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ABSTRACT |
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INTRODUCTION |
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'As a means of relief from the leaping heart when passion is excited . . . they [the engendered sons of God] contrived and implanted the form of the lung - soft and bloodless . . . as a kind of padding around the heart . . .'
(Plato, 427-347 BC) (Cournand, 1982)
Although our understanding of the physiology of the lung has greatly changed since the time of Plato, the interaction between the heart and the lungs is still recognised to affect both respiratory and cardiac function. For example, cardiogenic gas mixing, though partially a result of instantaneous changes in the rate of O2 consumption and CO2 production (Bosman & de Lee, 1965), largely results from direct mechanical interactions between the heart and the lung. Lung gas volume decreases during diastole and increases during systole as the filling and emptying heart displaces the lungs (Bosman et al. 1965; Bosman & de Lee, 1965; Lloyd, 1989). Just as the heart influences lung gas volume, the presence of the lung surrounding the heart also significantly limits ventricular filling and thus limits cardiac output via the Frank-Starling mechanism. Brookhart & Boyd (1947) observed that the interaction between the heart and the lung results in intra-thoracic pressure within the cardiac fossa exceeding that in the lateral pleural space, and that an increase in lung volume is accompanied by an increase in extra-cardiac pressure. It was subsequently recognised that this increase in extra-cardiac pressure is the mechanism whereby the application of positive end-expiratory pressure and increasing lung volume act to constrain ventricular filling and limit cardiac output (Fewell et al. 1980a,b; Kingma et al. 1987).
Not only does the constraint applied to the heart by the lungs change when airway pressure and lung volume are changed, it also changes with developmental age. In the fetus, the lungs are liquid filled and significantly constrain ventricular filling (Grant et al. 1992b; Grant & Walker, 1996). However, this constraint is largely eliminated immediately following the aeration of the lungs at birth (Grant et al. 1992a, 1994). Within days of birth, the lungs once again significantly constrain the heart and produce up to 50% of the total constraint experienced by the neonatal heart (Grant et al. 1994); by contrast, in the adult only 25-30% of the total cardiac constraint arises from the lung (Kingma et al. 1987).
Although developmental changes in the chest wall (Agostoni, 1959) and pericardium (Naimark, 1995; Naimark et al. 1998) may, in part, account for the changes observed in ventricular constraint throughout development, changes within in the lungs themselves may also contribute. For example, in anticipation of birth, clearance of liquid from the fetal lung begins during labour (Berger et al. 1998) and is largely complete shortly after birth (Maloney et al. 1989). Just as clearance of this fluid is essential for postnatal gas exchange (Berger et al. 1996), a reduction in lung-liquid volume, and the subsequent aeration of the lungs, appears also to be essential to decrease ventricular constraint, to increase diastolic filling of the heart, and to increase stroke volume significantly at birth (Grant, 1999). How development of the lung itself impacts upon ventricular constraint later in life is not known, even though it is known that structural development of the lung continues well into childhood (Boyden, 1977; Burri & Weibel, 1977). Therefore, the purpose of this study was to determine whether a change in the distortability of the lung tissue itself occurs during development that might account for the reduced pleural component of ventricular constraint observed in the adult relative to the neonate (Grant, 1999), i.e. we aimed to determine whether the neonatal lung resists neighbouring structures encroaching into its space to a greater extent than the adult lung. Moreover, as the pressure recorded in the cardiac fossa exceeds that measured on the lateral pleural surface (Brookhart & Boyd, 1947), we sought to determine whether the distortability of the lung surface within the cardiac fossa differs from that of the lateral surface of the lung. Finally, we sought to determine how the distortability of the lung is affected by elevations in airway pressure (Paw) throughout development as increments in Paw have a negative impact upon cardiac function, especially in early life.
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METHODS |
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All surgical and experimental procedures were performed in accordance with the guidelines of the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes established by the National Health and Medical Research Council of Australia and were approved by the Monash Medical Centre Committee on Ethics in Animal Experimentation.
