Christopher L. Skelly

Flying-fox species density--a spatial risk factor for Hendra virus infection in horses in eastern Australia.

Hendra virus causes sporadic but typically fatal infection in horses and humans in eastern Australia. Fruit-bats of the genus Pteropus (commonly known as flying-foxes) are the natural host of the virus, and the putative source of infection in horses; infected horses are the source of human infection. Effective treatment is lacking in both horses and humans, and notwithstanding the recent availability of a vaccine for horses, exposure risk mitigation remains an important infection control strategy. This study sought to inform risk mitigation by identifying spatial and environmental risk factors for equine infection using multiple analytical approaches to investigate the relationship between plausible variables and reported Hendra virus infection in horses. Spatial autocorrelation (Global Moran’s I) showed significant clustering of equine cases at a distance of 40 km, a distance consistent with the foraging ‘footprint’ of a flying-fox roost, suggesting the latter as a biologically plausible basis for the clustering. Getis-Ord Gi* analysis identified multiple equine infection hot spots along the eastern Australia coast from far north Queensland to central New South Wales, with the largest extending for nearly 300 km from southern Queensland to northern New South Wales. Geographically weighted regression (GWR) showed the density of P. alecto and P. conspicillatus to have the strongest positive correlation with equine case locations, suggesting these species are more likely a source of infection of Hendra virus for horses than P. poliocephalus or P. scapulatus. The density of horses, climate variables and vegetation variables were not found to be a significant risk factors, but the residuals from the GWR suggest that additional unidentified risk factors exist at the property level. Further investigations and comparisons between case and control properties are needed to identify these local risk factors.

Leptospirosis in American Samoa 2010: epidemiology, environmental drivers, and the management of emergence.

Leptospirosis has recently been reported as an emerging disease worldwide, and a seroprevalence study was undertaken in American Samoa to better understand the drivers of transmission. Antibodies indicative of previous exposure to leptospirosis were found in 15.5% of 807 participants, predominantly against three serovars that were not previously known to occur in American Samoa. Questionnaires and geographic information systems data were used to assess behavioral factors and environmental determinants of disease transmission, and logistic regression was used to identify factors associated with infection. Many statistically significant factors were consistent with previous studies, but we also showed a significant association with living at lower altitudes (odds ratio [OR] = 1.53, 95% confidence interval [CI]: 1.03-2.28), and having higher numbers of piggeries around the home (OR = 2.63, 95% CI: 1.52-4.40). Our findings support a multifaceted approach to combating the emergence of leptospirosis, including modification of individual behavior, but importantly also managing the evolving environmental drivers of risk.

Reappraisal of velocity criteria for carotid bulb/internal carotid artery stenosis utilizing high-resolution B-mode ultrasound validated with computed tomography angiography

