA assays done here - using fluorescein-labelled and unlabelled peptide substrates - gave new insights into the substrate binding specificity of the enzyme. Single-molecule fluorescence experiments, in solution and with surface-immobilised enzyme, were done to probe the interaction of FMDV 3Cpro with FRET-labelled peptide substrates. It was demonstrated that single-molecule sensitivity could be reached, and that the peptide HiLyte488-APAKQLLC(HiLyte647)FDLLKK is a suitable FMDV 3Cpro substrate for single-molecule fluorescence experiments. Single-molecule TIRF (smTIRF) was used to look at the interaction of this FRET peptide with surface-immobilised FMDV 3Cpro, and it was shown that the enzyme retains its biological function after surface attachment. Furthermore, the smTIRF experiments yielded novel and detailed information on the catalytic mechanism of the protease, and the single-molecule data was shown to be consistent with existing ensemble results as well as ensemble fluorescence data obtained here. This work is the first demonstration of single-molecule level experiments on FMDV 3Cpro. A quick and convenient smTIRF protocol was developed, and the experiments done using this protocol yielded novel information on the mechanism of the enzyme. This information will undoubtedly be a step towards more rational FMDV 3Cpro inhibitor design.
