Eye bank issues : II . Preservation techniques : warm versus cold storage Most of the tissue used for penetrating keratoplasty is issued through eye banks that store the corneoscleral button either in hypothermic storage at 2 -- 6 °C or in organ culture at 31 -- 37 °C . Introduction Throughout the world post-mortem eye tissue is used for keratoplasty . The generally accepted storage method for the whole globe is the `` moist chamber '' ; a moistened pot at 2 -- 6 °C introduced in 1935 -LSB- 1 -RSB- . The corneoscleral button is stored in tissue culture medium , either in the hypothermic storage method at 2 -- 6 °C introduced in 1974 -LSB- 2 -RSB- or in the organ culture method at 31 -- 37 °C introduced in 1976 -LSB- 3 -RSB- . Corneas can not reliably be frozen . The prevailing storing technique today is the storage of the corneoscleral button . The storage time can be extended by removing the corneoscleral button from the globe . A longer storage time permits greater flexibility in the use of the donor tissue and prevents wastage . In addition in many countries , for different reasons , legal or ethical , corneoscleral disc excision in situ is preferred to the removal of the whole globe . Moreover , the preparation of lamellae and mushroom-shaped grafts from a corneoscleral button is nowadays possible with help of an artificial anterior chamber . With the introduction of the preservation media , corneal surgeons have to rely on highly skilled technicians employed in eye banks selecting and storing the donor tissue . The original hypothermic storage solution , the M -- K medium , has been succeeded by other solutions claiming better and longer maximum storage results . The hypothermic method is common all over the world . Although organ culture originates from the United States -LSB- 3 , 4 -RSB- it has been strongly promoted by the Eye Bank of Århus in Denmark -LSB- 5 , 6 -RSB- and is now widely applied in Western Europe but not commonly used elsewhere . After some modifications shortly after its introduction the organ culture storage technique has stayed the same . The storage media became commercially available although some eye banks still prefer to prepare them themselves . They differ slightly in composition between banks and countries -LSB- 7 -RSB- . Both storage methods , hypothermic and organ culture will be compared considering technical aspects , tissue evaluation possibilities , storage time , microbiological safety , graft survival and future applications with regard to the increased interest in lamellar grafting . Technical aspects General Procurement and storage techniques have to be performed under aseptic conditions . Increasingly , eye banks have a formally established quality assurance program . This and the increasing regulation may affect banks working on a smaller scale . For example in France the number of operating eye banks reduced form 226 in 1993 to 43 in 2004 . Hypothermic storage The technique is simple : refrigerator storage with minimal handling . It requires no complex or expensive equipment . The storage solutions are commercially available and manufacturer recommendations should be followed for temperature , maximal storage time , expiry date and other factors . The vials may allow inspection of the endothelium by specular microscopy -LRB- Fig. 1 left -RRB- . During storage the cornea remains thin and , provided donor screening permits release of the tissue , it is directly available for surgery.Fig . 1Corneoscleral buttons in different vials for hypothermic storage -LRB- left -RRB- and in the incubator during organ culture -LRB- right -RRB- The medium consists of a tissue culture medium , supplemented with antibiotics , deturgescent agents like dextran and chondroitin sulphate to prevent corneal swelling in vitro , and other additives such as energy sources , antioxidants , membrane stabilizing and growth factors to improve the storage capacity . Inspection of the tissue by slit-lamp and/or specular microscope can be performed in a closed system . Organ culture The technique is relatively complicated , despite the fact that nowadays the storage solutions are commercially available . The corneas are stored in an incubator at 30 -- 37 ° C in a tissue culture medium , supplemented with fetal or newborn calf serum , antibiotics and antimycotics -LRB- Fig. 1 right -RRB- . Dehydrating macromolecules , necessary to maintain normal hydration in vitro , are ingested by the corneal cells at a physiological temperature and found accumulated in vacuoles in the cells and layers of the cornea -LSB- 8 , 9 -RSB- . Therefore they are omitted from the storage solution . As a result the cornea swells to about twice its normal thickness during storage . The swelling should be reversed before transplantation . This is performed by placing the cornea in the storage medium supplemented with dextran . This so-called transport medium is also used for the transport of the cornea at room temperature . The extent of deswelling depends on the dextran concentration , varying from 4 -- 8 % in the different banks , resulting in a thickness of about 0.5 to 0.7 mm , depending on the preference of the surgeon -LRB- s -RRB- using the tissue from a certain bank . The maximum time the cornea spends in the transport medium also varies between banks ; from less than one up to seven days -LSB- 7 , 8 -RSB- . The risk of the ingested dextran in relation to the export area and transport time is judged differently . Depending on the media used , renewal of the medium occurs after 10 -- 14 days of storage -LSB- 7 -RSB- . For inspection of the endothelium , mandatory after storage , an invasive technique has to be used , which has to be performed under strict aseptic conditions . The necessary transfer of the cornea from the storage to the transport solution averts a stored cornea from being directly available for use . Besides , a minimal storage period is required for microbiological testing . All this makes the technique more complicated than the hypothermic storage method . Tissue evaluation General Irrespective of the storage method -LRB- s -RRB- used the donor should be adequately screened . Tissue that is potentially hazardous to eye bank personnel and the recipient should be excluded in addition to tissue that poses a risk for the success of the surgery . Physical assessment , serologic testing and evaluation of medical and social history of the donor are mandatory . Routine inspection of the endothelium is also part of the donor evaluation . Moreover , it can play an important role in setting higher and more-uniform quality standards for tissue acceptance . It may also help to increase the donor supply by assessing corneas that may otherwise be arbitrarily excluded for transplantation on the basis of age or time post mortem . The possibilities for evaluation of the endothelium are dependent of the storage method used . Studies linking graft outcome with morphometric parameters of solely the endothelium are still lacking . A model has been presented to calculate endothelial cell loss in the long run of 10 -- 20 years after penetrating keratoplasty -LSB- 10 -RSB- . In this way it is possible to predict when cell density would reach levels that are incompatible with maintenance of transparency and graft function . The model provides a rationale for the setting of minimum donor cell densities . However , the definite cut-off points are still at the discretion of the bank and surgeon . Hypothermic storage Determination of endothelial cell density is a standard method of corneal tissue evaluation according to the Medical Standards of the Eye Bank Association of America , effective since December 2001 . In general this will be a pre-storage evaluation of the endothelium by specular microscopy -LRB- Fig. 2 left -RRB- . Because the appearance of the endothelial cells varies with temperature , type and time of preservation and media , evaluation at room temperature is recommended . When it is impossible to obtain an endothelial cell count , this requirement may be waived on a case-by-case basis by the Medical Director.Fig . 