All-cause mortality in patients with diabetes under glucagon-like peptide-1 agonists: A population-based, open cohort study.

AIM: The glucagon-like peptide-1 receptor agonist (GLP1a) liraglutide has been described to benefit patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk. However, there are still uncertainties relating to these cardiovascular benefits: whether they also apply to an unselected diabetic population that includes low-risk patients, represent a class-effect, and could be observed in a real-world setting. METHODS: We conducted a population-based, retrospective open cohort study using data derived from The Health Improvement Network database between Jan 2008 to Sept 2015. Patients with T2DM exposed to GLP1a (n=8345) were compared to age, gender, body mass index, duration of T2DM and smoking status-matched patients with T2DM unexposed to GLP1a (n=16,541). RESULTS: Patients with diabetes receiving GLP1a were significantly less likely to die from any cause compared to matched control patients with diabetes (adjusted incidence rate ratio [aIRR]: 0.64, 95% CI: 0.56-0.74, P-value<0.0001). Similar findings were observed in low-risk patients (aIRR: 0.64, 95% CI: 0.53-0.76, P -value=0.0001). No significant difference in the risk of incident CVD was detected in the low-risk patients (aIRR: 0.93, 95% CI: 0.83-1.12). Subgroup analyses suggested that effect is persistent in the elderly or across glycated haemoglobin categories. CONCLUSIONS: GLP1a treatment in a real-world setting may confer additional mortality benefit in patients with T2DM irrespective of their baseline CVD risk, age or baseline glycated haemoglobin and was sustained over the observation period.

Cervical screening programmes: can automation help? Evidence from systematic reviews, an economic analysis and a simulation modelling exercise applied to the UK.

OBJECTIVES: To assess the effectiveness and cost-effectiveness of adding automated image analysis to cervical screening programmes. DATA SOURCES: Searching of all major electronic databases to the end of 2000 was supplemented by a detailed survey for unpublished UK literature. METHOD: Four systematic reviews were conducted according to recognised guidance. The review of 'clinical effectiveness' included studies assessing reproducibility and impact on health outcomes and processes in addition to evaluations of test accuracy. A discrete event simulation model was developed, although the economic evaluation ultimately relied on a cost-minimisation analysis. RESULTS: The predominant finding from the systematic reviews was the very limited amount of rigorous primary research. None of the included studies refers to the only commercially available automated image analysis device in 2002, the AutoPap Guided Screening (GS) System. The results of the included studies were debatably most compatible with automated image analysis being equivalent in test performance to manual screening. Concerning process, there was evidence that automation does lead to reductions in average slide processing times. In the PRISMATIC trial this was reduced from 10.4 to 3.9 minutes, a statistically significant and practically important difference. The economic evaluation tentatively suggested that the AutoPap GS System may be efficient. The key proviso is that credible data become available to support that the AutoPap GS System has test performance and processing times equivalent to those obtained for PAPNET. CONCLUSIONS: The available evidence is still insufficient to recommend implementation of automated image analysis systems. The priority for action remains further research, particularly the 'clinical effectiveness' of the AutoPap GS System. Assessing the cost-effectiveness of introducing automation alongside other approaches is also a priority.

Effect of femoral fracture and intramedullary fixation on lung capillary leak.

BACKGROUND: Pulmonary injury is an important complication in the trauma patient with long-bone fractures. The purpose of this study was to determine the effect of femoral fracture or fracture and intramedullary fixation on lung capillary leak. The contribution of leukocytes to lung injury in this model was also determined. METHODS: The pulmonary capillary filtration coefficient was determined in lungs of rats after femur fracture or fracture and reamed or unreamed intramedullary fixation. Pulmonary arterial vascular resistance and lung neutrophil content were also determined. RESULTS: Fracture alone did not cause lung injury, whereas fracture and intramedullary fixation elicited lung capillary leak. Fracture alone and intramedullary fixation increased pulmonary vascular resistance, whereas unreamed intramedullary fixation caused lung leukosequestration. CONCLUSION: Femoral fracture alone does not cause an increase in pulmonary microvascular permeability. Femoral fracture and intramedullary fixation causes lung capillary leak, which is not increased by reaming the femoral canal.

Aspiration of activated charcoal elicits an increase in lung microvascular permeability.

BACKGROUND: Gastric decontamination with orally administered activated charcoal is the recommended treatment for many poisonings. However, ingestion of central nervous system depressants resulting in loss of protective airway reflexes may result in pulmonary aspiration of activated charcoal. Although activated charcoal has been reported to be an inert substance, evidence suggests that pulmonary aspiration of charcoal is associated with lung edema formation and pulmonary compromise. This study tested the hypothesis that intratracheal instillation of activated charcoal disrupts the integrity of the lung microvascular barrier. METHODS: The capillary filtration coefficient (Kf,c), a sensitive measure of lung microvascular permeability, was determined isogravimetrically prior to and after intratracheal instillation of activated charcoal 0.04 g/kg (12% weight/vol solution, pH 7.4) or an equal volume of sterile water in isolated, perfused rat lungs. Arterial blood gas analysis was determined prior to and after tracheal instillation of activated charcoal or sterile water in a separate group of animals. RESULTS: Intratracheal instillation of activated charcoal resulted in a significant increase in pulmonary microvascular permeability compared to lungs treated with sterile water or control lungs (delta Kf,c = +0.21 +/- 0.076; -0.014 +/- 0.04; and -0.041 +/- 0.02 mL/min/cm H2O/100 g lung tissue, respectively, p < 0.05 ANOVA). There was no significant difference in baseline blood gases in the 3 experimental groups. There was a significant decrease in arterial Po2, bicarbonate, and pH in animals administered activated charcoal compared to time-matched controls and animals administered sterile water. CONCLUSIONS: Intratracheal instillation of activated charcoal is associated with a significant increase in lung microvascular permeability and arterial blood gas derangements. The effects of activated charcoal on pulmonary microvascular barrier integrity may contribute to the lung edema formation and pulmonary compromise observed following clinical aspiration of activated charcoal.

Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins.

Intestinal ischemia-reperfusion (I-R) is associated with lung injury and the acute respiratory distress syndrome. The hypothesis of this study was that intestinal I-R activates circulating neutrophils to promote elastase-mediated lung injury. Isolated rat lungs were perfused with blood or plasma obtained after intestinal I-R, and lung neutrophil retention and injury and bronchoalveolar lavage (BAL) elastase were measured. Perfusion with I-R blood caused lung neutrophil accumulation and injury and increased BAL elastase. These effects were attenuated by the elastase inhibitor L-658758. Interference with neutrophil adherence before gut reperfusion blocked BAL elastase accumulation. The role of endothelial junction proteins (cadherins) in I-R-elicited lung damage was also evaluated. Activated human neutrophils proteolyzed cadherins in human umbilical vein endothelial cells. Furthermore, plasma of patients with acute respiratory distress syndrome contained soluble cadherin fragments. The results of this study suggest that the elastase released by systemically activated neutrophils contributes to lung neutrophil accumulation and pulmonary microvascular injury. Elastase-mediated proteolysis of endothelial cell cadherins may represent the mechanism through which lung microvascular integrity is disrupted after intestinal I-R.

An experimental study of lumbar destabilization. Restabilization and bone density.

STUDY DESIGN: An investigation of the effects of bone density on lumbar spine stability using destabilizing and restabilizing procedures. OBJECTIVES: To measure cadaveric vertebral bone densities computed tomographic scans and to correlate the measured densities with lumbar spine stability in the intact and during sequential destabilization and restabilization. SUMMARY OF BACKGROUND DATA: The stabilizing effects of lumbar pedicle screw fixation have been widely described. Numerous construct failure mechanisms have been observed, including screw loosening in osteoporosis. Although previous studies have analyzed the effect of bone density on the compression strength of bone similar to that used in interbody fusion and the relationship of pedicle screw pull-out strength to vertebral bone density, a combined study of bone density and construct stability using an interbody bone spacer with pedicle fixation has not been performed. METHODS: Bone densities were measured in 20 human cadaveric lumbar spines using computed tomography scans and a hydroxyapatite phantom. After the specimens were mounted in a testing frame, the L4-L5 motion segments were subjected to cyclic axial compression-torsional loads, and axial and rotational intervertebral displacements were monitored. Laminectomy, facetectomy, and pedicle screw-plate fixation were performed sequentially in three specimens. Ten others underwent these procedures with an additional destabilization procedure, discectomy, after facetectomy. Seven others underwent the same sequence as the previous group, followed by the insertion of interbody bone. Cyclic testing was resumed after each procedure. RESULTS: Average bone densities varied widely among the specimens. Average bone densities of the pedicle and of the vertebral body for individual specimens were well-correlated (r = 0.897). Displacements were recorded as a percentage of the intact state before destabilization; average percentages are reported as follows: axial displacements increased after facetectomy (145%) and subsequent discectomy (251%), and rotational displacements increased after facetectomy (295%) and discectomy (390%). Instrumentation without interbody bone resulted in specimens with decreased axial (126%) and rotational (156%) displacements. The addition of interbody bone further decreased axial (111%) and rotational (117%) displacements. The rotational stabilization provided by instrumentation was well-correlated with vertebral bone density (r = 0.804). This correlation was enhanced by the use of interbody bone (r = 0.939). CONCLUSION: The unstable lumbar spine can be partially stabilized using fixation. Interbody bone provides additional stability. The immediate stability provided by pedicle screws is greater in lumbar vertebrae with higher bone density.

Complement-mediated lung injury and neutrophil retention after intestinal ischemia-reperfusion.

Complement-mediated neutrophil activation appears to play an important role in ischemia-reperfusion (I/R) injury in a variety of tissues, including the heart, lung, and small bowel. The objective of this study was to determine whether inhibition of the alternative and classic complement cascades by administration of soluble complement receptor 1 (sCR1) prevents the increased neutrophil stiffness, lung neutrophil retention, and pulmonary microvascular injury elicited by a systemic inflammatory insult. Isolated lungs were perfused with blood obtained from animals subjected to 2 h of intestinal ischemia and 20 min of reperfusion (I/R) or control (nonischemic) surgery. Intestinal I/R resulted in a significant increase in neutrophil stiffness, lung neutrophil retention, and increased pulmonary microvascular permeability, effects that were prevented by administration of sCR1 before intestinal reperfusion. The results of this study suggest that I/R injury in the gut is a potent systemic inflammatory stimulus that induces complement-mediated neutrophil stiffness, lung neutrophil entrapment, and pulmonary microvascular dysfunction.

Lack of weight gain of sheep following iodine supplementation in inland regions of the South Island.

Weight gain response to iodine supplementation was investigated in five groups of sheep in different seasons. In only one spring period in one trial was a significant response obtained.