Lungs were collected from six newborn lambs (7-9 days old), six neonatal lambs (27-32 days old) and six adult sheep (Merino/Border-Leicester cross) that had been administered 10 000 (newborn and neonate) to 40 000 U (adult) heparin (I.V.) and killed with an overdose of sodium pentobarbitone (150 mg kg-1 I.V.). The heart was dissected away from the lungs and the trachea was cannulated. The left lung was then gently positioned on a bag of small styrofoam beads which was shaped to conform to either the lateral surface of the lung or the cardiac fossa. Suction was applied to the bag of styrofoam beads to produce a firm, moulded base upon which the lungs rested (Fig. 1). The lung surface was regularly moistened with saline throughout the study.
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Lung distortion was assessed by lowering a metal rod of a known surface area onto the surface of adult, neonatal and newborn sheep lungs with pressures of 20, 40, 80 and 120 g cm-2. Measurements were repeated in triplicate at each of three levels of Paw (2.5, 5.0 and 15 cmH2O).
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The tracheal cannula was connected to a time-limited, pressure-controlled ventilator (Bourns BP 200, Riverside, CA, USA) and the lungs were inflated a minimum of 5 times from 0 to 30 cmH2O Paw to ensure a constant volume history and a uniform inflation. The ease with which the lung was distorted by localised pleural pressure was assessed by lowering a metal rod of known weight (30 g) and known surface area (0.5 cm2) onto the surface of the lung with applied pressures (Pappl) of 0, 20, 40, 80 and 120 g cm-2 as recorded with a calibrated strain gauge (Statham Transducers Inc., Oxnard, CA, USA). In keeping with the techniques of Robertson et al. (1973), the metal rod was lowered onto the lung over a 3-5 s period using the micromanipulator until the first pressure step of 20 g cm-2 was reached. At this point the depth of distortion was also recorded. Several seconds later (7-12 s, average 10 s) the metal rod was lowered further until the next level of pressure was attained. Our procedure was reproduced precisely for each step and for each lung so we could compare distortability between levels of positive end-expiratory pressure (PEEP) and between ages. Although our original intent was to vary the location, the small size of the newborn lungs did not allow for this. This range of Pappl was also selected to correspond with the original work of Robertson et al. (1973). The distortability of each lung was assessed in triplicate while Paw was maintained at three randomly assigned levels (2.5, 5 and 15 cmH2O). The results from these three trials were averaged to attain a single data set for each lung. Paw was cycled from 0 to 30 cmH2O 5 times between each assessment of distortability. Measurements were performed on both the lateral surface of the lung and the surface of the lung that formed the cardiac fossa.
Statisitics
Data were averaged and are presented as means ± S.E.M. Within each age group, we compared the depth of distortion produced at each level of Pappl and each level of Paw using a two-way analysis of variance (ANOVA) for repeated measures (SigmaStat, SPSS Inc., Chicago, IL, USA). The changes in distortability induced by changes in Paw were also assessed using a two-way ANOVA. A Student-Newman-Keuls test was used to isolate differences that were detected by these ANOVA. Student's paired t tests were used to compare the depth of distortion produced in the lateral lung and the cardiac fossa by each level of applied force. A probability (P) of < 0.05 was considered significant.
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RESULTS |
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The depth of distortion in the lateral and cardiac fossal surface of the adult lung increased significantly (P < 0.002) as Pappl was increased at each given level of Paw (Fig. 2). The greatest distortion was observed at the highest level of Pappl (120 g cm-2) and at the lowest level of Paw (2.5 cmH2O). Increasing Paw in the adult lung significantly decreased the depth of distortion observed in both the lateral surface (P < 0.002) and cardiac fossa (P < 0.02; Fig. 2). Distortability decreased by as much as 33% when Paw was increased to 5 cmH2O and by as much as 74% when Paw was increased to 15 cmH2O (Fig. 3).
