V 80 no 1 spring 2011

The University of Western Ontario Medical Journal Volume 80, Issue 1, Spring 2011 www.uwomj.com ~-----------------------------------

EDITORIAL

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Onwards Laura Hinz

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FEATURE ARTICLES The use of nanotechnology in cancer management Yuding Wang, Chanseok Rh ee, Nianxin Jiang, Suganth Suppiah, Zoya Bahreini Faculty Reviewer: Dr. C. Hamm, MD

Near-infrared spectroscopy to assess penile blood flow: a possible novel technique for the diagnosis of vasculogenic erectile dysfunction Paul A. Kudlow, Sidney B. Radomski, MD, FRCSC Faculty Reviewer: Dr. Gerald Brock, MD, FRCSC

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HEALTH TECHNOLOGY ARTICLES Surgical treatment for articular cartilage injuries in the athlete's knee Sandeep Dhaliwal and Brennan Ballantyne Faculty Reviewer: Dr. Marie-Eve Lebel, MD

Computed tomography (CT) based calcium scoring in the diagnosis and prognostication of coronary artery disease (CAD) Jai Prashanth Jayakar, Adrian Matthews and Joshua Rosenblat Faculty Reviewer: Dr. Aashish Goe/a, MD MSc FRCPC

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Direct-to-consumer genetic testing in Canada Laura Allen, Mosko Hamidi and Niran Argintaru Faculty Reviewer: Dr. W. Liang, JD, MD

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Improving healthcare with information technology Karline Treurnicht Naylor, Paul Kudlow, Felix Li and Kevin Yuen Faculty Reviewe r: Dr. Kellie Leitch MD, MBA, FRCSC

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Using texts for safe sex: technology in adolescent sexual health Stephanie Gottheil, Paul A. Kudlow Faculty Reviewer: Dr. Lois Champion. Critical Care and Anesthesia

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PACS, SRR and the future of radiology Ashley Kim and Emma Farley Faculty Reviewer: Dr. Richard Rankin

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Lab-on-a-chip technology: the future of point-of-care diagnostic ability Melissa J. MacPherson, Mayoorendra Ravichandiran

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Faculty Reviewer: Dr. Cyrus Hsia, MD, FRCPC

An Interview with Dr. Ting-Yim Lee, PhD Lauren Sham, Abdul Naeem, Joyce TW Cheung

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Molecular genetics in clinical practice for the rapid identification of pathogenic organisms Roman Shapiro Faculty Reviewer: Dr. Caroline Hamm

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The application of three dimensional laser surface scanning and imaging in a case of total nasal reconstruction Michal Brichacek Faculty Reviewer: Dr. Douglas C. Ross, MD MEd FRCSC

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Candles to computers: the story of minimally invasive procedures Pencil/a Lang Faculty Reviewer: Dr. Terry Peters, PhD

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The University of Western Ontario Medical Journal EDITORIAL TEAM

EXECUTIVE TEAM EDITOR-IN-CH IEF

LAURA HINZ (MEDS 2011) PASQUA LE MONTALEONE (MEDS 2011)

SENIOR ASSOCIATE ED ITOR

PENCILLA LANG (MEDS 2011)

JUNIOR ASSOCIATE ED ITORS LAYOUT EDITOR

PAUL KUDLOW (MEDS 2013) JOYCE T.W . CHEUNG (MEDS 2013) MAYOORENDRA RAV ICHANDIRAN (MEDS 2013)

DEPARTMENTAL EDITORS CLINICAL PROCEDURES

SAN DEEP DHALIWAL (MEDS 2013), BRENNAN BALLANTYNE (MEDS 2014)

DIAGNOSTIC REVIEW

JAI JAYAKAR (MEDS 2013), ADRIAN MATTHEWS (MEDS 2013), JOSH ROSEN BLAT (MEDS 2014)

ETHICS AND LAW

MOSKA HAMI DI (MEDS 2013), LAURA ALLEN (MEDS 2013), NIRAN ARGINTARU (MEDS 2014)

HEALTH PROMOTION

PAUL KUDLOW (MEDS 2013), STEPHANIE GOTTHEIL (MEDS 2014)

HISTORY OF MEDICINE

PENCILLA LANG (MEDS 2011)

INTERDISCIPLINARY

EMMA FARLEY (MEDS 2013), ASHLEY KIM (MEDS 2013)

MEDICINE AND TECHNOLOGY

MAYOORENDRA RAVICHANDIRAN (MEDS 2013), MELISSA MACPHERSON (MEDS 2014)

PROFILES

JOYCE TW CHEUNG (MEDS 2013), ABDUL NAEEM (MEDS 2014), LAUREN SHAM (MEDS 2014)

