Each year the South Western Sydney Clinical School awards Paper of the Year prizes in a number of categories: : biomedical; clinical; and epidemiological/health services research.
J Immunol. 2013 Aug 1;191(3):1404-12. doi: 10.4049/jimmunol.1300856. Epub 2013 Jun 24.
Mast cell-restricted, tetramer-forming tryptases induce aggrecanolysis in articular cartilage by activating matrix metalloproteinase-3 and -13 zymogens.
Magarinos NJ, Bryant KJ, Fosang AJ, Adachi R, Stevens RL, McNeil HP.
ABSTRACT: Mouse mast cell protease (mMCP)-6-null C57BL/6 mice lost less aggrecan proteoglycan from the extracellular matrix of their articular cartilage during inflammatory arthritis than wild-type (WT) C57BL/6 mice, suggesting that this mast cell (MC)-specific mouse tryptase plays prominent roles in articular cartilage catabolism. We used ex vivo mouse femoral head explants to determine how mMCP-6 and its human ortholog hTryptase-β mediate aggrecanolysis. Exposure of the explants to recombinant hTryptase-β, recombinant mMCP-6, or lysates harvested from WT mouse peritoneal MCs (PMCs) significantly increased the levels of enzymatically active matrix metalloproteinases (MMP) in cartilage and significantly induced aggrecan loss into the conditioned media, relative to replicate explants exposed to medium alone or lysates collected from mMCP-6-null PMCs. Treatment of cartilage explants with tetramer-forming tryptases generated aggrecan fragments that contained C-terminal DIPEN and N-terminal FFGVG neoepitopes, consistent with MMP-dependent aggrecanolysis. In support of these data, hTryptase-β was unable to induce aggrecan release from the femoral head explants obtained from Chloe mice that resist MMP cleavage at the DIPEN↓FFGVG site in the interglobular domain of aggrecan. In addition, the abilities of mMCP-6-containing lysates from WT PMCs to induce aggrecanolysis were prevented by inhibitors of MMP-3 and MMP-13. Finally, recombinant hTryptase-β was able to activate latent pro-MMP-3 and pro-MMP-13 in vitro. The accumulated data suggest that human and mouse tetramer-forming tryptases are MMP convertases that mediate cartilage damage and the proteolytic loss of aggrecan proteoglycans in arthritis, in part, by activating the zymogen forms of MMP-3 and MMP-13, which are constitutively present in articular cartilage.
Int J Cardiol. 2013 Aug 20;167(4):1276-81. doi: 10.1016/j.ijcard.2012.03.162. Epub 2012 May 4.
Risk factor modification in diabetic patients following angiographic identification of multi-vessel disease.
Hee L, Thomas L, Ang X, Yang L, Lo S, Juergens CP, Mussap CJ, Dignan R, French JK.
ABSTRACT: There is little information on whether identification of multi-vessel disease (MVD) in patients with diabetic mellitus (DM) affects risk factor management. From 1125 consecutively screened patients between June 2006 and March 2010, we examined 227 diabetic patients with MVD on coronary angiography. Diabetic control and cholesterol levels were assessed by glycated haemoglobin (HbA1c) and total cholesterol (TC) respectively which were evaluated at baseline and at 1-year follow-up. Patients were grouped by age into <55(n=33), 55-65(n=75), 66-75(n=75) and >75(n=44). Target levels were defined as HbA1c<7% and TC<4.0 mmol/L. Patients <55 years had the highest HbA1c at 9.1[7.6-11.2]% with the lowest proportion of patients (n=3; 11.1%) within target at baseline, while 66-75 years had the best HbA1c at 7.1[6.4-7.8]% with the highest proportion (n=28, 45.2%) reaching target (p<0.0001). At 1-year, the poorest HbA1c control was again observed in the age <55 with fewer patients achieving target compared to the 66-75 age group (HbA1c: 8.5% vs 6.9%; % of patients at target: 20.7% vs 54.5%; p<0.0001). Furthermore, the group <55 years demonstrated the worst TC control at 1-year with a significant increase compared to the baseline TC (p=0.01). Patients with a lower body mass index (BMI) were likely to have an improvement in HbA1c and reach target (p=0.01). Paradoxically, patients who were current smokers demonstrated a beneficial effect on optimal TC control (29.2% vs 15.4%, p=0.027). In younger diabetic patients, risk factor modification at 1-year was poor despite identification of MVD. Developing an effective education and monitoring programme to improve glycaemic control in this high risk group should be a priority.