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The depth of distortion in both the left lateral surface (upper left) and the left cardiac fossa (upper right) of the adult lung increased significantly as Pappl was increased. In the adult, increasing Paw decreased the magnitude of distortion at every Pappl with the smallest distortions for each level of Pappl occurring at the highest level of Paw. As in the adult lung, the depth of distortion in both the left lateral surface (left panels) and the left cardiac fossa (right panels) of the neonatal and newborn lungs also increased as Pappl was increased. Unlike the adult, increasing Paw from 2.5 to 5.0 cmH2O in the neonatal and newborn lung did not decrease the magnitude of distortion. The neonatal and newborn lungs only became less distortable when Paw was increased to 15 cmH2O. (Data represent the mean ± S.E.M., n = 6.)
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Although increasing Paw to 15 cmH2O decreased the distortability of all lungs, the magnitude of this effect varied with age. Increasing Paw to 15 cmH2O decreased the depth of distortion by up to 74% in the adult. Surprisingly, with the same increase in Paw, the depth of distortion decreased by only 46% in the newborn lungs and significantly less (27%) in the neonatal lungs. Data (means ± S.E.M., n = 6) represent the change in distortability induced by increasing Paw to 15 cmH2O and are presented as a percentage change from the depth of distortion induced by each level of Pappl when Paw equalled 2.5 cmH2O.
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The depth of distortion in the lateral surface of the newborn and neonatal lung also increased significantly (P < 0.001) over a range of Pappl from 0 to 80 g cm-2 (Fig. 2). The depth of distortion in the cardiac fossal surface of these lungs increased significantly over the entire range of Pappl (P < 0.001). As with the adult lung, the greatest distortion was observed at the highest Pappl and at the lowest Paw. In contrast to the adult lung, increasing Paw from 2.5 to 5 cmH2O did not significantly alter the depth of distortion observed in either the lateral surface or the cardiac fossa of the newborn and neonatal lungs (Fig. 2) at any given Pappl. Only when Paw was increased to 15 cmH2O did the depth of distortion decrease significantly (Fig. 3).
Although increasing Paw to 15 cmH2O decreased the depth of distortion induced by each Pappl, the magnitude of this decrease differed for each age group (Fig. 3). Increasing Paw to 15 cmH2O decreased the distortability of the lateral lung surface significantly more in the adult than in either the newborn or neonatal lung (Fig. 3, P < 0.05). Moreover, increasing Paw decreased the distortability of the newborn lung significantly more than the neonatal lung (P < 0.05).
Baseline (at Paw = 2.5 cmH2O) levels of distortability are shown in Table 1. The adult lungs were distorted approximately 50% more by each level of Pappl than the newborn and neonatal lungs (Table 1). The newborn and neonatal lungs were equally distorted by each Pappl. The adult lungs also differed from the newborn and neonatal lungs in regional distortability. The cardiac fossa of the adult lung was significantly less distortable than the lateral surface (Fig. 4). No difference was evident in the newborn and neonatal lungs. The cardiac fossa and lateral surface of neonatal lungs were equally distorted with each given level of Pappl (Table 1).
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No such difference was observed in either the newborn or the neonatal lungs (see Table 1). Symbols represent the mean ± S.E.M. (n = 6) recorded when Paw was maintained at 2.5 cmH2O.
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DISCUSSION |
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Our study revealed that the distortability of the lung increases significantly between the newborn period and adulthood, which suggests that the lung resists neighbouring structures encroaching into its space to a greater extent in early life than it does in the adult. As discussed below, this finding is consistent with previous observations that the lungs provide a greater limitation to the filling of the heart in the fetus and neonate than they do in the adult (Kingma et al. 1987; Grant et al. 1994; Grant, 1999). Our study also revealed that in the adult the surface of the lung that comprises the cardiac fossa is significantly less distortable than the lateral surface of the same lung, a result that is in keeping with the observation that the pleural pressure within the cardiac fossa exceeds that at the lateral surface of the lung (Brookhart & Boyd, 1947). Finally, our study confirms a previous report that increases in Paw substantially decrease the distortability of the adult lung (Robertson et al. 1973). In contrast, increasing Paw from 2.5 to 5 cmH2O had no effect on the distortability of the newborn and neonatal lung. The failure of increased Paw to decrease newborn and neonatal lung distortability may have the fortuitous benefit of limiting the impact that PEEP has upon cardiac function in the mechanically ventilated sick newborn.