2Evaluation of the endothelium by specualr microscopy -LRB- left -RRB- and light microscopy after artificial swelling of the intercellular space -LRB- right -RRB- Selection criteria and cut-off points for the morphology of the corneal endothelium are not defined . In most cases only descriptions of the endothelial mosaic are used : swollen cells , dark spots , guttae , lysed cells , mild to severe polymegethism and pleomorphism -LSB- 11 -RSB- . Most specular microscopes are equipped with software programs to determine parameters describing the endothelial mosaic in terms of variation in cell shape andthe percentage of hexagonal cells in addition to the assessment of the cell density . The obtained morphometric results may help to standardize descriptions , but only provided the microscopes are well calibrated and the necessary interactive manipulation is performed by an experienced observer . Organ culture After organ culture specular microscopy is not suitable for visualization of the endothelium . Therefore light microscopy is applied , bright field or phase contrast . It is necessary to visualize the endothelial cells by swelling the intercellular space with a hypotonic solution . This allows inspection over the entire endothelial surface -LRB- Fig. 2 right -RRB- . The mechanism has been described by Kirk and Hassard -LSB- 12 -RSB- and was worked out for the corneal endothelium by Sperling -LSB- 13 -RSB- . Because it is an invasive technique , it must be performed under aseptic conditions . The swelling is transient , it disappears after a couple of minutes and is dependent on the integrity of the cellular membranes . In dead and necrotic cells and in their direct neighborhood swelling will not occur . Before and after storage balanced salt solution -LRB- BSS -RRB- , phosphate buffered saline -LRB- PBS -RRB- , 1.8 % sucrose -- PBS mixture or hypo-osmotic BSS may induce swelling , while for tissue in solutions with dehydrating agents a stronger stimulus with 1.8 % sucrose might be necessary -LSB- 7 -RSB- . Induction of swelling and the swelling pattern are dependent on storage time and medium -LSB- 14 -RSB- . Therefore the interpretation of images requires experience and constant working conditions . The application of a vital stain such as trypan blue -LSB- 15 , 16 -RSB- preceding the artificial swelling of the intercellular space may help to recognize dead or necrotic cells or denuded Descemet 's membrane . Microscopes should be well calibrated both for manual counting as for evaluation by image analysis programs -LSB- 17 -RSB- . These software programs are commercially available , either specifically designed for endothelial evaluation , or as general programs adapted to do this . All programs aim for automated cell analysis that is independent of the observer and experience . However , in general , reliable parameters for the endothelial mosaic are only obtained interactively . This still requires experienced observers . Manual counting by Gunderson 's method -LSB- 18 -RSB- can provide reliable cell counts -LSB- 19 -RSB- , but for parameters such as variation in cell size and the percentage of hexagonals image analysis is necessary . The quality of the corneal stroma can be evaluated by light microscopy . The significance of the presence of lysed keratocytes for the survival of the graft has not yet been investigated -LSB- 20 -RSB- . Storage time General As the endothelium is essential for graft clarity and survival , the maximum allowed storage time is predominantly determined by maintenance of the endothelial function and integrity -LSB- 21 -RSB- . Regression lines , coefficients and equations have been published for storage time and damage or loss of endothelial cells . In Fig. 3 the regression lines are collected for different storage methods -LSB- 22 -- 24 -RSB- . The referred studies have in common that the vital stain with trypan blue is used to assess endothelial damage . The figure clearly demonstrates the differences in endothelial viability and explains the differences in the allowed maximum storage period.Fig . 3Regression lines showing endothelial cell damage and loss in different storage solutions assessed after staining with trypan . The regression formulas for the M -- K medium , the Optisol GS and the organ cultures are respectively : y = 11.8 x + 11.6 , y = 0.19 x + 4.2 , and y = 0.11 x − 1.8 Hypothermic storage The original M -- K medium claimed a storage period of up to 10 days . Solutions introduced later , such as the modified M -- K medium , K-sol , Dexsol , Likorol , Optisol -LRB- Plus , GS -RRB- claimed better storage capabilities and a maximum storage period of 14 -- 16 days . Changes in the endothelium as a result of post-mortem time and other variables , such as cause of death , donor age , circumstances of death etc. , might result in the transplantation of corneas of inferior quality after storage . Because degenerative changes will progress during hypothermic storage , endothelial cell loss has to be taken into account -LSB- 25 -RSB- , and might even lead to complete cell death . The need for methods to detect corneas not tolerating the prolonged hypothermic storage has therefore been suggested -LSB- 26 -RSB- . To reduce the risk of primary graft failure , the recommended storage periods are kept far below the claimed maxima . The applied period increased from 2 -- 3 days for the M -- K medium -LSB- 27 , 28 -RSB- up to 7 -- 10 days for Optisol -LSB- 7 , 25 -RSB- . In addition the time interval from death of the donor to storage of the cornea is generally kept relatively short , within 12 h or shorter -LSB- 7 -RSB- . Organ culture With organ culture the allowed storage period is longer . In addition the time interval between death and storage is generally extended to 24 -- 48 h , because significant wound healing can still occur during storage -LSB- 29 -RSB- . The loss of endothelial cells during storage may differ between individual corneas -LRB- Fig. 4 -RRB- and is supposed to reflect differences in vitality as a result of post-mortem time and other variables such as cause of death , donor age , circumstances of death etc. . In this respect , prolonged hypothermic storage might not be so different from organ culture . Severe endothelial cell loss during organ culture may also be caused by herpes simplex virus infection of the donor tissue -LSB- 30 , 31 -RSB- . Organ culture is therefore considered a stress test -LSB- 32 , 33 -RSB- . A storage period of up to 4 -- 5 weeks is possible -LSB- 32 -- 35 -RSB- . However , in order to detect tissue not tolerating the storage , according to European Eye Bank Rules , inspection of the endothelium after storage is mandatory.Fig . 