Reginald V. Lord

University of Notre Dame Australia, Fremantle, Western Australia, Australia

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Publications (116)832.08 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In patients with advanced heart failure, morbid obesity is a relative contraindication to heart transplantation due to higher morbidity and mortality in these patients. We performed a retrospective analysis of consecutive morbidly obese patients with advanced heart failure who underwent bariatric surgery for durable weight loss in order to meet eligibility criteria for cardiac transplantation. Seven patients (4 M/3 F, age range 31-56 years) with left ventricular ejection fraction (LVEF) ≤25 % underwent laparoscopic bariatric surgery. Median preoperative body mass index (BMI) was 42.8 kg/m(2) (range 37.5-50.8). There were no major perioperative complications in six of seven patients. Median length of hospital stay was 5 days. There was no mortality recorded during complete patient follow-up. At a median follow-up of 406 days, median BMI reduction was 12.9 kg/m(2) (p = 0.017). Postoperative LVEF improved to a median of 30 % (interquartile range (IQR) 25-53 %; p = 0.039). Two patients underwent successful cardiac transplantation. Two patients reported symptomatic improvement with little change in LV function and now successfully meet listing criteria. Three patients showed marked improvement of their LVEF and functional status, thus removing the requirement for transplantation. Bariatric surgery can achieve successful weight loss in morbidly obese patients with advanced cardiac failure, enabling successful heart transplantation. In some patients, cardiac transplantation can be avoided through surgical weight loss.
    Obesity Surgery 07/2015; DOI:10.1007/s11695-015-1789-1 · 3.74 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2015; 34(4):S184. DOI:10.1016/j.healun.2015.01.503 · 5.61 Impact Factor
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    ABSTRACT: Background: Biomarkers are needed to improve current diagnosis and surveillance strategies for patients with Barrett’s oesophagus (BO) and oesophageal adenocarcinoma (OAC). Macrophage inhibitory cytokine 1/growth differentiation factor 15 (MIC-1/GDF15) tissue and plasma levels have been shown to predict disease progression in other cancer types and was therefore evaluated in BO/OAC. Methods: One hundred thirty-eight patients were studied: 45 normal oesophagus (NE), 37 BO, 16 BO with low-grade dysplasia (LGD) and 40 OAC. Results: Median tissue expression of MIC-1/GDF15 mRNA was greater than or equal to25-fold higher in BO and LGD compared to NE (P<0.001); two-fold higher in OAC vs BO (P=0.039); and 47-fold higher in OAC vs NE (P<0.001). Relative MIC-1/GDF15 tissue expression >720 discriminated between the presence of either OAC or LGD vs NE with 94% sensitivity and 71% specificity (ROC AUC 0.86, 95% CI 0.73–0.96; P<0.001). Macrophage inhibitory cytokine 1/growth differentiation factor 15 plasma values were also elevated in patients with OAC vs NE (P<0.001) or BO (P=0.015). High MIC-1/GDF15 plasma levels (greater than or equal to1140 pg ml−1) were an independent predictor of poor survival for patients with OAC (HR 3.87, 95% CI 1.01–14.75; P=0.047). Conclusions: Plasma and tissue levels of MIC-1/GDF15 are significantly elevated in patients with BO, LGD and OAC. Plasma MIC-1/GDF15 may have value in diagnosis and monitoring of Barrett’s disease.
    British Journal of Cancer 03/2015; 112(8). DOI:10.1038/bjc.2015.100 · 4.82 Impact Factor
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    ABSTRACT: The identification and characterisation of differentially methylated regions (DMRs) between phenotypes in the human genome is of prime interest in epigenetics. We present a novel method, DMRcate, that fits replicated methylation measurements from the Illumina HM450K BeadChip (or 450K array) spatially across the genome using a Gaussian kernel. DMRcate identifies and ranks the most differentially methylated regions across the genome based on tunable kernel smoothing of the differential methylation (DM) signal. The method is agnostic to both genomic annotation and local change in the direction of the DM signal, removes the bias incurred from irregularly spaced methylation sites, and assigns significance to each DMR called via comparison to a null model. We show that, for both simulated and real data, the predictive performance of DMRcate is superior to those of Bumphunter and Probe Lasso, and commensurate with that of comb-p. For the real data, we validate all array-derived DMRs from the candidate methods on a suite of DMRs derived from whole-genome bisulfite sequencing called from the same DNA samples, using two separate phenotype comparisons. The agglomeration of genomically localised individual methylation sites into discrete DMRs is currently best served by a combination of DM-signal smoothing and subsequent threshold specification. The findings also suggest the design of the 450K array shows preference for CpG sites that are more likely to be differentially methylated, but its overall coverage does not adequately reflect the depth and complexity of methylation signatures afforded by sequencing. For the convenience of the research community we have created a user-friendly R software package called DMRcate, downloadable from Bioconductor and compatible with existing preprocessing packages, which allows others to apply the same DMR-finding method on 450K array data.