In 1983, Butler described the adult lung as the 'good hands' that hold the heart. However, he also recognised that the lungs do much more than simply cradle the heart. Because of their close apposition to the heart, the lungs act as a significant constraint to ventricular filling and thus limit cardiac function. The magnitude of this constraint increases with the increase in lung volume that accompanies the use of PEEP during mechanical ventilation (Kingma et al. 1987). In addition, the magnitude of the constraint applied to the heart by the lung changes dramatically throughout life. In fetal life, the lungs provide between 50 and 90% of the total constraint applied to the heart, and it is this constraint that helps determine the maximal level of fetal cardiac output (Grant et al. 1992a,b; Grant & Walker, 1996; Grant, 1999). Our earlier work also shows that the transition from fetus, with liquid-filled lungs, to newborn with air-filled lungs is accompanied by a marked decrease in the magnitude of the constraint that the lungs place upon the heart. As a result of this decrease in constraint, and as a result of the associated increase in ventricular preload, cardiac output increases at birth. In the days following birth, substantial changes must occur to restore the lungs as a major source of ventricular constraint since the neonatal lung accounts for approximately 50% of the total constraint applied to the heart. Further developmental changes must also occur later in life as the lungs only account for between 25 and 30% of the total constraint experienced by the adult heart (Kingma et al. 1987). Although both a decrease in chest-wall compliance (Agostoni, 1959) and an alteration in the properties of the pericardium (Naimark, 1995; Naimark et al. 1998) are likely to contribute to the changes in ventricular constraint that accompany development, our current findings suggest for the first time that developmental alterations in the properties of the lungs themselves are also important.
Brookhart & Boyd (1947) recognised that, while filling, the heart displaces the lung and, as a result, the intra-thoracic pressure within the cardiac fossa exceeds that of the lateral regions. Moreover, the difference between lateral pleural pressure and the pressure recorded from within the cardiac fossa increases as Paw is increased. Although geometric factors are thought to lead to a greater pressure within the cardiac fossa relative to the lateral surface, our data from isolated whole lungs, along with earlier data from isolated pleura, suggest that the characteristics of the lateral surface of the lung differ from those of the cardiac fossa. Our observation that the cardiac fossa of the adult lung was less distortable than the lateral surface is consistent with that of Nagao (1973) who showed that the pleura isolated from the cardiac fossa is significantly less compliant than the pleura isolated from the lateral surface of the lung. The reduced distortability of the cardiac fossa may also reflect the pleura acting as a stretched membrane on the surface of the parenchyma (Lai-Fook et al. 1976). The localised forces we applied to the concave cardiac fossa would further stretch the pleura, while similar forces applied to the convex lateral surface would reduce the stretch placed on the pleura.
Although Hajji et al. (1979) calculated that the tension in the pleural membrane increases as Paw is increased, the concept of the pleural membrane being the sole source of resistance to distortion is at odds with our observation that the adult lung was more distortable than the newborn and neonatal lung. As discussed by Hajji et al. (1979), when forces are applied to the lung over an area that is large relative to the ratio of tension (T) and shear modulus (
) (i.e. T/), then the deformations are relatively uninfluenced by the pleural membrane. Because tension increases with species size (and presumably with increased body size associated with growth) and because does not (Hajji et al. 1979), the actual distance over which the coupling of the membrane to the parenchyma occurs (T/) should increase with age. In our study the area of the probe remained constant, and as such, the influence of the pleural membrane tension should have increased in the adult and distortability should have decreased, not increased. Thus, developmental changes in the parenchyma or the pleural membrane must occur between the newborn/neonatal period and adulthood to account for the greater distortability of the adult lung.