THINKING ON YOUR FEET

ESTHER CHAN (MEDS 2013), ROMAN SHAPIRO (MEDS 2014)

ZEBRA FILES

M ICHAL BR ICHACEK (MEDS 2013), JULIE LEBERT (MEDS 2013)

HEALTH POLICY AND ECONOMICS

PAUL KUDLOW (MEDS 2013), KARLINE NAYLOR (MEDS 2013), HANG SHI (MEDS 2013)

EDITORIAL BOARD DR . LOIS CHAMPION

DR . FAISAL REHMAN

DR . MICHAEL RIEDER

DR . JIM SILCOX

DR . JEFFREY NISKER

DR . DOUGLAS QUAN

COVER ART: ABDUL NAEEM FRONT: I created the picture to reflect the emergence of medicine and hea lth with tech no logy.

BACK: What I am trying to convey with th is piece wa s to have a crystal ba ll t hat is looki ng in to t he f uture . The base acts as our current standing point looking into the future. The insid e of the crystal ball is a bio-mechanical hybrid of a human hand.

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Onwards Laura Hinz (Meds 2011)

hen fa ced with the wo rd " techno logy," images of robots, supercomputers, and rn a sive e lectri ca l circuit spring to mind . However, the concept of techno logy ste ms fro m G reek th inkers, long before the introducti on of any of tho e devices . 1 Techno logy encompasses mo re than gadgets and gizmos, it invo lves any nove l way of thinking, creating, or orga nizing that a ims to solve a pro bl em. Thus Hea lth Techno logy was an ideal theme fo r an issue of the U WO MJ , whose mandate has always been to in pire and ce lebrate new, innovati ve approac hes to medi c ine.

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In thi iss ue Dha liwa l and Ba llanty ne describe a tec hnique that use the bodies own ce ll s to heal art icul ar cartil age injuries. Thi s arti c le illustrates the perfect union between health and techno logy by suggestin g the idea that if manipulated correctl y, the body itse lf can be a so urce of hea ling. However, the technophiles will find the more common concepti on of techno logy in an e loquent arti c le by MacPherson and Rav ichand iran, describing adva nces in the fi e ld of microfluidi cs eng ineerin g.

I approached thi s issue with a certa in degree of trepidati on, as c ircuits and computer rema in reso lute ly beyond my grasp. Th ose w ith s imilar limitati ons will find hope in Gotthe il and Kudl ow 's arti cle, whi ch describes an adaptation of a commo n tec hno logy (namely text messaging) to serv ice a hea lth ni che. Not onl y is thi s a reso urce-e ffi c ient approach to techno logy, but it puts techno logica l deve lopment within the gras p of eac h indi vidual. You do not need to be an eng ineer in order to develop techno logy; you simply need to be inqui siti ve, observant, and creati ve.

Whil e the ultimate goa l of techno logy is to so lve probl ems, it can a lso create new o nes in its wa ke. For in tance, the Medi cine and the Law editors ex plore the ethica l implications of direct-toconsumer genetic testing. With the deve lopment o f new techno logy, we must consider how it will be utili zed, who it wil l affect, and what furth er changes it w ill bring.

It is thus reasonable, and nerves re li ed on changes in current. perh aps vita l, to look beyond medi c ine for medi ca l techno logies.

We have een countless exam pl e of the impa t of tec hno logy on med icine- e lectro ni c hea lth records, ge nomic seq uencing, robotic surgery. Perh aps less obvious is the impact of techno logy on each ind ivi dua l's habits and ways of thin king. T hi s jo urna l is in print fo rm , as many peop le object to readin g off a screen. Wh y? There is nothin g innate in our bra in that says that the printed wo rd must be black on a white background, sized 8.5x 11 wi th page that can tu m .

If yo u handed a book to someone accustomed to scro ll s, they may regard it with the same disda in as I currentl y reserve fo r e-readers.

As techno logy evo lves, our determ ination of w hat is no rm al or comfortable will change. If our editors had been asked to w ie ld a n o ld-fashi oned pen fo r thi s issue, the arti cles may have been much briefer as they lamented the loss of the qui cker and more ergo no mi c wo rd processer.

As thi s is my last contrib ution to the UWOMJ , I wo uld like to thank all of the writers, fac ul ty, adverti sers, and readers w ho make thi great pub li cation possibl e. Thi s issue ex pl ores fo rays into the unkn own, atte mpts to ex pand o ur kn ow ledge and improve our abili ty to hea l. To the C lass of 20 II , thi s i exactl y what we will be attempting to do as we head off on our va ri ous res idenc ies. I urge yo u to take the lessons of fo ur yea rs of c lini c, c lass, and camaraderie and temper it w ith the sage advice to ' don' t stop be li ev ing.' 4

REFERENCES I. O nlin e Etymo logy Dicti onary. http://www.etymonl ine.co m/ index .php? term=techn o logy. Accessed 09/02/20 II .