    Epigenetics & Chromatin 01/2015; 8. DOI:10.1186/1756-8935-8-6 · 4.46 Impact Factor
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    ABSTRACT: Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE, since most people with BE never develop EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision-making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histologic definitions of BE and early EAC; prevalence, incidence, natural history and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability. This article is protected by copyright. All rights reserved.
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    ABSTRACT: Background and aims Bariatric surgery improves health outcomes in the obese and reduces some aspects of obesity-associated systemic inflammation. Little is known however about its effects on circulating TNF-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin level, which regulate apoptosis and are implicated in atherogenesis. Our objective was to identify whether circulating TRAIL and osteoprotegerin levels are influenced by the energy restriction and weight loss that follows bariatric surgery in obese patients with glucose disorders. Methods 15 morbidly obese individuals with type 2 diabetes mellitus (T2D) or glucose intolerance were recruited for bariatric surgery. Participants were assessed for weight, waist circumference and BMI at baseline, then 2 and 12 weeks following energy restriction with bariatric surgery. Laparoscopic adjustable gastric band placement was performed. Fasted blood samples were collected and an oral glucose tolerance test was performed at each visit. Metabolic parameters and plasma chemistries were assessed. Circulating TRAIL, osteoprotegerin and leptin levels were measured. Results A significant increase in circulating TRAIL levels was observed at 12 weeks relative to baseline in participants who suppressed leptin levels. The percentage change in TRAIL was inversely related to the percentage change in fasting insulin and HOMA-β. In contrast, osteoprotegerin levels and the osteoprotegerin:TRAIL ratio were significantly reduced following bariatric surgery. The change in osteoprotegerin:TRAIL ratio positively related to the percentage change in fasting glucose. Conclusions Energy restriction after bariatric surgery is associated with increased circulating TRAIL levels and reduced osteoprotegerin levels and osteoprotegerin:TRAIL ratio in obese humans with dysglycaemia. Changes in the TRAIL and osteoprotegerin:TRAIL ratio related to changes in fasting insulin, suggesting a possible role in glucose improvements after bariatric surgery. Mechanistic studies will clarify the role of TRAIL and osteoprotegerin in health and disease.
    12/2014; DOI:10.1016/j.clnme.2014.09.004
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    ABSTRACT: Background Cathepsin E (CTSE), an aspartic proteinase, is differentially expressed in the metaplasia–dysplasia–neoplasia sequence of gastric and colon cancer. We evaluated CTSE in Barrett’s esophagus (BE) and cancer because increased CTSE levels are linked to improved survival in several cancers, and other cathepsins are up-regulated in BE and esophageal adenocarcinoma (EAC). Methods A total of 273 pretreatment tissues from 199 patients were analyzed [31 normal squamous esophagus (NE), 29 BE intestinal metaplasia, 31 BE with dysplasia (BE/D), 108 EAC]. CTSE relative mRNA expression was measured by real-time polymerase chain reaction, and protein expression was measured by immunohistochemistry. CTSE serum levels were determined by enzyme-linked immunosorbent assay. Results Median CTSE mRNA expression levels were ≥1,000-fold higher in BE/intestinal metaplasia and BE/D compared to NE. CTSE levels were significantly lower in EAC compared to BE/intestinal metaplasia and BE/D, but significantly higher than NE levels. A similar expression pattern was present in immunohistochemistry, with absent staining in NE, intense staining in intestinal metaplasia and dysplasia, and less intense EAC staining. CTSE serum analysis did not discriminate patient groups. In a uni- and multivariable Cox proportional hazards model, CTSE expression was not significantly associated with survival in patients with EAC, although CTSE expression above the 25th percentile was associated with a 41 % relative risk reduction for death (hazard ratio 0.59, 95 % confidence interval 0.27–1.26, p = 0.17). Conclusions CTSE mRNA expression is up-regulated more than any known gene in Barrett intestinal metaplasia and dysplasia tissues. Protein expression is similarly highly intense in intestinal metaplasia and dysplasia tissues.