We have made use of localised pleural pressures to demonstrate that lung distortability increases with age. How lung distortability changes in response to forces applied over a larger surface area, such as the left or right ventricle in situ, is not certain. Given that the tension of the pleural membrane increases with lung size (Hajji et al. 1979) and given that lung deformations are influenced less by the pleura when the force is applied over a larger area (Lai-Fook et al. 1976), developmental changes in lung parenchyma and changes in the size of the heart may influence this interaction. Although we applied force over a much smaller area (1 cm2) than would be the case in vivo, the depths of the distortions we observed are nonetheless in keeping with those that might be expected in vivo. For example, Anderson et al. (1984) reported that left ventricle (LV) minor-axis diameters increase approximately 1.5 cm during diastolic filling in neonatal lambs. Assuming that each wall of the LV (i.e. the free wall and the septum) moved one-half of this distance, the LV free wall would displace the lung approximately 0.75 cm per beat at a normal filling volume and pressure. The right ventricle (RV) would also displace the lung. As the cross-section of the RV is not round, and as the intraventricular septum moves towards the RV in diastole, the RV free wall might displace the lung to an even greater degree. Moreover, our observations correspond closely to the physiology observed in the intact animal. That is, a greater distortability of the lung in the adult relative to the neonate is in keeping with the lungs constraining the heart less in the adult than in the neonate (Kingma et al. 1987; Grant et al. 1994; Grant, 1999).
Postnatal development of alveoli may also contribute to the increase in distortability observed in the adult lung relative to the younger lung. In altricial species, such as the rat, alveoli develop primarily after birth (Burri et al. 1974; Burri & Weibel, 1977) whereas in more precocious species significant numbers of alveoli are present at birth. In the human, although alveoli are present before birth, the vast majority of alveoli develop between birth and adulthood (Thurlbeck, 1975). In the lamb, although the number of alveoli is higher at birth than in the human, the lung develops rapidly during the first 30-60 days following birth and then more progressively beyond 180 days of age (Davies et al. 1988) as the number of alveoli triples. This postnatal increase in alveoli in the sheep lung may correspond with our observed increase in lung distortability in the adult.
We specifically selected the range of Pappl utilised by Robertson et al. (1973) in studies in the dog to allow comparisons between studies and species. Although our results are qualitatively similar to these earlier studies, they differ quantitatively as the depth of distortion recorded at each level of Pappl and at each level of Paw was much greater in our study, perhaps reflecting a species-specific difference in lung structure. In the dog, Pappl of the same magnitude as that used in our study only distorted alveoli in the immediate sub-pleural area. Although we did not perform histological examinations of the parenchymal distortions introduced by our localised applied forces, the sheep parenchyma clearly responds differently to that of the dog. The greater depth of distortion in the adult sheep lungs suggests that those forces (interdependence) that act to resist localised distortion are smaller in the sheep than in the dog lung. Our data recorded from the neonatal lung approximate those from the adult dog. This may reflect the allometric relationship observed between body size and alveolar dimensions. As body size decreases, alveolar dimensions also decrease (Tenny & Remmers, 1963; Milsom, 1989), perhaps increasing the forces of interdependence that occur between alveoli.
We recognise that the range of pressures utilised by both Robertson et al. (1973) and ourselves exceed the normal physiological range of pressure acting between the lung and the heart. The higher pressure along with the smaller size of the younger lungs may account, in part, for the reduced distortability of the newborn and neonatal lungs relative to those of the adult. Future studies using lower pressures (Hajji et al. 1979) may help to clarify this possibility. Nonetheless, the range of Pappl does not account for our observation that increasing Paw does not alter distortability in the younger lungs and our observation that the cardiac fossa was less distortable than the lateral surface in the adult lungs. In addition, as previously mentioned, the tendency for the lungs to limit filling of the newborn heart is significant. For example, at an end-diastolic pressure of approximately 15 mmHg, the pressure between the lungs and left ventricle is approximately 10 mmHg, of which approximately 5 mmHg arises from the lung and chest wall and the remainder from the pericardium (see Fig. 4B in Grant et al. 1994). Although it was not possible to separate the effects of the lung and the chest wall in these early studies, our present results provide important new insights into the components of ventricular constraint by revealing that the lung itself is a variable source of ventricular constraint that is independent of the developmental decrease in chest wall compliance (Agostoni, 1959). Importantly, these findings increase our understanding of the important role that lung constraint normally plays in determining cardiac function. This information may be particularly relevant in settings where compliance of the lung might be reduced, such as during respiratory distress syndrome in the preterm infant.