2. Brown PJ . C ultu re, Illness and Me ntal Hea lth . In: nder tandin g and Apply ing Med ica l Anthropo logy. 1998 . Mayfield Pu bli hing Company.

Pg 183-4.

3. Do idge N . The Brai n T hat C hanges Itse lf: Sto ri es of Personal Triumph fro m th e Fronti ers of Bra in Science. 2007 . Penguin Books.

4. Schon , Ca in J, Perry . Don ' t top Be liev in '. Journ ey: Escape. 198 1.

The introduction of techno logy can a lso he lp to legi timi ze an a ilment by providing a solution. There are several "culture bound syndromes," those that ex ist among certain gro ups onl y2 Severa l years ago, the medi ca l schoo l curri c ulum would not have inc luded erectile dysfun ction . With very few treatments availabl e, the sti gma that shrouded this di sord er prevented many men from admitting to symptoms. With new techniques such as those described by Kudl ow and Radomski , the prospect of cure ha led to erectil e dys fun ction 's recognitio n as a legitimate diag nosis.

The phrase " Hea lth Techno logy" implies a separate part o f the whole, a branch o f study unto its own . However, innovations in a va riety of fi e lds ha ve had an impact on medi c ine. In hi s book "The Bra in that C hanges Itself," Dr. Do idge suggests that the concept of bra in plasticity was initi all y li mited by the prevailing mechani sti c v iew of the brain .3 Great ad vances were be ing made in eng ineering, which led sc ienti sts to liken the brain to a machine. Mac hines do not grow a nd change, thus the idea that the bra in could adapt after illness or injury was disregard ed. With the di scovery of e lectri city, a new conceptualization of the brain unfo lded with the suggesti on that

UWOMJ I 80 :1 I Spring 2011

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The use of nanotechnology in cancer management Yu ding Wang (Meds 2013)*, Chanseok Rhee (Meds 2013)*, Nianxin Jiang (Meds 2013)* Suga nt h Suppiah (Meds 2013)*, Zoya Bahreini (Meds 2013)* *Following authors contributed equally to this paper.

Faculty Reviewer: Dr. C. Hamm (Department of Oncology, Windsor Regional Cancer Centre) rug deli very y terns have prov ided th e phannace uti ca l industry a means of improvi ng the th erapeuti c pro perties of pre-ex i tin g drugs. These systems, such as lipid- or polymerbased nanoparti cles, alter the pharm aco kin eti cs and bi odi stributi on of th e drug th at is being carri ed 2 A nanoparti c le is form a ll y de fin ed as an eng ineered parti c le in nanometer ize. The inherent properti es of th e nanoparti c le make it an idea l vector to di stribute dru gs. The submi cron size, with di ameters less th an 200 nm , of th e nanoparti c le increases its intrace llular uptake, abili ty to penetrate thro ugh submucosa l layers and cross th e bl ood bra in barri er. 2 路3 Both synthetic and organic po lymers have been utili zed to create bi odegradable nanoparti c les, like the po lylactides th at undergo hydro lys is upon implanta ti on and broken down to lacti c ac id . The drugs are re leased via diffusion across the po lym er matri x and through biodeg radation o f the polymer itse l f.3 anoparti c les conju ga ted with ti ssue-speci ti c li gand also all ow th e deli very of th e drug to be more targeted, and redu ce th e amount of side e ffects.3.4 As a res ult, nanopartic les have th e potential to increase the potency and e ffi cacy of the drugs th at are a lready used in practi ce.

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Nan oparti cle could vastl y improve th e tools we have to fi ght cancer through a two- fold app roach: ( I) earl y detection o f cancer and (2) can cer th erapeuti cs. The nanoparti cles target th e site o f th e can cer for both diagno ti c and th erapeutic purpo es. The potenti al o f nanoparti cles in th e fi eld o f oncology i ho ld many promi ses.