4Percentage endothelial cell loss -LRB- endothelial cell density before storage minus the cell density after divided by the cell density before multiplying by 100 -RRB- during routine storage by organ culture is plotted for a given year Microbiological safety General Donor eye tissue is usually contaminated -LSB- 36 -RSB- and each eye bank has to cope with this . As a first step decontamination procedures are applied before enucleation or excision of the corneoscleral button . When properly performed these procedures are very effective at reducing the risk of contamination -LSB- 37 -RSB- . As a next step , antibiotics , and in the case of organ culture antimycotics , are present in the storage solutions . These are more effective if the contaminating microbes are metabolically active , which means that they are more effective in organ culture than during hypothermic storage . In addition the vulnerability of organ culture to microbial contamination can be exploited to detect microorganisms remaining from the donor and/or introduced into the culture medium by the environment or personnel . Theoretically , in organ culture the risk of contamination is therefore lower than in hypothermic storage . Hypothermic storage Antibiotics have little effect during hypothermic storage . Preoperative warming of the storage media to room temperature is important to enhance the decontamination effect . The optimal time period of room-temperature storage has yet to be established -LSB- 38 -RSB- . In addition , antibiotics accumulate in the tissue during storage -LSB- 39 -RSB- and become active in the eye after grafting as the temperature rises . Donor rims tested after grafting are positive for bacteria and fungi in 12 -- 28 % of the cases -LSB- 40 -RSB- . However , the value of routine donor rim cultures in clinical use is debated . On the one hand no relevance of infectious complications after keratoplasty has been reported -LSB- 41 , 42 -RSB- . On the other hand a 22 times increased incidence of endophthalmitis in the case of a positive rim culture -LSB- 43 -RSB- to a fully associated fungal infection following penetrating keratoplasty has been described -LSB- 44 -RSB- . The overall incidence of postoperative keratitis and endophthalmitis caused by microbes transferred with the donor cornea is low and varies from 0.2 % -LSB- 43 -RSB- to 0.41 % -LSB- 45 -RSB- and to 1.3 % -LSB- 46 -RSB- . The addition of alternative antibiotics to the current hypothermic storage solutions has been suggested , because donor corneas are often removed in hospitals and other settings where resistant bacteria may be thriving -LSB- 38 -RSB- . These may cause an increased incidence of endophthalmitis . From a microbiological point of view , however , it is disputable whether the addition of the latest antibiotics with the widest spectra is the best solution . Organ culture Contamination detected during organ culture varies between eye banks -LSB- 7 -RSB- . This may be dependent on the antibiotic cocktail present in the medium -LRB- narrow - to wide-spectrum antibiotics -RRB- , collection procedures , in situ excision or enucleation and the post-mortem time of collection and storage -LSB- 47 -RSB- . Microbiological testing of medium samples before surgery is mandatory as well as a quarantine period before issuing corneas . Microbiological safety of the tissue stored by organ culture is obtained by discarding contaminated tissue before grafting . The incidence of endophthalmitis reported after a properly performed organ culture procedure is 0 -- 0.1 % -LSB- 7 -RSB- . Sterility may be better with organ culture since microbial contamination will become more readily evident . Organ culture might be considered as the method of choice in circumstances where corneas are suspected of being at a higher risk of contamination . The mandatory reporting of adverse reactions and the central registration of these within the EU area where both the hypothermic and the organ culture techniques are used will demonstrate in time whether the incidence of endophthalmitis really differs between organ culture and hypothermic storage . Graft survival Only one prospective study is available comparing clinical results after grafting between the hypothermic storage and organ culture -LSB- 48 -RSB- . During the 1 -- 2 year study period no statistically significant differences in visual acuity , corneal thickness or endothelial cell density were found in keratoconus patients . Bourne -LSB- 49 -RSB- , however , found fewer endothelial cells after grafting on corneas stored by organ culture . At that time , M -- K medium was used to reverse the swelling , a method differing from the method used in Europe . Retrospective studies claim improved -LSB- 33 , 50 -RSB- or comparable results with organ culture -LSB- 34 , 35 , 51 -RSB- . The improvement is not ascribed to the storage itself but to the extra selections routinely included in organ culture preservation . In addition most of the studies were performed at a time when old-fashioned hypothermic storage methods did not always include inspection of the endothelium . Future aspects With the advent of new surgical techniques such as lamellar grafting , the issues for eyebanks are also changing . The risk for immunological graft rejection is theoretically lower in lamellar grafting . This may reduce the interest in HLA matching of donor and recipient , an important reason to prefer organ culture as a storage method . Organ culture provides sufficient time for typing and matching and is also thought to immunologically modify the tissue through the loss of passenger leucocytes and epithelium -LSB- 52 -RSB- . For a long time stored corneosclereal buttons were used for penetrating keratoplasty whereas lamellar grafting was performed with tissue from whole globes stored in a moist chamber . With the introduction of the artificial anterior chamber , the microkeratome and the intralase or femtosecond laser , this is changing quickly . Corneoscleral buttons which have been precut in order to reduce the manipulation of the donor tissue at the time of surgery will be new products of eye banks . For a reliable production of these precut buttons the intralase or femtosecond laser technique seems very promising -LSB- 53 -- 55 -RSB- . Whether the storage technique -LRB- hypothermic of organ culture -RRB- might affect the postoperative fate of the corneal lamella is still open for discussion . The revival of the mushroom technique is another development , where the eye bank would be expected to prepare the corneal button -LSB- 56 , 57 -RSB- . Hypothermic storage , where the thickness of the cornea is maintained and where the risk of epithelial ingrowth is low because there is no epithelial growth , seems to be more suitable for these indications . Conclusions With the more widespread use of the specular microcope and the introduction of hypothermic storage solutions claiming an intermediate storage period some of the advantages ascribed to organ culture -LSB- 58 -RSB- , such as scheduling operations and minimizing wastage of donor tissue , have become less important . Others still remain : allowing time for tissue typing and matching and extensive testing , detection of residual micro-organisms before surgery , and selecting and dispatching corneas with a well-defined endothelial quality assessed after storage . In addition the pool of possible donors can be enlarged thanks to the possibility of wound healing during organ culture and the inspection of the tissue after storage . Because organ cullture involves extensive testing of the quality of the donor cornea , there are theoretically no preset limits on donor age and postmortem time . To permit these possibilities the organ culture procedure is more complicated than the hypothermic storage . Well qualified personnel , advice of microbiological laboratory staff , and a well suited facility are essential for a proper organ culture procedure but may also be valuable for hypothermic storage . The higher costs of organ culture have to be balanced against the offered advantages and possibilities not permitted by the hypothermic storage . Whether organ culture will also be the proper storage technique for surgically manipulated corneoscleral buttons remains to be investigated .