    Annals of Surgical Oncology 10/2014; 22(7). DOI:10.1245/s10434-014-4155-y · 3.94 Impact Factor
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    ABSTRACT: Esophageal adenocarcinoma develops in response to severe gastroesophageal reflux disease through the precursor lesion Barrett esophagus, in which the normal squamous epithelium is replaced by a columnar lining. The incidence of esophageal adenocarcinoma in the United States has increased by over 600% in the past 40 years and the overall survival rate remains less than 20% in the community. This review highlights some of the signaling pathways for which there is some evidence of a role in the development of esophageal adenocarcinoma. An increasingly detailed understanding of the biology of this cancer has emerged recently, revealing that in addition to the well-recognized alterations in single genes such as p53, p16, APC, and telomerase, there are interactions between the components of the reflux fluid, the homeobox gene Cdx2, and the Wnt, Notch, and Hedgehog signaling pathways.
    Cancer biology & therapy 10/2014; 14(9):782-795. DOI:10.4161/cbt.25362 · 3.63 Impact Factor
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    ABSTRACT: Background Barrett’s esophagus with high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) can be effectively treated by single-session EMR, resulting in complete Barrett’s excision (CBE). CBE provides accurate histology for staging and clinical confirmation of neoplasia eradication but is limited by a high risk of esophageal stricture formation. Objective To evaluate the effectiveness of prophylactic temporary esophageal stenting to prevent post-CBE stricture formation. Design and Setting Single-center, investigator-initiated feasibility study. Patients Circumferential, short-segment Barrett’s esophagus (≤C3≤M5) with HGD or IMC. Intervention Single-stage CBE and insertion of a fully covered metal esophageal stent at 10 days that was removed at 8 weeks. Patients were followed for a minimum of 2 surveillance endoscopies. Main Outcome Measurement Symptomatic esophageal stricture formation. Results At the end of the follow-up period, 8 patients (57.1%) required esophageal dilation for symptomatic CBE-related (n = 7) or stent-related (n = 4) strictures. A median of 3 surveillance endoscopies were performed over a median endoscopic follow-up of 17 months (range 4-25 months). Single-stage CBE successfully eliminated Barrett’s intestinal metaplasia and neoplasia in 71.4% and 92.9% of patients, respectively. Four patients were admitted to the hospital, and 4 patients had early stent removal because of pain or dysphagia. Limitations Single-center feasibility study. Conclusions In a prospective study evaluating prophylactic esophageal stent insertion after single-stage CBE, esophageal strictures formed in more than of half the study cohort, and stents were associated with significant morbidity. An alternative method to reduce stricture formation is required. (Clinical trial registration number: NCT01554280.)
    Gastrointestinal Endoscopy 10/2014; 81(4). DOI:10.1016/j.gie.2014.08.022 · 4.90 Impact Factor
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    ABSTRACT: Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.
    Nature Communications 10/2014; 5:5224. DOI:10.1038/ncomms6224 · 10.74 Impact Factor
  • Dan Falkenback, Christopher W. Lehane, Reginald V. N. Lord
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    ABSTRACT: Background Robot-assisted general surgery operations are being performed more frequently. This review investigates whether robotic assistance results in significant advantages or disadvantages for the operative treatment of gastro-oesophageal reflux disease and achalasia.Methods The electronic databases (Medline, Embase, PubMed) were searched for original English language publications for antireflux surgery and Heller's myotomy between January 1990 and December 2013.ResultsThirty-three publications included antireflux operations and 20 included Heller's myotomy. The publications indicate that the safety and effectiveness of robotic surgery is similar to that of conventional minimally invasive surgery for both operations. The six randomized trials of robot-assisted versus laparoscopic antireflux surgery showed no significant advantages but significantly higher costs for the robotic method. Gastric perforation during non-redo robotic fundoplication occurred in four trials.Conclusions No consistent advantage for robot-assisted antireflux surgery has been demonstrated, and there is an increased cost with current robotic technology. A reported advantage for robotic in reducing the perforation rate during Heller's myotomy for achalasia remains unproven. Gastric perforation during robotic fundoplication may be due to the lack of haptic feedback combined with the superhuman strength of the robot.