NANOTEC HNOLOGY FOR CANCE R DI AGNOS I S Vari ous nanoparti cles such as ironox ide crystals, and QD emi conductor non-crysta ls, have shown great potenti a l for detectin g di sease markers, pre-cancerou s ce ll s, frag ments o f viruses, speci ti c prote in s, antibodi es and oth er di sease indi cators. 5 In th e fi eld o f onco logy, nanoparti c les ca n ass i t to no nin vasively detect tum ors at an ea rl y stage, perhaps months or even yea rs earli er th an th e conventi ona l di agnosti c too ls wo uld make th e same diagnos is, and thus res ult in max imum th erapeuti c bene fit and improve th e progno is o f th e patients. For instance, in brea t cancer, nanomedi c ine can potentia ll y use mo lec ular imag ing to acc urate ly di ag nose breast ca ncer when th e tumor ma has onl y I 00- 1,000 ce ll s , a s o ppose d to th e c urre nt im ag in g tec hniqu es like mammograph y, whi ch require th e detecti on o f more than one mi ll ion tumor ce ll s for acc urate c lini ca l dia gnos is. 6 QDs are emi conductor nanocry tals made up o f I00- 100,000 ato ms 7 Q D conta in e lectrons, which after excitati on, can re lax to th eir gro und state and release photon in th e proce s, lead ing to a vis ibl e flu ore cence. The flu ore cent signa ls of Q Ds are I 0-100 tim e bri ghter compared to orga ni c dyes and th e ir emi ss ion properti e make it poss ibl e to overcome ti sue auto flu orescence 8 路9 A lso, spec ia ll y-e ng ineered Q D coated with stea lth po lymer can resi t photobl eaching and ce llular deg radati on better th an conve nti onal

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fluo rophores (molecules capab le of flu orescence), a llowing studies to be carried out over time. 10 Due to a ll the e unique characteri stics, Q Ds can be conjugated to anti bodi es that have affi ni ty fo r tumorspec ific an tige ns, and they wi ll preferenti all y loca li ze to th e tumor cell s. T he ide ntification of th e changes in ce llular surface protein concentrati on can be an earl y ind ication of cancer. 10 Other studies have show n that by injecting Q D-labe lled me lanoma ce ll into mice, one can vi ua lize in vivo the m igrati on of tumor ce ll s to the lungs on imaging. 9 T his abi lity to track tu mor mi cro-meta tas i can lead to greater unde r tand ing of the behavior of metastati c cancer and d i covery of ne' treatment option .

In practice, identification of th e entine l lymph node (SLN) in breast cancer can be chall eng ing . Currently mapping is don e by using blue dye and radi o i otope . Thi technique obscure th e urg ical fie ld and can ca use rad iation to th e pat ient and hea lth care providers.

Superparamagnetic iro n oxide nanoparti cles a ll ows pre-operati ve M RJ v isualization and intra-o perati ve magnetometer- aided detection of S L , remo ing the need fo r harm ful radi o iotope and obscurin g dyes 8 anoparti c le can a lso make importa nt advance ments in di agnos ing and imag ing o f brain tumor , throu gh both preoperative and intraoperati ve brain mass detecti on, a llowing for early detection of precancerou ce ll and improv ing th e prognostic outcomes of cancer pati ent . C urrentl y, the most wide ly u ed MRJ contra t agents are based on paramagneti c gado linium (Gd(lll) ). 11 While still a luabl e, th e e ion are not w ithout the ir probl ems. They tend to diffuse freely through a tumor and pre ferenti all y image area where th ere i prominent blood-brain barri er breakdown , prov iding limited enhancement of th e infiltrating tum or marg in or areas of poorly va culari zed mi crometa tas is. Al so, th e permeability of blood-tumor barri er is not homogenous, whi ch mea n that th e ion cannot enter a ll area o f th e tum or equa lly. Furthem1ore, thi s contrast materia l has di ffi c ult y di c rimin atin g tum o r fro m CNS infl a mmation or infecti ons. N anoparti cles des igned to pre ferentia ll y target tumor areas, uch a uch as Ferum ox tran- 10, a dextrancoated iron oxide nan? parti cle, have been developed a new MRI contra t agents to avo 1d many o f th ese probl ems and provide a wide r window of opportumty for tumor imag ing and enhancement. II

NANOTECHNOLOGY AS CANCER T H ERAPEUTI C Many conventio na l cancer th erapeuti c agents work by induc ing ~e llular tox1c1ty causmg can cer cell death . Although cancer cell a re mherentl y more susceptible to th e e ffects of these age nt , the e agent a lso a ffect normal cell . .Tl~i s p.uts a con traint on the do age and f~:qu e.ncy of treatment as 1t mev 1tabl y ca.uses injllly to norma l cell s. . Th1 s constraint o fte n res ults 111 suboptimal treatment, which contnbu.tes to the persistence and recurrence of can cer after th e comp letiOn of chemotherapeuti c treatment. 13 Current advance 111

UWOMJ I 80 :1 I Spri ng 2011

nanotechnology seek to resolve these therapeutic constrai nts by a llowing for specific targeting of cancer cell s helping to increase drug efficacy while limiting un wanted toxicity.