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O B I O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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3.0 T cardiovascular magnetic resonance in patients treated with coronary stenting for myocardial infarction : evaluation of short term safety and image quality Purpose To evaluate safety and image quality of cardiovascular magnetic resonance -LRB- CMR -RRB- at 3.0 T in patients with coronary stents after myocardial infarction -LRB- MI -RRB- , in comparison to the clinical standard at 1.5 T. Methods Twenty-five patients -LRB- 21 men ; 55 ± 9 years -RRB- with first MI treated with primary stenting , underwent 18 scans at 3.0 T and 18 scans at 1.5 T. Twenty-four scans were performed 4 ± 2 days and 12 scans 125 ± 23 days after MI . Cine -LRB- steady-state free precession -RRB- and late gadolinium-enhanced -LRB- LGE , segmented inversion-recovery gradient echo -RRB- images were acquired . Patient safety and image artifacts were evaluated , and in 16 patients stent position was assessed during repeat catheterization . Additionally , image quality was scored from 1 -LRB- poor quality -RRB- to 4 -LRB- excellent quality -RRB- . Results There were no clinical events within 30 days of CMR at 3.0 T or 1.5 T , and no stent migration occurred . At 3.0 T , image quality of cine studies was clinically useful in all , but not sufficient for quantitative analysis in 44 % of the scans , due to stent -LRB- 6/18 scans -RRB- , flow -LRB- 7/18 scans -RRB- and/or dark band artifacts -LRB- 8/18 scans -RRB- . Image quality of LGE images at 3.0 T was not sufficient for quantitative analysis in 53 % , and not clinically useful in 12 % . At 1.5 T , all cine and LGE images were quantitatively analyzable . Conclusion 3.0 T is safe in the acute and chronic phase after MI treated with primary stenting . Although cine imaging at 3.0 T is suitable for clinical use , quantitative analysis and LGE imaging is less reliable than at 1.5 T. Further optimization of pulse sequences at 3.0 T is essential . Introduction The combination of functional cardiovascular magnetic resonance -LRB- CMR -RRB- and late gadolinium enhancement -LRB- LGE -RRB- is evolving as an important diagnostic -LSB- 1 , 2 -RSB- and prognostic -LSB- 3 -- 5 -RSB- modality in patients with ischemic heart disease . Because the availability of high field MR systems is increasing , the need arises to evaluate the performance and clinical value of these systems in cardiovascular disease . Earlier reports already suggested that 3.0 T MR systems offer higher temporal and spatial resolution , due to an increased signal-to-noise ratio , which would be especially advantageous in CMR scanning -LSB- 6 -- 8 -RSB- . However , these studies were all assessed in healthy volunteers and in patients with non-ischemic heart disease or suspected coronary artery disease , and without the presence of coronary stents -LSB- 6 -- 10 -RSB- . There is limited to no data about safety and image quality at 3.0 T CMR scanning in the acute or chronic phase after myocardial infarction -LRB- MI -RRB- , in patients treated with percutaneous coronary intervention and primary stenting . In these patients B0 inhomogeneities -LRB- induced by the heart-lung interface or from coronary stents -RRB- , flow artifacts , inhomogeneity of normal myocardial suppression in LGE -LRB- induced by B1 inhomogeneity -RRB- and poor cardiac triggering may interfere with the gain offered by the higher magnetic field . The aim of this study was to test whether CMR scanning at 3.0 T is safe and feasible in patients with coronary stents in the acute and chronic phase after MI , and to prospectively compare image quality at 3.0 T with the current clinical standard at 1.5 T. Furthermore , the presence and significance of different image artifacts are considered . Methods Patient population Patients were eligible for the study if they had been admitted with a first ST-elevation acute MI , according to standard electrocardiographic and enzymatic criteria -LSB- 11 -RSB- , and had undergone successful primary PCI with stent implantation . Exclusion criteria were electrocardiographic evidence of reinfarction , haemodynamic or other clinical instability or -LRB- relative -RRB- contraindications for CMR such as claustrophobia , pacemakers , intracerebral aneurysm clips or very irregular heart rhythm . Patients were treated with aspirin , heparin , abciximab , clopidogrel , statins , beta-blockade and ACE-inhibitors , according to ACC/AHA practice guidelines -LSB- 12 -RSB- . The study was approved by the local ethics committee and all patients gave written informed consent . CMR parameters Eighteen CMR scans were performed with a 3.0 T MR system -LRB- Intera , Philips , Best , The Netherlands -RRB- , with a gradient performance of 30 mT/m and slew rate of 150 T/m/s , using a six element cardiac phased array surface coil . Another 18 CMR scans were acquired with a 1.5 T MR system -LRB- Magnetom Sonata , Siemens , Erlangen , Germany -RRB- , with a gradient performance of 40 mT/m and slew rate of 200 T/m/s , using an eight element cardiac phased array surface coil . Cine imaging was performed at both field strengths using a SSFP pulse sequence , without parallel imaging . Long axis views , as well as short axis views covering the entire left ventricle were acquired during repeated breath-holds in expiration . At 3.0 T , cine SSFP sequence parameters were a temporal resolution between 25 ms and 50 ms , excitation angle of 45 ° , receiver bandwidth 868 Hz/pixel , TR/TE of 3.8 / 1.9 ms , matrix 192 × 155 and voxel size of 1.5 × 1.8 × 6.0 mm3 . At 1.5 T , the temporal resolution was between 35 ms and 50 ms with an excitation angle of 60 ° , receiver bandwidth 930 Hz/pixel , TR/TE of 3.2 / 1.6 ms , matrix 256 × 156 and voxel size of 1.4 × 1.9 × 6.0 mm3 . LGE images were acquired in mid-diastole using a 2D segmented inversion-recovery gradient-echo pulse sequence , 10 -- 15 min after intravenous injection of 0.2 mmol/kg of a gadolinium chelate -LRB- Dotarem , Guerbet , Roissy , France -RRB- . The LGE images were obtained in exactly the same orientation as the cine images . Sequence parameters at 3.0 T were an excitation angle of 25 ° , receiver bandwidth 434 Hz/pixel , TR/TE of 3.5 / 1.3 ms , matrix 192 × 119 , voxel size of 1.7 × 2.1 × 6.0 mm3 , triggering every other heart beat , and an inversion time between 250 ms and 350 ms to null remote myocardium . At 1.5 T , sequence parameters were an excitation angle of 25 ° , receiver bandwidth 130 Hz/pixel , TR/TE of 9.6 / 4.4 ms , matrix 256 × 166 , voxel size of 1.4 × 1.7 × 6.0 mm3 , triggering every other heart beat , and an inversion time between 220 ms and 300 ms to null remote myocardium . Safety and quality analysis To evaluate patient safety , a physician was present at the CMR scanner throughout the scan . Heart rhythm was monitored continuously . The patient was asked to report any discomfort and symptoms during the scan procedure . Additionally , a repeat catheterization was performed in 16 patients who underwent CMR examination in the acute phase after MI -LRB- 9 at 3.0 T , 7 at 1.5 T -RRB- . Stent position and patency after CMR scanning were visually assessed on the repeat catheterization and compared to the primary PCI . Occurrence of repeat intervention or hospitalization within 30 days of the CMR examination was recorded . Different types of artifacts were reviewed and marked as being clinically relevant if the artifact interfered with visualisation of the myocardium . Flow related artifacts in SSFP imaging -LSB- 13 -RSB- , and artifacts due to static field inhomogeneities such as the heart-lung interface were scored on cine images . Separately , we looked at artifacts caused by the coronary stent on the cine images , and measured the maximum artifact diameter , perpendicular to the length of the stent , using an appropriate cardiac view . In addition , the potential effect of B1 inhomogeneity on the homogeneous suppression of viable myocardium was visually assessed on LGE images . Furthermore , image quality of the cine and LGE images were scored on a separate workstation -LRB- Centricity Radiology v6 .1 , GE Medical Systems , Zeist , the Netherlands -RRB- by four independent observers , who were blinded for MR system and clinical history . To distinguish between image quality that is satisfactory for clinical use or high quality images for research purposes , images were scored on a scale from 1 to 4 : 1 not clinically useful ; 2 clinically useful , but of insufficient quality for quantitative analysis ; 3 clinically useful and of sufficient quality for quantitative analysis ; 4 excellent quality . The following definitions were used for evaluation