OBJECTIVE Reliability of the most commonly used duplex ultrasound (DUS) velocity thresholds for internal carotid artery (ICA) stenosis has been questioned since these thresholds were developed using less precise methods to grade stenosis severity based on angiography. In this study, maximum percent diameter carotid bulb ICA stenosis (European Carotid Surgery Trial [ECST] method) was objectively measured using high resolution B-mode DUS validated with computed tomography angiography (CTA) and used to determine optimum velocity thresholds for > or =50% and > or =80% bulb internal carotid artery stenosis (ICA). METHODS B-mode DUS and CTA images of 74 bulb ICA stenoses were compared to validate accuracy of the DUS measurements. In 337 mild, moderate, and severe bulb ICA stenoses (n = 232 patients), the minimal residual lumen and the maximum outer bulb/proximal ICA diameter were determined on longitudinal and transverse images. This in contrast to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method using normal distal ICA lumen diameter as the denominator. Severe calcified carotid segments and patients with contralateral occlusion were excluded. In each study, the highest peak systolic (PSV) and end-diastolic (EDV) velocities as well as ICA/common carotid artery (CCA) ratio were recorded. Using receiver operating characteristic (ROC) analysis, the optimum threshold for each hemodynamic parameter was determined to predict > or =50% (n = 281) and > or =80% (n = 62) bulb ICA stenosis. RESULTS Patients mean age was 74 +/- 8 years; 49% females. Clinical risk factors for atherosclerosis included coronary artery disease (40%), diabetes mellitus (32%), hypertension (70%), smoking (34%), and hypercholesterolemia (49%). Thirty-three percent of carotid lesions (n = 110) presented with ischemic cerebrovascular symptoms and 67% (n = 227) were asymptomatic. There was an excellent agreement between B-mode DUS and CTA (r = 0.9, P = .002). The inter/intraobserver agreement (kappa) for B-mode imaging measurements were 0.8 and 0.9, respectively, and for CTA measurements 0.8 and 0.9, respectively. When both PSV of > or =155 cm/s and ICA/CCA ratio of > or =2 were combined for the detection of > or =50% bulb ICA stenosis, a positive predictive value (PPV) of 97% and an accuracy of 82% were obtained. For a > or =80% bulb ICA stenosis, an EDV of > or =140 cm/s, a PSV of > or =370 cm/s and an ICA/CCA ratio of > or =6 had acceptable probability values. CONCLUSION Compared with established velocity thresholds commonly applied in practice, a substantially higher PSV (155 vs 125 cm/s) was more accurate for detecting > or =50% bulb/ICA stenosis. In combination, a PSV of > or =155 cm/s and an ICA/CCA ratio of > or =2 have excellent predictive value for this stenosis category. For > or =80% bulb ICA stenosis (NASCET 60% stenosis), an EDV of 140 cm/s, a PSV of > or =370 cm/s, and an ICA/CCA ratio of > or =6 are equally reliable and do not indicate any major change from the established criteria. Current DUS > or =50% bulb ICA stenosis criteria appear to overestimate carotid bifurcation disease and may predispose patients with asymptomatic carotid disease to untoward costly diagnostic imaging and intervention.

Evaluation and Treatment of Suspected Type II Endoleaks in Patients with Enlarging Abdominal Aortic Aneurysms

PURPOSE To evaluate angiographic diagnosis and embolotherapy of patients with enlarging abdominal aortic aneurysms and computed tomographic (CT) diagnosis of type II endoleak. MATERIALS AND METHODS A retrospective review was performed of all patients referred to a single vascular and interventional radiology section from January 1, 2003, to June 1, 2011, with a diagnosis of enlarging aneurysm and type II endoleak. Twenty-five patients underwent 40 procedures between 12 and 82 months after endograft insertion (mean, 48 mo) for diagnosis and/or treatment of endoleaks. RESULTS Type II endoleaks were treated with cyanoacrylate, coils, and ethylene vinyl alcohol copolymer in 16 patients. Technical success rate was 88% (14 of 16 patients) and clinical success rate was 100% (16 of 16 patients). Aneurysm growth was arrested in all cases over a mean follow-up of 27.5 months (range, 6-88 mo). Endoleaks in nine patients were misclassified on CT; two had type I endoleaks and seven had type III endoleaks. Four of the nine patients (two type I endoleaks and two type III endoleaks) were correctly classified after initial angiography. The other five type III endoleaks were correctly classified on CT after coil embolization of the inferior mesenteric artery. Direct embolization was performed via sac puncture with ethylene vinyl alcohol copolymer in two of the latter five patients and eliminated endoleaks in both. CONCLUSIONS Aneurysm growth caused by type II endoleaks was arrested by embolization. CT misclassification occurred relatively commonly; type III endoleaks purported to be type II endoleaks were found in 28% of patients (seven of 25).

Coal seam gas water: potential hazards and exposure pathways in Queensland

The extraction of coal seam gas (CSG) produces large volumes of potentially contaminated water. It has raised concerns about the environmental health impacts of the co-produced CSG water. In this paper, we review CSG water contaminants and their potential health effects in the context of exposure pathways in Queensland’s CSG basins. The hazardous substances associated with CSG water in Queensland include fluoride, boron, lead and benzene. The exposure pathways for CSG water are (1) water used for municipal purposes; (2) recreational water activities in rivers; (3) occupational exposures; (4) water extracted from contaminated aquifers; and (5) indirect exposure through the food chain. We recommend mapping of exposure pathways into communities in CSG regions to determine the potentially exposed populations in Queensland. Future efforts to monitor chemicals of concern and consolidate them into a central database will build the necessary capability to undertake a much needed environmental health impact assessment.