Psycho-Oncology. 2013 Jul;22(7):1557-64. doi: 10.1002/pon.3166. Epub 2012 Sep 3.
Some things change, some things stay the same: a longitudinal analysis of cancer caregivers' unmet supportive care needs.
Girgis A, Lambert SD, McElduff P, Bonevski B, Lecathelinais C, Boyes A, Stacey F.
OBJECTIVE: The objective of this study was to identify caregivers' unmet needs and the psychosocial variables associated with unmet need count within the first 24 months post-survivor diagnosis.
METHODS: Caregivers completed a comprehensive survey measuring the primary outcome, psychosocial variables, and demographics of interest at 6 (n=547), 12 (n=519), and 24 (n=443) months post-survivor diagnosis.
RESULTS: Although prevalence of unmet needs significantly decreased over time, almost a third of caregivers still reported unmet needs at 24 months. Unmet needs were more prevalent among caregivers of lung cancer survivors, at 6 and 24 months. Top ranking unmet needs across time included 'managing concerns about cancer coming back', 'reducing stress in the person with cancer's life', 'understanding the experience of the person with cancer', and 'accessible hospital parking'. At 24 months, some of the top ranking unmet needs were related to caregivers' well-being and relationships. Increased interference in activities due to caregiving, anxiety, depression, avoidant and active coping, and out-of-pocket expenses was associated with reporting more unmet needs. Less involvement in caregiving roles and increased physical well-being and social support were associated with reporting less unmet needs. For some variables (e.g. anxiety and depression), association with unmet needs strengthened over time.
CONCLUSIONS: This is the first longitudinal analysis of caregivers' unmet needs as they enter early and extended survivorship. Findings provide valuable insights into caregiver's unmet needs over time and identified a sub-group of caregivers at risk of experiencing unmet needs, extending previous research and informing the timing and content of psychosocial services.
Am Heart J. 2012 Apr;163(4):649-56.e1. doi: 10.1016/j.ahj.2012.01.014.
Safety and efficacy of rescue angioplasty for ST-elevation myocardial infarction with high utilization rates of glycoprotein IIb/IIIa inhibitors.
Shugman IM, Hsieh V, Cheng S, Parikh D, Tobing D, Wouters N, van der Vijver R, Lo Q, Rajaratnam R, Hopkins AP, Lo S, Leung D, Juergens CP, French JK.
BACKGROUND: Fibrinolytic therapies remain widely used for ST-elevation myocardial infarction, and for "failed reperfusion," rescue percutaneous coronary intervention (PCI) is guideline recommended to improve outcomes. However, these recommendations are based on data from an earlier era of pharmacotherapy and procedural techniques.
METHODS AND RESULTS: To determine factors affecting prognosis after rescue PCI, we studied 241 consecutive patients (median age 55 years, interquartile range [IQR] 48-65) undergoing procedures between 2001 and 2009 (53% anterior ST-elevation myocardial infarction and 78% transferred). The median treatment-related times were 1.2 hours (IQR 0.8-2.2) from symptom onset to door, 2 hours (IQR 1.3-3.2) from symptom onset to fibrinolysis (93% tenecteplase), and 3.9 hours (IQR 3.1-5.2) from fibrinolysis to balloon. Procedural characteristics were stent deployment in 95% (11.6% drug eluting) and 78% glycoprotein IIb/IIIa inhibitor use, and Thrombolysis In Myocardial Infarction (TIMI) 3 flow rates pre-PCI and post-PCI were 41% and 91%, respectively (P < .001). At 30 days, TIMI major bleeding occurred in 16 (6.6%) patients, and 23 (9.5%) patients received transfusions; nonfatal stroke occurred in 4 (1.7%) patients (2 hemorrhagic). Predictors of TIMI major bleeding were female gender (odds ratio 3.194, 95% CI 1.063-9.597; P = .039) and pre-PCI shock (odds ratio 3.619, 95% CI,1.073-12.207; P = .038). Mortality at 30 days was 6.2%, and 3.2% in patients without pre-PCI shock. One-year mortality was 8.2% (5.3% in patients without pre-PCI cardiogenic shock), 5.2% had reinfarction, and the target vessel revascularization rate was 6.4% (2.6% in arteries ≥ 3.5 mm in diameter). Pre-PCI shock, female gender, and post-PCI TIMI flow grades ≤ 2 were significant predictors of 1-year mortality on multivariable regression modeling, but TIMI major bleeding was not.