of the cine images : 1 poor quality , extensive artifacts , completely obscuring endocardial borders ; 2 moderate quality , assessment of global function is possible , partly using assumptions , but regional wall thickening is not possible in all segments , due to interfering artifacts ; 3 good quality , assessment of global and regional function is possible , despite some small artifacts ; 4 excellent quality , functional analysis is possible and there is no interference of artifacts . And for the evaluation of LGE images : 1 poor quality , extensive artifacts , infarcted myocardium is not visible ; 2 moderate quality , infarcted myocardium is visible , but delineation is not possible in all segments ; 3 good quality , infarcted myocardium is easy to distinguish from viable myocardium , despite some small artifacts ; 4 excellent quality , no artifacts . Two scores were given for each scan : 1 for the set of cine images and 1 for the set of LGE images . After completing the independent image quality assessment , all 4 observers exchanged their scores for each case and agreed on a consensus score . Statistical analysis Continuous variables with normal distribution are expressed as mean ± SD , or as median -LRB- 25th -- 75th percentile -RRB- . Comparison of the baseline characteristics and stent artifact diameter was done by using an unpaired Student 's t-test . The consensus score of image quality of both field strengths was assessed for statistical difference by a Mann-Whitney U test . All statistical tests were two-sided with a significance level of P < 0.05 . SPSS 12.0.1 for Windows -LRB- SPSS Inc. , Chicago , USA -RRB- was used for analysis . Results Twenty-five consecutive patients with 36 CMR studies were included in the study . One patient was studied on both MR systems in the acute phase , 9 patients -LRB- 5 on 3.0 T , 4 on 1.5 T -RRB- were studied both in the acute phase and in the chronic phase , and 1 patient -LRB- 3.0 T -RRB- was studied twice in the chronic phase after MI . The baseline characteristics of all 25 patients are listed in Table 1 . On each system , 12 CMR scans were performed in the acute phase after MI , at 4 ± 2 days after primary PCI , and 6 CMR studies in the chronic phase , at 125 ± 23 days after primary PCI . One patient refused contrast injection during scanning in the chronic phase . Table 1Patient characteristicsNumber of patients25Age -LRB- years -RRB- 55 ± 9Men21 -LRB- 84 -RRB- BMI -LRB- kg/m2 -RRB- 25.5 ± 1.9 Risk factorsDiabetes mellitus0 -LRB- 0 -RRB- Hyperlipidaemia3 -LRB- 12 -RRB- Hypertension6 -LRB- 24 -RRB- Smoking16 -LRB- 64 -RRB- Family history of CAD8 -LRB- 32 -RRB- Maximum peak CK-MB -LRB- U/L -RRB- 308 -LRB- 197 -- 464 -RRB- Infarct-related arteryLAD18 -LRB- 72 -RRB- RCx3 -LRB- 12 -RRB- RCA4 -LRB- 16 -RRB- Values are presented as number -LRB- ratio in % -RRB- , mean ± standard deviation or median -LRB- 25th -- 75th percentile -RRB- ECG electrodes were positioned and displaced until an optimal ECG signal was acquired . Although it took more time to obtain a stable ECG waveform with a clearly delineated R wave at 3.0 T than at 1.5 T -LRB- 10 -- 15 min vs. < 2 min respectively -RRB- , it did not affect image quality , since scans were repeated when trigger problems occurred . Stent safety and artifacts at 3.0 T No patient reported any discomfort or symptoms during the CMR scan procedure . In addition , there were no clinical events during , or shortly after scanning at 3.0 T , and none of the patients underwent a repeat intervention or hospitalization for any reason within 30 days . The mean number of stents implanted per patient per scan at 3.0 T was 1.3 ± 0.7 , with a mean stent length of 19 ± 5 mm and diameter of 3.2 ± 0.4 mm . Further specifications of the implanted coronary stents are listed in Table 2 . Repeat catheterization was performed 2 -LRB- 1 -- 4 -RRB- days after scanning in 9 of the 12 patients who underwent 3.0 T CMR scanning in the acute phase after MI . Angiographic evaluation revealed no differences in stent position and patency compared to the initial result after primary PCI . Table 2Type and number of coronary stents used per CMR examinationField strength and timingNumber of patientsNumber and type of coronary stents present during CMRa3 .0 T acute phase91 × Multi-Link Vision12 × Multi-Link Vision21 × Driver3 .0 T chronic phase31 × Multi-Link Vision21 × Driver/2x TAXUS Libertéb11 × Driver1 .5 T acute phase41 × Prokinetic12 × Prokinetic21 × Lekton Motion11 × Lekton Motion/2 × Multi-Link Vision11 × Multi-Link Vision11 × AVE11 × Multi-Link Zeta11 × CYPHERb1 .5 T chronic phase21 × Lekton Motion12 × Lekton Motion11 × AVE11 × Multi-Link Zeta11 × CYPHERbaStent material and manufacturer -- Multi-Link Vision : cobalt chromium alloy , Abbott Vascular ; Driver , cobalt chromium alloy , Medtronic ; TAXUS Liberté , 316L stainless steel , Boston Scientific ; Prokinetic , cobalt chromium alloy , Biotronik ; Lekton Motion : 316L stainless steel , Biotronik ; Multi-Link Zeta , 316L stainless steel , Abbott Vascular ; AVE : 316L stainless steel , Medtronic ; CYPHER : 316L stainless steel , CordisbDrug-eluting stent During cine imaging , the coronary stent was visible in 14 of the 18 scans -LRB- 78 % -RRB- , with a susceptibility related signal loss of 12.8 ± 4.3 mm in diameter . Due to severe interference of the coronary stent in 6 scans -LRB- 33 % -RRB- , analysis of surrounding myocardium was impossible -LRB- Fig. 1A -RRB- . Through-plane flow artifacts were present in 14 scans -LRB- from the aorta in 9 scans , from the pulmonary trunk in 7 scans , from the left ventricle in 3 scans -RRB- , and hindered visualization of the myocardium in 7 scans -LRB- 39 % -RRB- . In-plane flow artifacts were present in 4 scans , but were not clinically relevant . In the majority of the scans -LRB- 94 % -RRB- dark band artifacts appeared at the transition between myocardium and lung , with a predilection for the anterolateral wall , which resulted in severe image distortion in 8 scans -LRB- 44 % -RRB- . Overall , artifacts were responsible for clinically relevant image deformation in 12 scans -LRB- 67 % -RRB- , of which half was caused by the coronary stent -LRB- in 6 scans -RRB- . Fig. 1Short axis cine SSFP images in different patients , demonstrating a signal void from a coronary stent with myocardial interference at 3.0 T -LRB- A , white arrow head -RRB- , and a smaller signal void without interference at 1.5 T -LRB- B , white arrow head -RRB- No effect could be observed of B1 inhomogeneity on the suppression of viable myocardium on LGE images at 3.0 T. Stent safety and artifacts at 1.5 T Also during scanning at 1.5 T , no patient reported any discomfort or symptoms , and there were no clinical events during , or shortly after scanning . None of the patients underwent a repeat intervention or hospitalization for any reason within 30 days after CMR scanning . The mean number of implanted stents per patient per scan at 1.5 T was 1.2 ± 0.5 -LRB- see also Table 2 -RRB- . The mean stent length was 19 ± 5 mm with a mean diameter of 3.2 ± 0.4 mm , which was comparable with the stent length and diameter scanned at 3.0 T -LRB- p = ns -RRB- . In 7 of the 12 patients who underwent CMR scanning at 1.5 T in the acute phase , repeat catheterization at 2 -LRB- 2 -- 4 -RRB- days after scanning revealed no differences in stent position and patency compared to post-PCI . During cine imaging , the coronary stent was visible in 6 of the 18 scans -LRB- 33 % -RRB- , with a susceptibility related signal loss of 5.5 ± 0.3 mm in diameter , which was significantly smaller than at 3.0 T -LRB- P < 0.01 -RRB- . Furthermore , visible stents did not cause clinically important image deformation -LRB- Fig. 1B -RRB- . Besides the small signal void from coronary stents , no other artifacts were observed at 1.5 T. Also at 1.5 T there was no effect of B1 inhomogeneity on the suppression of viable myocardium on LGE images . Evaluation of image quality