Cancer specific nanoparticle directed drug de li very takes advantage of cancer physiology by both a pas ive and active drug de livery mechani sm. In the passive drug delivery mechani sm, nanoparticl es are selective ly concentrated at the ite of the tumour by the enhanced permeability and retention effect (EPR). 14 The EPR work due to the inherent faulty phys io logy of fast grow ing tumour. lt is known that tumours require angiogenesis for continued growth .

However, the g rowth of these new blood vesse l is di sorgani zed and leaky due to enlarged junctions between endothelial cell as well as defi c iencies in the underlyin g base ment membrane. 15 Whi le normal endothelium junctions are typicall y 5 to I 0 nm in ize, 13 ga ps between the leaky endothe lium of the tumour are signifi cantl y larger and range from I 00 to 750 nm . 16 Concurrentl y, the di sorga ni zed growth of the tumour a lso res ults in form ation of a disorganized lymphatic network. 14 The leaky va culature and the lack of a lymphatic network result in the accumulation of nanoparticles in the cancer interstitium, passivel y concentrating dru g at the site of the tumour. 14 Novel nanoparti cle chemotherapy, Doxil (a pegy lated liposomal doxorubicin nanoparticle), takes advantage of the EPR. In vitro ex periments have shown Dox il to have a I 0-fo ld increase of doxorubicin concentration (the chemotherapeutic drug (or payload)) within the tumour compared with conventional doxorubicin administration. 17 A lthough clinical trials comparing Dox il and conventional doxorubi c in administration have shown no stati tical improvement in survival (overall and disease free) , Doxil was neverthe less shown to significantly decrease the ri sk of cardiotoxic effects of doxorubicin use (a significant side-effect limiting dosage and usage) . 17 It shou ld be noted that the pegylation procedure helps the nanoparticle escape from macrophage detection 18, whi le the lipo omal core structure helps protect the bound doxo rubicin to achieve a significantly longer half-life than free doxirubincin a lso contributing to the increased concentration of drug seen at the site of tumour.1 7, 18 The active drug delivery mechanism works by targeting specific receptors preferentiall y expressed on the tumour cell. For examp le, folate receptors are prefere ntiall y expressed in some cancer phenotypes whi le showing limited expression in normal ti ssue . 19 Experimental findings in mouse model s comparing conventional paclitaxel (given as free dru g) with a heparin-folate-taxol (heparin as carrier molecule and fo late as targeting molecule) showed the folatedirected nanoparticles to have more potent activity against tumour growth. 12 Another example is the transferrin receptor. In vitro studies using MCF-7 (human breast cancer cell line) comparing transferrinconjugated paclitaxel-loaded nanoparticles treatment versus free paclitaxel showed the transferrin-conjuated paclitaxel treatment to have greater inhibitory effect on cell growth. 20 Although drugs can be delivered to the tumour, another significant impediment remains due to chemotherapeutic drug resi stance. The most studied cause of resistance is the membrane associated protein pump p-glycoprotein (p-gp) 2 1 The p-gp is expressed in a number of cell types in the body and functions to effectively pump chemotherapeutic agents out of the cell , conferring resistance. Nanoparticle drug design could sidestep this impediment by a number of poss ible mechanisms . One such mechanism is to coadminister a p-gp antagonist along with the therapeutic drug, thus inhibiting the p-gp function. 21 Clinical trial s eva luating various potential antagonistic agents have shown disappointing results thus far, though new compounds continue to be discovered with improved binding specificity to p-gp 21 Another mechani sm cou ld rely on receptor mediated endocytosis and subsequent endosomes formation as means for gaining access to the cell cytoplasm, which could

effectively mask the nanoparticle until a high concentration of therapeutic drug is released to reach therapeutic effect, essentially overwhe lming the p-gp. 12 In vitro and in vivo mouse model have shown that drug resista nce can be overcome through thi mechanism .

21 Nanopa rti c le as a means for drug delivery offers many unique benefits in the treatment of cancer compared to other targeted drug therapies proposed such as ant ibody-d ru g conjugates . Firstly, nanopa rticles cou ld carry a significantly large r drug payload per ligand-receptor binding event compared to antibody-dru g conjugates as we ll a being more versatile in the type of drug its ab le to carry since drugs are stored w ithin the nanopartic le, with limited exposu re to enviro nment, while the type and number of drugs conjugated to an antibody cou ld ignificantly affec t its kinetics and biodistrubution. 18 Secondly, nanoparticles are large enough to target multipl e li gands allowing for multiva li ent bind ing and se lectivity enhancement.