CONCLUSIONS: Rescue PCI with contemporary treatments can achieve mortality rates similar to rates for contemporary primary PCI in patients without pre-PCI shock. Whether rates of bleeding can be reduced by different pharmacotherapies and interventional techniques needs clarification in future studies.
Stroke. 2012 Aug;43(8):2097-101. doi: 10.1161/STROKEAHA.112.659888. Epub 2012 May 22.
Clinical significance of impaired cerebrovascular autoregulation after severe aneurysmal subarachnoid hemorrhage.
Jaeger M, Soehle M, Schuhmann MU, Meixensberger J.
BACKGROUND AND PURPOSE: The purpose of this study was to investigate the relationship between cerebrovascular autoregulation and outcome after aneurysmal subarachnoid hemorrhage.
METHODS: In a prospective observational study, 80 patients after severe subarachnoid hemorrhage were continuously monitored for cerebral perfusion pressure and partial pressure of brain tissue oxygen for an average of 7.9 days (range, 1.9-14.9 days). Autoregulation was assessed using the index of brain tissue oxygen pressure reactivity (ORx), a moving correlation coefficient between cerebral perfusion pressure and partial pressure of brain tissue oxygen. High ORx indicates impaired autoregulation; low ORx signifies intact autoregulation. Outcome was determined at 6 months and dichotomized into favorable (Glasgow Outcome Scale 4-5) and unfavorable outcome (Glasgow Outcome Scale 1-3).
RESULTS: Twenty-four patients had a favorable and 56 an unfavorable outcome. In a univariate analysis, there were significant differences in autoregulation (ORx 0.19±0.10 versus 0.37±0.11, P<0.001, for favorable versus unfavorable outcome, respectively), age (44.1±11.0 years versus 54.2±12.1 years, P=0.001), occurrence of delayed cerebral infarction (8% versus 46%, P<0.001), use of coiling (25% versus 54%, P=0.02), partial pressure of brain tissue oxygen (24.9±6.6 mm Hg versus 21.8±6.3 mm Hg, P=0.048), and Fisher grade (P=0.03). In a multivariate analysis, ORx (P<0.001) and age (P=0.003) retained an independent predictive value for outcome. ORx correlated with Glasgow Outcome Scale (r=-0.70, P<0.001).
CONCLUSIONS: The status of cerebrovascular autoregulation might be an important pathophysiological factor in the disease process after subarachnoid hemorrhage, because impaired autoregulation was independently associated with an unfavorable outcome.
Ann Behav Med. 2012 Oct;44(2):225-35. doi: 10.1007/s12160-012-9385-2.
Distressed partners and caregivers do not recover easily: adjustment trajectories among partners and caregivers of cancer survivors.
Lambert SD, Jones BL, Girgis A, Lecathelinais C.
BACKGROUND: Although a number of cross-sectional studies document the distress experienced by partners and caregivers of cancer survivors, few have considered their potential differential patterns of adjustment over time.
PURPOSE: Identify distinct trajectories of anxiety and depression among partners and caregivers of cancer survivors and predictors of these trajectories.
METHODS: Participants completed a survey to examine the impact of caring for, or living with, a cancer survivor at 6, 12, and 24 months post-survivor diagnosis. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (N(anxiety) = 510; N(depression) = 511).
RESULTS: Anxiety trajectories included: no anxiety (15.1% scored <3; 37.8% scored 3-5); chronic, borderline anxiety (33.2%); and chronic, clinical anxiety (13.9%). The depression trajectories were: no depression (38.9% scored <2; 31.5% scored around 3); a sustained score of 7 (25.5%); and chronic, clinical depression (4.1%). Variables associated with the trajectories included most of the psychosocial variables.