With scanning at 3.0 T , localized shimming was compulsory in every scan to obtain better image quality -LRB- Fig. 2 -RRB- . At 1.5 T , there was no need for adjustments in sequence parameters or the use of local shimming to optimize image quality . At 3.0 T , in 44 % of the cases , image quality was not sufficient for quantitative analysis and assessment of regional function of the left ventricle -LRB- Table 3 -RRB- . For clinical purposes and global assessment of left ventricular function , image quality at 3.0 T and 1.5 T were comparable . Image quality of LGE images was not sufficient for quantitative analysis in 53 % of the cases at 3.0 T , and 12 % of the images were not useful for clinical purposes . Both image quality of cine and LGE imaging at 3.0 T were significantly lower compared to 1.5 T -LRB- P < 0.001 -RRB- . Fig. 2Four chamber cine SSFP images at 3.0 T in end-diastole -LRB- A & C -RRB- and end-systole -LRB- B & D -RRB- , at the same slice position in one patient . Upper panels are without and lower panels with localized shimming . Dark band artifacts -LRB- apex -RRB- and flow artifacts -LRB- around the atrioventricular valves -RRB- are reduced with localized shimmingTable 3Consensus score of image quality of cine and late gadolinium-enhanced images for 1.5 T and 3.0 TCine SSFP imagesLate gadolinium-enhanced images1 .5 T3 .0 T1 .5 T3 .0 T1 . Not clinically useful0 -LRB- 0 % -RRB- 0 -LRB- 0 % -RRB- 0 -LRB- 0 % -RRB- 2 -LRB- 12 % -RRB- 2 . Clinically useful , no quantitative analysis0 -LRB- 0 % -RRB- 8 -LRB- 44 % -RRB- 0 -LRB- 0 % -RRB- 7 -LRB- 41 % -RRB- 3 . Clinically useful , quantitatively analyzable0 -LRB- 0 % -RRB- 4 -LRB- 22 % -RRB- 1 -LRB- 6 % -RRB- 8 -LRB- 47 % -RRB- 4 . Excellent quality18 -LRB- 100 % -RRB- 6 -LRB- 33 % -RRB- 17 -LRB- 94 % -RRB- 0 -LRB- 0 % -RRB- Values are presented as absolute numbers -LRB- percentage -RRB- Discussion In this paper we report on our initial experience with CMR scanning at 3.0 T in a clinical situation . We found that it is safe and feasible to perform CMR scanning at 3.0 T in the acute and chronic phase after MI in patients treated with primary stenting . Image quality of cine imaging at 3.0 T is of sufficient quality for global assessment of left ventricular function , however , quantitative analysis is not possible in almost half of the patients , due to dark band , flow and stent artifacts . Image quality of LGE studies were significantly better at 1.5 T. Therefore further optimization of pulse sequences at 3.0 T is essential . MR imaging is considered to be contraindicated in patients with ferromagnetic implants , primarily because of the potential risks associated with migration , the induction of an electrical current and heating of the implant -LSB- 14 , 15 -RSB- . According to earlier reports and the American Society for Testing and Materials International , the overall magnetic field interaction and heating for coronary stents is limited or absent at 1.5 T and 3.0 T , as tested in vitro -LSB- 16 -- 18 -RSB- . In vivo studies concerning stent safety at 1.5 T demonstrated that CMR scanning is safe in patients early after coronary artery stent placement -LSB- 19 -- 21 -RSB- . In this in vivo study using both 1.5 T and 3.0 T , no clinical signs were observed by the attending physician , and no substantial side effects or clinical events occurred during or within 30 days of CMR scanning . In addition , in the patients who underwent a repeat catheterization there was no angiographic evidence of stent migration , confirming the in vitro data . As discussed by Schär et al. -LSB- 7 -RSB- , dark band and flow artifacts in SSFP cine imaging can be solved using optimized sequence parameters , localized shimming and correct water resonance frequency adjustment . In the clinical setting of the present study , it was not always possible to solve these artifact problems despite sequence optimization and localized shimming , especially in the presence of stent artifacts . The larger and diagnostically interfering artifacts of coronary stents at 3.0 T as opposed to the smaller stent artifacts at 1.5 T are an important issue in patients after MI , since primary PCI with stent implantation is the method of choice to re-establish coronary flow -LSB- 22 -RSB- . For clinical application , it may be more advantageous to return to spoiled gradient-echo cine imaging at 3.0 T , which includes longer acquisition times and lower contrast between blood and myocardium , but is less sensitive for off-resonance artifacts and equally accurate as SSFP cine imaging -LRB- Fig. 3 -RRB- -LSB- 9 , 23 -RSB- . Fig. 3Short axis cine SSFP image -LRB- A -RRB- and cine spoiled gradient-echo image -LRB- B -RRB- , at the same slice position in one patient at 3.0 T . The coronary stent artifact on a SSFP image is larger than on a spoiled gradient-echo image -LRB- white arrows heads -RRB- . Flow artifacts -LRB- A , asterisk -RRB- are less visible with spoiled gradient-echo imaging at 3.0 T We initially intended to evaluate differences in signal - and contrast-to-noise ratios -LRB- SNR and CNR -RRB- of both pulse sequences as well . At 1.5 T good noise estimates could be made using the technique described by Constantinides et al. -LSB- 24 -RSB- . However , this method did not work at 3.0 T due to a different reconstruction algorithm , even without parallel imaging , and by switching off clear and image enhancement filters . Subtraction methods with two consecutive scans to estimate noise are inaccurate in a mobile tissue as the heart -LSB- 25 -RSB- . Other methods were beyond the scope of this initial study . Despite the fact that SNR 's and CNR 's were therefore omitted from this study , it is interesting to mention that an important reason for inferior quality of LGE images at 3.0 T was that infarcted myocardium was sometimes difficult to delineate from the left ventricular cavity -LRB- Fig. 4 -RRB- . Fig. 4Short axis LGE images 15 min after injection of contrast at 3.0 T -LRB- A -RRB- and 1.5 T -LRB- B -RRB- , in different patients . Visual assessment of infarct extent and location was more difficult at 3.0 T than at 1.5 T , since it was sometimes difficult to delineate infarcted myocardium from the left ventricular cavity at 3.0 T We used the same contrast agent and dose at both field strengths . The contrast dose has been optimized for 1.5 T in the past -LSB- 26 , 27 -RSB- , but might be different at 3.0 T as T1 relaxation rates are in general field strength dependent . However , a recent study of Sharma and colleagues showed that there were only minor differences in post contrast myocardial T1 relaxation times between 1.5 T and 3.0 T , using a contrast dose of 0.2 mmol/kg -LSB- 28 -RSB- . As long as inversion times are set appropriately at each field strength as done in this study , it is not to be expected that significant differences in LGE image quality are caused by contrast dose effects . In conclusion , our study demonstrates that it is safe and feasible to perform CMR scanning at 3.0 T in the acute and chronic phase after MI in patients treated with primary stenting . Although cine imaging at 3.0 T is of sufficient quality for clinical use , quantitative assessment is less reliable compared to 1.5 T , mainly due to dark band , flow and stent artifacts . Further optimization of pulse sequences at 3.0 T is essential to make 3.0 T CMR scanning suitable for clinical cardiology . Limitations The use of different MR systems , from different vendors , with different coils and sequence parameters , of course introduces confounding factors for a comparison . However , the sequences were optimized for their field strength to evaluate safety , feasibility and image quality rather than technical differences . A second limitation is that patients did not undergo a CMR examination at both 1.5 T and 3.0 T. Because the MR systems were on two different locations , it was not feasible to study the same patient twice in the acute phase after MI .