Diurnal heart rate reactivity: A predictor of severity of experimental coronary and carotid atherosclerosis

BACKGROUND Elevated awake resting heart rate (HR) has been shown to be a major risk factor for cardiovascular disease. Since coronary ischaemic events appear to peak during transition from sleep to awake HR, we sought to determine whether the degree of diurnal HR fluctuation (dHRV) is an independent predictor of coronary and peripheral atherogenesis. In this study, we varied both baseline HR and dHRV using sino-atrial node ablation (SNA) in a primate model of diet-induced atherogenesis and determined the degree of plaque formation relative to both HR parameters. METHODS HR was recorded continuously for 6 months by an implantable intraaortic sensor/transmitter in 17 active unrestricted male cynomolgus monkeys. In nine monkeys, SNA was employed to create a wide spectrum of dHRV, and the power amplitude of dHRV was determined for the daily HRV cycle with power spectral analysis. After a 6-month diet induction period, percent coronary and carotid stenosis, intimal thickness and area were quantitated in each animal. RESULTS Total serum cholesterol and mean HR were no different between high ( n= 10) and low ( n= 7) dHRV groups (866 mg% vs. 740 mg%, P> 0.2 and 130 +/- 22 and 115 +/- 13, P> 0.1, respectively). Percent carotid stenosis was markedly greater in both high HR and dHRV animals ([HR], 54 +/- 19 vs. 35 +/- 10, P< 0.04) and ([dHRV], 54 +/- 17 vs. 32 +/- 10, P< 0.01). Significant increases in all measures of coronary atherogenesis were found in high dHRV animals when compared with those with low dHRV (percent stenosis: 48% +/- 22 vs. 23% +/- 16, P< 0.02), (lesion area: 1.2 +/- 0.8 vs. 0.3 +/- 0.3, P< 0.02), and (intimal thickness: 0.3 +/- 0.1 vs. 0.1 +/- 0.1, P< 0.01), respectively. While there was a trend towards greater coronary atherogenesis in animals with high HR, this did not reach statistical significance. CONCLUSION Elevated HR and dHRV are both associated with enhanced experimental atherosclerotic plaque formation. However, a greater degree of carotid and coronary atherogenesis is observed in animals with high dHRV. These findings suggest that elevated dHRV is a stronger predictor for susceptibility to atherogenesis than elevated HR alone. Such a relationship may be attributed to the potential role of dHRV in modulating the frequency of adverse near wall haemodynamic forces, which have been shown to induce atherosclerotic plaques. Lowering of dHRV in humans by exercise or pharmacological agents may have a beneficial role in retarding atherosclerotic plaque induction, progression and complication.

Prevention of restenosis by a herpes simplex virus mutant capable of controlled long-term expression in vascular tissue in vivo.

Neointimal hyperplasia resulting from vascular smooth muscle cell (SMC) proliferation and luminal migration is the major cause of autologous vein graft failure following vascular coronary or peripheral bypass surgery. Strategies to attenuate SMC proliferation by the delivery of oligonucleotides or genes controlling cell division rely on the use of high concentrations of vectors, and require pre-emptive disruption of the endothelial cell layer. We report a genetically engineered herpes simplex virus (HSV-1) mutant that, in an in vivo rabbit model system, infects all vascular layers without prior injury to the endothelium; expresses a reporter gene driven by a viral promoter with high efficiency for at least 4 weeks; exhibits no systemic toxicity; can be eliminated at will by administration of the antiviral drug acyclovir; and significantly reduces SMC proliferation and restenosis in vein grafts in immunocompetent hosts.

Attenuated herpes simplex virus 1 blocks arterial apoptosis and intimal hyperplasia induced by balloon angioplasty and reduced blood flow

Injury caused by distention of the arterial wall by balloon angioplasty can result in apoptosis and vascular smooth muscle cell proliferation. Here, we report that a brief exposure of the arterial lumen to a genetically engineered, attenuated herpes simplex virus 1 blocks activation of caspase 3-dependent apoptosis and MAPK-dependent cell proliferation induced by carotid artery balloon angioplasty and ligation to reduce blood flow. The procedure enables the restoration of the endothelial cell layer lining the lumen and prevents neointimal hyperplasia and restenosis. These findings have a broad application in prevention of balloon angioplasty-induced restenosis.