    ANZ Journal of Surgery 08/2014; 85(3). DOI:10.1111/ans.12731 · 1.12 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-1072. DOI:10.1016/S0016-5085(14)63909-3 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-1075. DOI:10.1016/S0016-5085(14)63922-6 · 13.93 Impact Factor
  • Dan Falkenback, Christopher W. Lehane, Reginald V. N. Lord
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    ABSTRACT: Background Robot-assisted surgery is a technically feasible alternative to open and laparoscopic surgery, which is being more frequently used in general surgery. We undertook this review to investigate whether robotic assistance provides a significant benefit for oesophagogastric cancer surgery.Methods Electronic databases were searched for original English-language publications for robotic-assisted gastrectomy and oesophagectomy between January 1990 and October 2013.ResultsSixty-one publications were included. Thirty-five included gastrectomy, 31 included oesophagectomy and five included both operations. Several publications suggest that robot-assisted subtotal gastrectomy can be as safe and effective as an open or laparoscopic procedure, with equal outcomes with regard to the number of lymph nodes resected, overall morbidity and perioperative mortality, and length of hospital stay. Robotic assistance is associated with longer operation times but also with less blood loss in some reports. A significant benefit for robotic assistance has not been shown for the more extensive operations of oesophagectomy or total gastrectomy with D2-lymphadenectomy. There are very few oncologic data regarding local recurrence or long-term survival for any of the robotic operations.Conclusions No significant differences in morbidity, mortality or number of lymph node harvested have been shown between robot-assisted and laparoscopic gastrectomy or oesophagectomy. Robotic surgery, with its relatively short learning curve, may facilitate reproducible minimally invasive surgery in this field but operation times are reportedly longer and cost differences remain unclear. Randomized trials with oncologic outcomes and cost comparisons are needed.
    ANZ Journal of Surgery 05/2014; 84(10). DOI:10.1111/ans.12591 · 1.12 Impact Factor
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    ABSTRACT: To examine the relationship between hospital volume and patient outcomes for New South Wales hospitals performing oesophagectomy and gastrectomy for oesophagogastric cancer. A retrospective, population-based cohort study of NSW residents diagnosed with a new case of invasive oesophageal or gastric cancer who underwent oesophagectomy or gastrectomy between 2001 and 2008 in NSW hospitals using linked de-identified data from the NSW Central Cancer Registry, the National Death Index and the NSW Admitted Patient Data Collection. A higher-volume hospital was defined as one performing > 6 relevant procedures per year. Odds ratios for > 21-day length of stay, 28-day unplanned readmission, 30-day mortality and 90-day mortality, and hazard ratios (HRs) for 5-year absolute and conditional survival. Oesophagectomy (908 patients) and gastrectomy (1621 patients) were undertaken in 42 and 84 hospitals, respectively, between 2001 and 2008. Median annual hospital volume ranged from 2 to 4 for oesophagectomies and ranged from 2 to 3 for gastrectomies. Controlling for known confounders, no associations between hospital volume and > 21-day length of stay and 28-day unplanned readmission were found. Overall 30-day mortality was 4.1% and 4.4% for oesophagectomy and gastrectomy, respectively. Five-year absolute survival was significantly better for patients who underwent oesophagectomy in higher-volume hospitals (adjusted HR for lower-volume hospitals, 1.28 [95% CI, 1.10-1.49]; P = 0.002) and for those with localised gastric cancer who underwent gastrectomy in higher-volume hospitals (adjusted HR for lower-volume hospitals, 1.83 [95% CI, 1.28-2.61]; P = 0.001). These data support initial surgery for oesophagogastric cancer in higher-volume hospitals.
    The Medical journal of Australia 04/2014; 200(7):408-13. DOI:10.5694/mja13.11182 · 3.79 Impact Factor
  • Gastroenterology 01/2014; 146(Suppl 1):S-1075. · 13.93 Impact Factor
  • Gastroenterology 01/2014; 146(Suppl 1):S-1075. · 13.93 Impact Factor
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    ABSTRACT: The effect of the laparoscopic adjustable gastric band (LAGB) on the esophagus has been the subject of few studies despite recognition of its clinical importance. The aim of this study was to investigate the frequency and clinical effect of esophageal dysmotility and dilatation after LAGB. We undertook a retrospective analysis of 50 consecutive patients with no dysmotility on perioperative video contrast swallow who underwent primary LAGB operation. All patients had serial focused postoperative contrast studies for band adjustments at least 6 months post-LAGB. Clinical and radiological outcomes were assessed. Median follow-up time was 18 months (range 7-39 months), and the median number of contrast swallows per patient was 5. The mean excess weight loss (EWL) overall was 47 % (standard deviation (SD) 22.3). Radiological abnormalities were recorded in 17 patients (34 %, 95 % confidence interval (CI) 21-49 %), of whom 15 had radiological dysmotility and 7 had esophageal dilatation (five patients had both dysmotility and dilatation). Of these 17 patients, six (35 %) developed significant symptoms of dysphagia, gastroesophageal reflux disease (GERD) or regurgitation requiring fluid removal. In comparison, 12 of 33 (36 %) patients without radiological abnormalities developed symptoms requiring fluid removal (p = 1.00). Patients with radiological abnormalities were significantly older than those without these abnormalities. Symptoms were alleviated by removing fluid in most patients. The LAGB operation results in the development of radiological esophageal dysmotility in a significant proportion of patients. It is not clear if these changes are associated with an increased risk of significant symptoms. Fluid removal can reverse these abnormalities and their associated symptoms.