O O B I I O O O O O O O O O O O O O O B O O O O O O B O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

late gadolinium enhancement
cardiovascular magnetic resonance
safety


Ophthalmologists , suicide bombings and getting it right in the emergency department Background The number and extent of worldwide suicide attacks has risen sharply in recent years . The objectives of this retrospective study are : to determine the prevalence and outcome of the victims who sustained ocular injury , to describe the activities of ophthalmologists in the setting of an emergency department -LRB- ED -RRB- receiving mass casualties of a suicide bombing attack and to illustrate some of the treatment obstacles that they encountered and the protocol . The number and extent of worldwide suicide attacks has risen sharply in recent years -LSB- 1 , 2 -RSB- . The perpetrators typically mingle among crowds of civilians and detonate an explosive device that is usually strapped on their bodies with the intent of sacrificing their own lives in order to cause the death of as many others as possible . The injuries sustained by survivors of these well-planned attacks combine the lethal effects of penetrating trauma , blast injury , and burns -LSB- 3 -RSB- . Suicide attacks on civilians were historically confined to a limited number of countries , but the outrageous and devastating destruction of the Twin Towers in New York City on 11 September 2001 and the bombings in London and Madrid established the universality of such terrorism . With the rise in terror-related activities in urban settings , ophthalmologists worldwide may find themselves treating ocular trauma under conditions unlike any they had experienced before , and certainly remote from the relatively orderly setting of an emergency room in which traumatic ocular injuries can usually be counted on one hand at any given time . Since the beginning of the latest Israeli-Palestinian Intifada on 29 September 2000 , more than 4,600 people -- mostly civilians -- have been killed or injured by suicide bombings in that area -LSB- 4 -RSB- . The Tel Aviv Sourasky Medical Center -LRB- TASMC -RRB- is the largest hospital in the Tel Aviv metropolitan area . As such , most of the victims of the suicide bombing attacks in its catchment area are evacuated to TASMC , and a special treatment protocol has evolved for coping with the unusual logistic needs of such events . The objectives of this retrospective study are : to describe the activities of ophthalmologists in the setting of an ED receiving mass casualties of a suicide bombing attack , to illustrate some of the treatment obstacles that they encountered and the protocol that evolved for overcoming them , and to determine the prevalence and outcome of the victims who sustained ocular injury . Methods IRB approval was obtained for this retrospective interventional case series study . Clinical data on all casualties evacuated to the TASMC due to suicide bombing-related injuries were collected from the trauma registry records and reviewed . Their demographic data were obtained from the main admitting office records . The senior surgeon stationed at the ED entrance is rapidly provided essential information on the type/location of injuries from the arriving ambulance 's paramedical personnel . He/she pages the designated on-site specialist according to prioritization for urgent management . Ocular injuries are defined as any blunt , penetrating , or perforating trauma or blast-related damage to the eye , orbit , or ocular adnexa . The terms we used to describe ocular injuries conform to the recommendations the United States Eye Injury Registry and the International Society of Ocular Trauma -LSB- 5 -RSB- . Individuals with nonpenetrating or non-lacerating ocular injuries , non-penetrating debris in their eyelids , or superficial burns of the eyelids were excluded from this study , as were victims who died of their injuries before undergoing ophthalmologic treatment for whatever ocular damage had been suffered . The ocular injuries for each eye were categorized according to type : it was possible to have multiple occurrences of the same type -LRB- i.e. , multiple corneal lacerations -RRB- and of several types -LRB- i.e. , corneal laceration and retinal detachment -RRB- in the same eye . All records of ocular - and orbital-related trauma that were documented in the trauma registry were collected and analyzed together with hospital and outpatient clinic records . The analysis included age , gender , mechanism of injury , anatomic site of injury , Injury Severity Score -LRB- ISS -RRB- -LSB- 6 -RSB- , length of stay , length of intensive care unit stay , and surgical procedures . Ophthalmic information included the initially diagnosed ocular condition , all surgeries performed during the ED stay and afterwards , and final ocular test findings . The data were entered using Excel spreadsheet -LRB- Microsoft Office -RRB- and a simple descriptive statistical analysis was performed . Results There were 13 suicide bombing attacks in the Tel Aviv metropolitan area between October 2000 and October 2004 . A total of 352 patients were evacuated to the TASMC ED , and 198 of them were hospitalized . The other 154 patients suffered from minor injury or shock for which they were given appropriate treatment and instruction and sent home . The overall severity of suicide bomb-related trauma was very high : the mortality rate was 8.4 % when the attack occurred in open spaces , 15.5 % in closed spaces and 20.3 % when the bomb exploded inside a bus . The ISS was 1 -- 14 for 74 % of the patients -LRB- non-hospitalized -RRB- and ≥ 16 for the remaining 26 % of the patients -LRB- admitted to hospital -RRB- . One of the prominent hallmarks of suicide bombing injuries is the extremely high prevalence of head injuries : among our patients , 49 % suffered from head and neck injuries , 9 % head and extremity injuries , 4 % head and torso injuries , and 38 % torso and other injuries -LRB- all data are taken from the experience with the 13 bombings in Tel Aviv -RRB- . Seventeen patients -LRB- 4.8 % -RRB- were listed in the trauma database as having any ocular or periocular trauma , and several had more than one type of injury . The types of recorded trauma were : open globe injuries -LRB- n = 7 -RRB- , closed globe injury consisting of severe subconjunctival hemorrhage -LRB- n = 2 -RRB- , partial thickness lamellar laceration of cornea -LRB- n = 8 -RRB- -LRB- lamellar flap -RRB- of which five were burn-related and three were due to small foreign bodies , and extraocular injuries -LRB- n = 6 -RRB- , which included three orbital fractures due to primary blast injury and three eyelid lacerations . Primary repair of open globe was performed in six eyes that underwent primary closure of laceration . One patient who was diagnosed during the initial triage as suffering from open globe injury died during the initial trauma surgery , thus no ocular procedure was performed . Two other eyes underwent primary exploration of subconjunctival hemorrhage that was suspected as being open globe due to massive subconjunctival : no laceration was found intraoperatively , and contusion was diagnosed . The one eye that was found to be unsalvageable underwent primary enucleation . After the initial eye surgery , two patients died from their other injuries within 24 h of the explosions . Of the eight patients with partial thickness lamellar laceration of cornea , three were discharged and given instructions to return as outpatients on the following day . Five other patients who required and received medical treatment for non-ocular-related medical problems were hospitalized and continued eye treatment as inpatients . All patients in which superficial burns were found -LRB- n = 5 -RRB- were treated by manual removal of corneal foreign body and antimicrobial drops , and their recovery was uneventful . Secondary surgical intervention was performed on four patients -LRB- all surviving patients who initially underwent primary closure of open globe -RRB- within 1 week of the initial trauma : large intravitreal foreign bodies were extracted in three of them , and an intra-lenticular foreign body was extracted from the fourth -LRB- Table 1 -RRB- . At final follow-up -LRB- ≥ 2 years post-trauma -RRB- , the visual acuity of the three patients who suffered from large intravitreal foreign bodies were finger counting -LRB- FM -RRB- - hand movement -LRB- HM -RRB- . The silicone oil was removed in two of these patients and retained in the third ; two of them are wearing large cosmetic contact lenses due to corneal opacities that were cosmetically disturbing . The patient who underwent surgery due to intra-lenticular foreign body and penetrating keratoplasty had final visual acuity of 6/12 -LRB- Table 1 -RRB- . Table 1Relevant data of suicide bombing survivors who sustained open globe injuryNo.Age , years/sexPrimary