Therefore, nanoparti c les can use mu lti ple weak liga nd interactions to greatl y increase the pool of cancer binding targets whereas si ng le li ga nd recogn ition offered by antibod y- conjugates require strong affi nity to be effective.22 Thirdly, nanoparticle des ign could allow the rate of release to be tailored for the drug of action . For example, topoi somerase I inhibitors such as the camptothecin-based drugs are reversible inhibitors of the enzyme, and therefore, have better efficacy if exposure of drug is pro longed 23 Lastl y, nanoparti c ls co uld a llow for the co- localization of different type of agents to work synergisticall y within the target cell to increase drug efficacy. 22 CONCLUSION Nanoparticles hold new promise as means for earlier detection and better treatment of cancer. Imagine a future w here nanoparticles can help detect cancer before it even has a chance to manifest, and se lective ly destroy cancer cells while leaving the normal cells unharmed . Cancer, in such a ci rcumstance, cou ld become a hi ghl y managea ble condition. However, despite our current resea rch there is much we still do not understand. Nanoparticles offer a new avenue to tackle these cha llenges. More research is needed in thi s promi sing and dynamic fi eld of cancer therapeutics.

REFERENCES 1. Canadian Cancer Society Cancer Statistic 2009 ; Avai lab le from : hllp:/1 www.cancer.ca/canada-wide/ about% 20cancer/ cancer% 20s tat is ti cs/-/ med ia/CCS/C anada%20w ide/F i les% 2 0 List/Eng! ish% 20ti les% 20head i ng/ pd f0/o20not% 20in% 20pub l ications% 20section/ S tats% 202009 E% 20 dn %20Cancer.as hx 2. Allen TM , and Cull is PR. Drug delivery system : entering the mainstream.

Science. 2004 Mar I 9;303(5665): I 8 I 8-22.

3. Panyam J, and Labhasetwar Y. Biodegradable nanoparticles for drug an d gene delivery to ce ll s and tissue. Adv Drug Deliv Rev. 2003 Feb 24;55(3): 329-47 .

4. Moses MA , Brem H, Langer R. Advancing the fie ld of drug delivery: taki ng aim at cancer. Cancer Cell. 2003 Nov;4(5):337-4 I. 5. Rathy Ravindran. anotechno logy In Cancer Diagnosis and Treatment: an Overview. Oral and Max ill ofacial Pathology Joumal. 20 II Jan-Jun;2( I): 101-106.

6. Tanaka T, Decuzzi P, Cristofani lli M, et a/. Nanotechnology for breast cancer therapy. Biomed Microdevices. 2009 Feb; I I (I ):49-63 .

7. Mazumder, S, Dey, R, Mitra, MK , et a/. Review : Biofunctionalized Quantum Dots in Biology and Medicine. Journa l ofNanomateri a ls, 2009 .

8. Gunasekera UA, PankJlUrst QA, Douek M. Imaging app lications of nanotechno logy in cancer. Target On col. 2009 Sep;4(3): I 69-8 I. 9. Voura EB, Jaiswal JK, Mattoussi H, Simon SM. Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning micro copy. at Med . 2004 Sep; I 0(9):993-8.

10. Ro enb lum LT, Kosaka N, Mit unaga M , eta/. In vivo molecular imaging using nanomaterials: general in vivo characteristics of nano-sized reagents and applications for cancer diagnosis . Mo l Membr Bioi. 20 I 0 Oct;27(7): 274-85.

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11. Ori ve G. Ali 0 , Anitua E, et a/. Biomateri al-based techn ologies fo r brain anti-cancer therapeuti cs and imaging. Biochim Biophys Acta. 20 I 0 Aug; 1806( I ):96- 107.

12. Cho K, Wang X. ie S, Chen ZG. Shin DM . Therapeuti c nanoparti cle fo r drug deli very in ca ncer. Clin Can cer Re . 2008 Mar I ; 14(5): 13 10-6.

13. Haley B, Frenkel E. Nanoparti cles for drug de livery in cance r treatment.

Urol Oncol. 2008 Jan-Feb;26( I ):57-64.

14. Maeda H. The enhanced perm eability and retention (EPR) effe ct in tum or va culature: th e key role of tum or-se lective macromolec ul ar drug targetin g. Ad v nzyme Regul. 200 I ;41 : 189-207.

15. Baban DF, ey mour LW. ontrol of tumour va cular permeability. Ad v Drug Deli v Rev. 1998 Oct 5;34( I ): I 09-11 9.

16. Campbell RB. Tumor physiology and deli very of nanopharm ace uti cal .

Anticancer gem Med Chern . 2006 ov;6(6) :503- 12.