We chose to compare lungs at equal Paw because of our interest in the effect of PEEP on lung distortability and constraint of the heart. Although we did not measure lung compliance or functional residual capacity in our experiments, the lungs we studied were from normal healthy animals and, as a result, we believe that lung compliance would not have differed substantially between the three groups. As discussed by Agostoni (1959), the compliance of the lung does not differ significantly between the newborn, neonate or adult dog. Just as a decrease in lung compliance does not seem to explain the decreased distortability of the younger lungs, reduced lung volume also does not appear to be the explanation. Each lung we studied appeared well aerated and free of atelectasis. Moreover, our use of PEEP would be expected to increase lung volume to an equivalent level in each group, given that compliance is expected to be similar in each group. When we increased PEEP from 2.5 to 5 cmH2O in the young lungs, distortability did not change and ultimately decreased when PEEP was further increased to 15 cmH2O. At each level of PEEP the distortability of the young lungs remained less than that observed in the adult lungs at 2.5 cmH2O PEEP. These findings suggest that reduced lung volume in the younger lungs was not a major factor in the limited distortability of these lungs.
What impact lung disease has upon lung distortability, its effects on cardiac filling, and its response to PEEP are important issues that were not addressed in our current study. It is possible that lung distortability might be further reduced in the sick newborn infant with reduced lung compliance. How distortability of the abnormally compliant lung might respond to increases in PEEP is also unknown. First, it is possible that increasing PEEP in this setting might act to decrease lung distortability as it does in the adult lung. Alternatively, if lung volume is particularly important in altering lung distortability, increases in PEEP in low compliance lungs might have a limited effect on distortability as lung volume would remain largely unchanged. Finally, it is possible that the application of PEEP to lungs with low compliance might actually increase lung distortability by opening up collapsed alveoli. The answers to these questions remain unclear and require further study. Nonetheless, our current study provides important new information on the mechanical properties of the lung and the implications that these properties have for cardiac filling, and it is based upon these results that further studies can be designed.
In summary, the reduced pleural component of ventricular constraint observed in the adult relative to the neonate may correspond to an increase in the distortability of the lung tissue itself during development i.e. the adult lung resists neighbouring structures encroaching into its space to a lesser degree than does the newborn and neonatal lung. In addition, the lung surface of the cardiac fossa is more difficult to distort than the lateral surface of the lung, perhaps contributing to the higher pressures recorded in the cardiac fossa relative to the lateral pleural surface. Although increasing Paw acts to decrease the distortability of the adult lung, this is not the case for the neonatal and newborn lung, at least in the lower levels of Paw commonly used in clinical management of the sick neonate. Our results suggest that the clinical use of low levels of Paw may be associated with less pulmonary constraint to ventricular filling, and thus may have a less detrimental effect upon cardiac function in the newborn than in the adult.
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REFERENCES |
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Acknowledgements
D.A.G. and A.M.W. were supported by the National Health and Medical Research Council of Australia. J.-C.F. was a recipient of an Overseas Postgraduate Research Scholarship (DEETYA, Australia), a Monash Graduate Scholarship (Monash University) and a Glaxo-Wellcome Paediatric Pneumonology Scholarship, and was supported by the Department of Education, Canton Zurich Switzerland. The authors acknowledge the technical assistance of Elizabeth M. Skuza and Vojta Brodecky.
Corresponding author
D. A. Grant: Ritchie Centre for Baby Health Research, Monash Institute of Reproduction and Development, Monash University, Level 5, Monash Medical Centre, 246 Clayton Road, Clayton, Melbourne, Victoria 3168, Australia.
Email: daniel.grant{at}med.monash.edu.au
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