Median arcuate ligament syndrome in the pediatric population

OBJECTIVES Median arcuate ligament syndrome (MALS) is a vascular compression syndrome with symptoms that overlap chronic functional abdominal pain (CFAP). We report our experience treating MALS in a pediatric cohort previously diagnosed with CFAP. PATIENTS AND METHODS We prospectively evaluated 46 pediatric (<21years of age) patients diagnosed with MALS at a tertiary care referral center from 2008 to 2012. All patients had previously been diagnosed with CFAP. Patients were evaluated for celiac artery compression by duplex ultrasound and diagnosis was confirmed by computed tomography. Quality of life (QOL) was determined by pre- and postsurgical administration of PedsQL™ questionnaire. The patients underwent laparoscopic release of the median arcuate ligament overlying the celiac artery which included surgical neurolysis. We examined the hemodynamic changes in parameters of the celiac artery and perioperative QOL outcomes to determine correlation. RESULTS All patients had studies suggestive of MALS on duplex and computed tomography; 91% (n=42) positive for MALS were females. All patients underwent a technically satisfactory laparoscopic surgical release resulting in a significant improvement in blood flow through the celiac artery. There were no deaths and a total of 9 complications, 8 requiring a secondary procedure; 33 patients were administered QOL surveys. 18 patients completed the survey with 15 (83%) patients reporting overall improvement in the QOL. Overall, 31/46 patients (67%) reported improvement of symptoms since the time of surgery. CONCLUSIONS MALS was found to be more common in pediatric females than males. Laparoscopic release of the celiac artery can be performed safely in the pediatric population. Surgical release of the artery and resultant neurolysis resulted in significant improvement in the blood flow, symptoms, and overall QOL in this cohort. The overall improvement in QOL outcome measures after surgery leads us to conclude that MALS might be earlier diagnosed and possibly treated in patients with CFAP. We recommend a multidisciplinary team approach to care for these complex patients.

Natural History of Carotid Artery Occlusion

Carotid artery occlusion (CAO) is a risk factor for stroke ipsilateral to the occlusion and puts patients in a high-risk category when contralateral endarterectomy is performed. The purpose of this study was to evaluate the long-term outcomes of patients with internal CAO and to determine risk factors predictive of subsequent neurological event, contralateral carotid intervention, or death. Patients with internal CAO shown by duplex ultrasonography were retrospectively identified and followed between January 2002 and June 2010 (follow-up: 1-101 months, mean: 52 months) at a tertiary care hospital. All had multiple duplex examinations available for review. Chi-square analysis was used to determine risk factors for neurologic event, contralateral intervention, or all-cause morality. Multivariate Cox proportional hazard analysis was conducted using univariate risk factors with P values <0.1. Survival was estimated using the Kaplan-Meier method (P < 0.05 significant). Eighty patients with internal CAO were identified and available for analysis. On initial encounter, 30 (38%) were symptomatic, with 26 (87%) having symptoms referable to the side of the occluded internal carotid artery. During follow-up, seven (9%) had a neurologic event, of which six (86%) were referable to the occluded side; 14 (18%) patients underwent a contralateral operation. Nineteen (24%) patients died during the period of study. Although numerous variables of multivessel disease were significant with χ(2) analysis, there was no significant risk factor associated with neurologic event on multivariate analysis. However, the development of a hemodynamically significant stenosis (>50%) or occlusion of the external carotid artery (ECA) ipsilateral to the occlusion on follow-up (P < 0.027) was associated with increased risk of death. Kaplan-Meier analysis showed 7-year survival for patients with ECA disease at follow-up was significantly worse (16.2% ± 10.3% [n = 21] vs. 79% ± 8.7% [n = 59]; P < 0.00001). Frequently, patients present with neurological symptoms referable to the side of the internal CAO. Eighty-six percent of neurologic events that occur in follow-up are attributable to the side of the occluded carotid, indicating that the occluded side continues to contribute to neurologic morbidity over time. Multivariate analysis revealed no single factor to be predictive of subsequent neurologic events. With significant risk of death in patients found to have ipsilateral ECA stenosis during follow-up, it seems reasonable to continue surveillance of the occluded carotid.