National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme, and NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula.

No abstract

Nitric oxide (NO) and ornithine, products of NO synthase or arginase, respectively, have opposing biological activities. The effect of mediators of leukocyte activation and inhibition on arginine metabolism of resident mouse peritoneal exudate cells (MPEC) was determined. Factors that increased basal NO synthase activity, interferon (IFN)-gamma and lipopolysaccharide (LPS), decreased arginase activity in intact cells. Transforming growth factor (TGF)-beta1 decreased IFN-gamma-stimulated NO synthase activity and produced a reciprocal increase in urea and ornithine release. TGF-beta1 had no effect on the activity of these enzymes in LPS-stimulated MPEC. Corticosterone (Cort, 100 ng/ml) decreased the basal activity of both enzymes. However, Cort inhibited NO synthase activity and increased ornithine release in MPEC exposed to IFN-gamma or LPS. The difference between arginase activity in intact cells vs. that of cell lysates suggested intracellular inhibition of arginase activity. Products of NO synthase, NO and citrulline, were shown to inhibit MPEC arginase activity under maximal assay conditions. Intracellular pH was not altered by exposure of MPEC to LPS, IFN-gamma, TGF-beta, and Cort. This reciprocal change in arginine metabolism is proposed to be an important component of wound healing. Expression of NO synthase creates a cytotoxic environment that may be important to the early phase of wound healing. As wound healing progresses, increased arginase activity produces an environment favorable for fibroblast replication and collagen production.

The pulsed-laser polymerization (PLP) technique for determination of free radical propagation rate coefficients (kp) by gel permeation chromatography analysis has been extended to systems with rapid chain growth. A mathematical model is developed to gain a better understanding of the relative importance of propagation, termination, and transfer events on the laser-generated molecular weight distributions. Insights from the model are used to define appropriate PLP experimental conditions for vinyl acetate (VAc), for which measured kp values are an order of magnitude higher than values measured for styrene and methyl methacrylate at the same temperature. The behavior of VAc is contrasted with methyl methacrylate, both by experimental means and through simulation. Results suggest that VAc radicals not only propagate quickly but also have a higher rate of termination than methacrylate or styrene monomer systems, explaining the formation of broad, featureless molecular weight distributions under typical PLP experimental conditions. This work demonstrates the value of mathematical modeling to aid in the design of optimal PLP experiments.

In patients with normal intracranial pressure, PEEP at 5 cm H2O did not significantly alter intracranial pressure. The clinical relevance of the intracranial pressure increase at PEEP levels of 10 and 15 cm H2O is questionable because cerebral perfusion pressure did not change and remained > 60 mm Hg. In patients with increased intracranial pressure, higher levels of PEEP did not significantly change intracranial pressure or cerebral perfusion pressure.

Walsh, T. S. et al. (2016) Staff education, regular sedation and analgesia quality feedback, and a sedation monitoring technology for improving sedation and analgesia quality for critically ill, mechanically ventilated patients: a cluster randomised trial. Lancet Respiratory Medicine, 4(10), pp. 807-817. (doi:10.1016/S2213-2600(16)30178-3) This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.

BackgroundEarly identification of peripheral arterial disease (PAD) and subsequent instigation of risk modification strategies could minimise disease progression and reduce overall risk of cardiovascular (CV) mortality. However, the feasibility and value of primary care PAD screening is uncertain.AimThis study (the PIPETTE study — Peripheral arterial disease In Primary carE: Targeted screening and subsequenT managEment) aimed to determine the value of a proposed primary care PAD screening strategy. Outcomes assessed were: prevalence of PAD and agreement of ankle– brachial index (ABI)-defined PAD (ABI ≤0.9) with QRISK®2-defined high CV risk (≥20).Design and settingA cross-sectional observational study was undertaken in a large general practice in Merthyr Tydfil, Wales.MethodIn total, 1101 individuals with ≥2 pre-identified CV risk factors but no known CV disease or diabetes were invited to participate. Participants underwent ABI measurement and QRISK2 assessment, and completed Edinburgh Claudication Questionnaires.ResultsA total of 368 people participated in the study (participation rate: 33%). Prevalence of PAD was 3% (n = 12). The number needed to screen (NNS) to detect one new case of PAD was 31. Refining the study population to those aged ≥50 years with a smoking history reduced the NNS to 14, while still identifying 100% of PAD cases. Of participants with PAD, 33% reported severe lifestyle-limiting symptoms of intermittent claudication that warranted subsequent endovascular intervention, yet had not previously presented to their GP. The QRISK2 score predicted high CV risk in 92% of participants with PAD.ConclusionThe low PAD yield and the fact that QRISK2 was largely comparable to the ABI in predicting high CV risk suggests that routine PAD screening may be unwarranted. Instead, strategies to improve public awareness of PAD are needed.

Summary In a randomised cross‐over trial, midazolam, a new water soluble benzodiazepine was compared with the conventional diazepam preparation (Valium) in 34 patients aged 16—45 years who were undergoing outpatient conservation dentistry. Midazolam hydrochloride (0.17 mg/kg) was virtually free of venous complications and showed advantages over diazepam (0.32 mg/kg) in providing a faster onset of action, higher incidence of amnesia and more rapid recovery. Midazolam produced a higher incidence of respiratory side effects: hiccough (17.6% compared with 2.9%), brief apnoea following induction (11.8% compared with 5.8%), and airway obstruction during maintenance (8.8%, compared with 0%). These may be related to the greater potency of midazolam as suggested by the smaller total dose required. Cardiovascular changes and operating conditions were similar.