17. Markm an M. Pegylated liposomal doxorubi cin in the trea tm ent of ca ncers of the breast and o ary. Ex pert Opin Pham1 acoth er. 2006 Aug;7( II ): 1469-74.

18. Dav i ME, Chen ZG . hin DM . anoparti cle therapeuti cs: an emerging treatment modali ty for ca ncer. at Re Drug Discov. 2008 ep;7(9) :

22. Ferrari M. Cance r nan otechnology: opportunities and challenges. at Rev Ca ncer. 2005 Mar;5(3): 16 1-71.

23 . Pommier Y. Topo i omera e I inhibitors: molecu lar and cellular detenninants of acti vity. 2003 . Available from : http://discover.nci .nih .gov/ pommier/topo !.hun

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19. hen H. Ahn R. Va n den Bossc he J,et a/. Folate-medi ated intrace llular drug deli very increases th e anti ca nce r effi cacy of nanopart ic ul ate formul ation of ar eni c tri ox ide. Mol Cance r Ther. 2009 Ju1 ;8(7): 1955-63 .

20. ahoo K , Labh aset\\ ar V.E nh anced antipro li fe rati e ac ti\ it y of transferrin -conj ugated pac litaxe l-loaded nanoparti cles is medi ated via sustained intrace ll ular drug retent io n. Mol Pharm . 2005 Sep-Oct;2( 5 ): 373-83.

21 . Thoma H, oley HM . Overcoming multidrug resistance in ca ncer: an update on the clini cal trategy of inhibiting p-glycoprotein . Cancer ontrol. 2003 Mar-A pr; I 0(2) : 159-65 .

SUN STAR

For more mforma1on contact Suns tar at 1 800 265路8353 V1s1t GUMbrand.com 2011 Sumlar An!HIU\o lilt l \1001

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UWOMJ I 80 :1 I Spring 2011

Near-infrared spectroscopy to assess penile blood flow: a possible novel technique for the diagnosis of vasculogenic erectile dysfunction Paul A. Kudlow (Meds 2013), Sidney B. Radom ski, MD, FRCSC Faculty Reviewer: Dr. Gerald Brock, MD, FRCSC (Division of Urology, Department of Urology)

rectile dysfunction (E D) i defi ned as the consistent inabili ty to achieve and ma intain an erecti on uffic ient to pennit sati sfactory sex ua l perfo rmance or intercourse 1• The vast majo ri ty of cases of ED are primaril y of organi c and vascular etiol ogy, although psychol ogical factors also play a ro le in many cases 1 • Affecting an e timated 2 milli on Ca nadi ans and beco ming increas ing ly commo n w ith age, ED has been shown to compromi se overa ll quali ty of li fe and is assoc iated w ith depression, anx iety, and loss of se lf-es teem 2 To date, the diagnosis of ED is typi cally made o n hi story and physica l exam 3· 4 . In recent years however, increased understanding of the hemodynami cs invo lved in vasc ul ogeni c ED has lead to the development of a number of di ffe rent di ag nosti c tests.

These include penil e brachial index, intracave rn ous pharmaco logic testing, penile tumescence mo nitorin g, co lor duplex ultraso nography, cave rno sograph y a nd ph a rmaco logic cave rn oso metry, penil e scintig raphy, and selecti ve pudendal arteriography! · 5 Whil e each yields inforn1ati on of some diagnostic va lue, there is yet to be a sing le test or "gold standard" for diagnosis of EDJ Much of thi s could be due to that fact that many of the current tests are compl ex , ex pensive, invasive, and often inacc urate. Given these limitations, and es peciall y in light of advanci ng effi cac iou ora l therapi es readil y ava ilabl e, some spec ia li sts arg ue that these tests should be reserved for pecial cases of ED where a diagnos is is important or urgery is required . Howeve r, an oppos ing view is that a minima ll y invas ive and cost-effective test may till be of va lue in compl eting the appropriate management of a patient w ith suspected va culogenic ED6 .

E

Thi s stud y was und e rtake n to exa min e nea r- infra re d spectroscopy (N lRS) as an approach to study penile bl ood flow and thereby explore a potenti a l nove l diagnosti c too l for assess ing vascul ogeni c ED. N IRS has emerged as a new techno logy within recent yea rs for monitoring blood fl ow non-in vasive ly and sa fe ly.