    Obesity Surgery 11/2013; 24(4). DOI:10.1007/s11695-013-1134-5 · 3.74 Impact Factor
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    ABSTRACT: The contribution of immune cells to the inflammasome that characterises type 2 diabetes mellitus and obesity is under intense research scrutiny. We hypothesised that early changes in glucose metabolism following gastric banding surgery may relate to systemic inflammation, particularly cell-mediated immunity. Obese participants (BMI 43.4 ± 4.9 kg/m(2), n = 15) with diabetes or impaired glucose tolerance (IGT) underwent laparoscopic adjustable gastric banding surgery. Measurements taken before, and at 2 and 12 weeks after surgery included: fasting glucose, glucose levels 2 h after a 75 g oral load, glucose incremental AUC, oral glucose insulin sensitivity index (OGIS), circulating immune cell numbers and activation, and adipokine levels. Subcutaneous and visceral adipose tissue were collected at surgery, and macrophage number and activation measured. There were significant reductions in fasting and 2 h glucose, as well as improved OGIS at 2 and 12 weeks. At 12 weeks, 80% of the diabetic participants reverted to normal glucose tolerance or IGT, and all IGT participants had normalised glucose tolerance. The 12 week fall in fasting glucose was significantly related to baseline lymphocyte and T lymphocyte numbers, and to granulocyte activation, but also to the magnitude of the 12 week reduction in lymphocyte and T lymphocyte numbers and TNF-α levels. In a model that explained 75% of the variance in the change in fasting glucose, the 12 week change in T lymphocytes was independently associated with the 12 week fall in fasting glucose. Rapid improvements in glucose metabolism after gastric banding surgery are related to reductions in circulating pro-inflammatory immune cells, specifically T lymphocytes. The contribution of immune cell-mediated inflammation to glucose homeostasis in type 2 diabetes and its improvement after bariatric surgery require further investigation.
    Diabetologia 09/2013; DOI:10.1007/s00125-013-3033-7 · 6.88 Impact Factor
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    Nicholas Clemons, Wayne Phillips, Reginald V N Lord
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    ABSTRACT: Esophageal adenocarcinoma develops in response to severe gastresophageal reflux disease through the precursor lesion Barrett's esophagus, in which the normal squamous epithelium is replaced by a columnar lining. The incidence of esophageal adenocarcinoma in the USA has increased by over 600% in the past 40 y and the overall survival rate remains less than 20% in the community. This review highlights some of the signaling pathways for which there is some evidence of a role in the development of esophageal adenocarcinoma. An increasingly detailed understanding of the biology of this cancer has emerged recently, revealing that in addition to the well-recognized alterations in single genes such as p53, p16, APC and telomerase, there are interactions between the components of the reflux fluid, the homeobox gene Cdx2 and the Wnt, Notch and Hedgehog signaling pathways.
    Cancer biology & therapy 06/2013; 14(9). · 3.63 Impact Factor

Publication Stats

3k Citations
832.08 Total Impact Points

Institutions

  • 2014–2015
    • University of Notre Dame Australia
      Fremantle, Western Australia, Australia
  • 2010–2015
    • St. Vincent's Hospital Sydney
      • Department of Upper Gastrointestinal Tract Surgery
      Sydney, New South Wales, Australia
  • 2008–2014
    • University of New South Wales
      • • Faculty of Medicine
      • • Department of Surgery
      Kensington, New South Wales, Australia
  • 2013
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 2012
    • St. Vincent Hospital
      Green Bay, Wisconsin, United States
  • 1999–2006
    • University of Southern California
      • Department of Surgery
      Los Angeles, California, United States
  • 2000–2003
    • University of Cologne
      • Department of Vascular Surgery
      Köln, North Rhine-Westphalia, Germany
    • University of California, Los Angeles
      Los Ángeles, California, United States
    • City University Los Angeles
      Los Ángeles, California, United States
  • 2002
    • University of Southern Mississippi
      Mississippi, United States
  • 2001
    • Lund University
      • Department of Surgery
      Lund, Skåne, Sweden