CONCLUSIONS: Findings highlight that most caregivers maintained their baseline level of distress, which is particularly concerning for participants reporting chronic anxiety or depression.
JACC: Cardiovascular Imaging. 2011 Mar; 4:234-242.
Atrial dilation and altered function are mediated by age and diastolic function but do not occur before the eighth decade.
Boyd AC, Schiller NB, Leung DY, Ross DL, Thomas L.
OBJECTIVES: This study investigated changes in left atrial (LA) volumes and phasic atrial function, by deciles, with normal aging.
BACKGROUND: LA volume increase is a sensitive independent marker for cardiovascular disease and adverse outcomes. To use this variable more effectively as a marker of pathology and a gauge of outcome, physiological changes due to aging alone need to be quantitated.
METHODS: A detailed transthoracic echocardiogram was performed in 220 normal subjects; 89 (41%) were male and their age ranged from 20 to 80 years (mean 45 ± 17 years). Maximum (end-ventricular systole), minimum (end-ventricular diastole), and pre-a-wave volumes were measured using the biplane method of disks. LA filling, passive emptying, conduit and active emptying volumes, and fractions were calculated. Transmitral inflow, pulmonary vein flow, and pulsed-wave Doppler tissue imaging parameters were measured as expressions of left ventricular diastolic function. For purposes of analysis, subjects were divided by age deciles.
RESULTS: LA indexed maximum (0.05 ml/m(2) per year) and minimum (0.06 ml/m(2) per year) volume increased with age but only became significant in the eighth decade (26.0 ± 6.3 ml/m(2), p = 0.02, and 13.5 ± 3.9 ml/m(2), respectively; p < 0.001). Impaired left ventricular diastolic relaxation was apparent in decade 6 and was associated with a shift in phasic LA volumes so that LA expansion index and passive emptying decreased with increasing age, whereas active emptying volume increased.
CONCLUSIONS: In normal healthy subjects, LA indexed volumes remain nearly stable until the eighth decade when they increase significantly. Therefore, an increase in LA size that occurs before the eighth decade is likely to represent a pathological change. Changes in phasic atrial volumes develop earlier consequent to age-related alteration in LV diastolic relaxation.
Do multidisciplinary teams make a difference in the management of lung cancer?
Boxer MM, Vinod SK, Shafiq J and Duggan KJ.
BACKGROUND: There is limited evidence regarding the effectiveness of multidisciplinary team (MDT) meetings in lung cancer. The objective of this study was to compare the patterns of care for patients with newly diagnosed lung cancer who were presented at a lung cancer MDT meeting with the patterns of care for patients who were not presented.
METHODS: All patients who had lung cancer newly diagnosed in South West Sydney (SWS) between December 1, 2005, and December 31, 2008, were identified from the local Clinical Cancer Registry. Patient and tumor characteristics and treatment receipt were compared between patients who were and were not presented at MDT meetings. A logistic regression model was constructed to determine predictors for receiving treatment and survival.
RESULTS: In total, there were 988 patients, including 504 patients who were presented at MDT meetings and 484 who were not presented at MDT meetings. The median patient age was 69 years and 73 years in the MDT group and the non-MDT group, respectively (P < .01). There was no pathologic diagnosis for 13% of non-MDT patients compared with 4% of MDT patients (P < .01). Treatment receipt for MDT patients versus non-MDT patients was 12% versus 13%, respectively, for surgery (P value nonsignificant); 66% versus 33%, respectively, for radiotherapy (P < .001); 46% versus 29%, respectively, for chemotherapy (P < .001); and 66% versus 53%, respectively, for palliative care (P < .001). In patients with good performance status, the MDT group had significantly better receipt of radiotherapy among patients with stage I through IV nonsmall cell lung cancer (NSCLC) and had significantly better receipt of chemotherapy among patients with stage IV NSCLC. MDT discussion was an independent predictor of receiving radiotherapy, chemotherapy, and referral to palliative care but did not influence survival.
CONCLUSIONS: MDT discussion was associated with better treatment receipt, which potentially may improve quality of life for patients with lung cancer. However, it did not improve survival.