surgical interventionSecondary surgical interventionForeign body extractedFurther surgeryFinal outcomeFinal visual acuity117/fClosure of open globePatient died within 24 h of trauma216/fNonePatient died within 24 h of trauma362/mEnucleation417/fClosure of open globeLensectomy , vitrectomy , removal of foreign body , endolaser silicone oil injectionMetal shrapnell -LRB- 5 mm -RRB- Silicone oil removalPreserved globe flat retinaFC518/fClosure of open globeLensectomy , vitrectomy , removal of foreign body , endolaser silicone oil injectionMetal ball -LRB- 2 mm -RRB- Preserved globe flat retinaHM619/fClosure of open globeLensectomy , vitrectomy , removal of foreign body , endolaser silicone oil injectionGlass fragment -LRB- 3 mm -RRB- Silicone oil removalPreserved globe flat retinaHM727/mClosure of corneal perforationPenetrating keratoplasty , lensectomy , vitrectomy endolaser , intraocular lens implantationGlass fragment -LRB- 1 mm -RRB- 6/12FC , finger counting ; HM , hand movement Discussion The dynamics of an emergency receiving center of victims of a suicide bombing attack are alien to most ophthalmologists . Today , the setting is characterized by large numbers of victims who sustain injuries that are more complex and more severe than those that had occurred during earlier periods of terror activity -LSB- 7 , 8 -RSB- . Importantly , suicide bombings are more likely to occur in closed spaces , unlike other mass trauma scenarios such as car bombs , train wrecks , and other outdoor explosions : over 62 % of injuries that occur in closed spaces are to the face , head , and neck , thus posing a far greater risk to the ocular structures . In our experience , 17/352 -LRB- 4.8 % -RRB- of the survivors of suicide bombing attacks sustained eye injuries , and 9/17 -LRB- 52 % -RRB- required urgent attention . This rate is surprisingly lower when compared to previous reports , which documented that close to 10 % of survivors of terrorist blasts have significant eye injuries -LSB- 13 -RSB- . We have no explanation for the low rate , but we can speculate that because of their close proximity to the hospital together with the efficiency of the Israeli Magen David -LRB- Red Cross -RRB- , almost all survivors are speedily brought to the hospital for examination after terror-related episodes and are listed as admissions in the trauma records , even those with no complaints or only minor ones . Thus , the large number of admitted individuals artificially decreases the percentage of eye victims . Importantly , 41 % of all of the reported ocular injuries -LSB- 9 -- 13 -RSB- were severe in degree . The final visual outcome of all the surgeries we performed was poor : globe preservation was successfully achieved in most cases -LRB- 6/7 -RRB- , but only one patient with an intra-lenticular foreign body had useful vision postoperatively . In order to provide the best treatment in such a complicated setting , special adaptations must be made to the treatment algorithm of the ophthalmology team . In terms of individual trauma cases , the victim of a suicide bombing attack is no different from any other eye trauma patient . The sudden presentation of large numbers of injured patients , however , presents two types of challenges : the logistical one of rapidly processing masses of casualties through the system and the medical one of providing the best possible trauma care to severely wounded patients -LSB- 14 -RSB- . According to our protocol , all patients who complain of eye symptoms and all unconscious patients who sustain head or face injuries must be checked by an ophthalmologist . This requires special disaster on-call lists of ophthalmologists who are able to arrive to the hospital on extremely short notice since , thanks to the highly efficient organization of our Red Shield ambulance facilities , blast victims usually arrive at the hospital within minutes and are hurried to either diagnostic tests or directly to operating theaters . Upon arrival to the ED , every victim of a terrorist attack is triaged by a senior surgeon who synchronizes the activities of the multifaceted operation . The ophthalmologists already present in the hospital and the ones on-call who arrive to the ED are in contact with that surgeon in order to expeditiously locate the victims with ocular injuries , examine them , and send them to the operation theaters , intensive care units , imaging studies or home . There is a directive in our department that all available staff members must contact the hospital immediately upon learning about any suicide bombing attack to check whether their services are required . In the event of large-scale attacks , they are prepared to be recruited to assist in triaging and in treating all the victims , not just those with ocular injuries . The triage procedure is the key to the successful management of large trauma events : the most important rule is that all patients must be checked by the ophthalmologist wherever they are located on the hospital premises . Trauma patients invariably require urgent treatment and some are sent directly from the ER to either imaging units or immediately to the trauma surgical unit . The senior ophthalmologist on the premises must contact trauma registration services , get a list of all admitted patients -LRB- usually assigned numbers upon admission -RRB- and make sure that each and every one of them is examined , even during emergency surgery or during imaging interventions for non-ophthalmological injuries . When an open globe is suspected , the eye is immediately patched , and the finding is reported to the surgeon in charge of the patient : the staff is instructed not to intervene in the treatment of the eye . Further evaluation is done only when it is certain that there is no danger of expulsive hemorrhage . Only patients suspected as suffering from open globe injury undergo urgent primary closure of the wound . Since that patient invariably presents with multiple injuries and may not be fit for transfer to the ophthalmology operating theater , however , special alterations to the surgical protocol may be required . For instance , no ophthalmological microscope is available in our trauma center because space is limited in the trauma room due to the concomitant performance of many surgeries and given the cumbersome structure of an ophthalmic microscope . There is , however , a high-quality neurosurgical microscope that has a long arm that can be placed at sufficient distance from the patient and the life-support machines so that it can be used without disturbing the anesthesiologists and other trauma teams as they work , and this microscope is used with great success during primary closure . Other eye surgery procedures are postponed , either until the patient has been stabilized or they are scheduled for a later date . This highlights the first critical responsibility of the ophthalmologist in the mass trauma setting , that of identifying which surgical procedures must be carried out immediately . The order of surgical intervention deserves special attention : due to the characteristic complexity of the injuries , most of the patients required multiple procedures immediately following the trauma . The established protocol adopted among our surgeons is -LRB- in descending order -RRB- : trauma surgery -LRB- for life-threatening conditions , performed by either trauma surgeons or neurosurgeons -RRB- , ophthalmologic interventions -LRB- immediate surgery or instructions for palliative care -RRB- , and orthopedic and plastic surgery interventions . Finally , terrorist bombings present a danger to the ED staff members that is never associated with any other mass casualty situation : there is a very real chance of explosion by a second-hit , either by explosive material remaining on the perpetrator 's body , or , even more threatening , a second suicide bomber who infiltrates the ED disguised as one of the victims and detonates the bomb inside the crowded ED . Thus , a unique caveat in the ED protocol for terrorist bombing attacks is heightened vigilance , starting from the chaotic first minutes after the arrival of the victims . Providing medical assistance in an ED to victims of suicide bombing attacks is a harrowing experience : physicians who work in an urban hospital are more and more likely to be exposed to such events -LSB- 14 -RSB- . In his excellent editorial , Hirshberg wrote `` Urban terrorism , the scourge of the 21st century , is already at our doorstep and surgeons are called upon to play leadership roles in shaping the emergency response in their hospitals . Learning from the experience of those for whom the unthinkable has become a daily reality can help us develop and implement more effective answers to the threats in our own communities '' -LSB- 14 -RSB- .

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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