The techno logy uses photons of lig ht in the near infrared spectrum to assess concentration changes of oxygenated and deoxygenated hemog lobin in ti ssues 6. It can provide information concerning both oxygen saturation and re lati ve bl ood vo lume changes within the o rgan of interest. A lthough N l RS has been w idely used to assess muscle and cerebra l blood flo w, it use in the assess ment of penil e blood flow has been limited 6 . We exam ined the use of N IRS to detect pe nile blood flow and to determine if increases in oxygenated hemoglobin (0 2Hb) concentrations corre late with erections.

METHODS Two groups of men were exam ined. Group I cons isted of I 0 youn g men with no erecti le difficulties, mean age 19 years (range 18-22).

These men allowed us to determine the techni ca l as pects of NIRS monitoring on the peni s (i.e. optica l sensor placement and how to secure the sensor) and the feas ibility of assessing penile blood flow with visual sex ual stimulation (YSS). Group 2 consisted of 12 men

with prostate ca ncer undergo ing a bilateral nerve sparin g radical pro tatectomy (RP). Mea n age of the patient was 55 years (ra nge 44-66) . These men underwent N IRS w ith YSS preoperatively and at 3 months postoperati ve ly w ith and wi thout 20 mg of va rdenafi l. Each compl eted a va lidated psycho metrica ll y va lidated questi onnaire li EF (Internati onal Index of Erectile Function) pre and postoperative ly.

During N IRS testing each man was asked to assess if an erecti on occurred during the YSS .

RESULTS With Group I we were ab le to create a re-usable NIRS optical sensor probe which wa taped to the penis . In 7110 of the men an erectio n occurred wi th YSS and wi th NIRS testing. 0 2Hb concentrati on increased in a ll 7 men (Figure I). In G ro up 2 the mean II EF preoperati ve core was 25 (range 5-30) and the postoperative score was 11 . 1 (range 1-26). With N!RS testing preoperatively without va rdenafi l, 8112 men felt they had some erect ion wi th YSS, and in 7/8 of these men there wa an increase in 0 2Hb concentrati on. In the o ne in whi ch N IRS was unsuccess ful the erecti on was minima l. In

Figure I. Norma l ma les with good erections after VSS. Increase in 02Hb. thi s same group, 9/ 12 men with N IRS testing showed increases in 0 2Hb concentrati on w ith YSS, 2 of which fe lt they had no erection (Fi gure 2). When vardenafi l was g iven preoperati vely wi th NIRS testing, 12112 men fe lt they had some erection a nd I 0/12 of the e men had an increase in 0 2Hb concentration. Postoperati vely wi tho ut va rdenafi l on N IRS testing 2/12 men fe lt they had some erection and 7/ 12 men we re fo und to have increases in 0 2Hb concentrati on incl uding the 2 men that had some erection. When va rdenafil was

UWOMJ I 80:1 I Spring 2011

7

added postoperati vely 7/12 men fe lt they had some erecti on and 7112 men had increa es in 0 2 Hb concentrati on on NIR te ting (5 pati ents wi th an erection and 2 wi thout). There was a rapid rise in 0 2 Hb concentration in men wi th excellent erection .

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DI SC SS IO To date, management of a pati ent with suspected ED is often centred on a goa l-ori ented approach4•7•8 • Treatment selecti on i ba ed on pati ent preference following a thorough di cussion with a treating physician regarding therapeuti c options with minimal diagnosti c te ting. Reason for this empiri ca l approach probabl y stem from the relati vely safe and highly effective medi cati ons currentl y ava ilab le for ED9 De pite thi s, studi e compl eted on ou tcome ana ly e of the goa l-directed approach, often indicate low pati ent sati faction rate JO , IJ . l2. In part, thi s could be due to the fact that without a thorough under tanding of the et iology and pathoph ysiology of a given patients D, commonly preferred therapi e may be ineffective.

Pe rh aps a di ag no is-based, (pathoge ne i - pec i fi e) trea tm ent approach to pati ents with suspected ED may yield better outco mes 12 In thi preliminary tudy, we demon trated that NIR can be used to as e penil e bl d flow with ex ual timul ati on.

Accordingly, we perfom1ed a eries of penil e IRS studi es on both healthy subject , and on patient presenting with va ri ou degree of · D. Upon ana ly i , a ri se in OzHb concentratio n on N IR wa found to correlate very well to pati ent perceived erecti ons. The results from thi s earl y in vestigati on suggest that it may be clini ca lly u eful ~ r the practicing urologi t. The appea l of thi s modality i further upported by its perceived advantage : low equipment cost, tran p rtability, operator non-dependence, simp le operati on, and sa fety Desp ite these indi cati on for a di agnosti c role of a peni le IR device, the criti ca l measure of the clinica l utility of any new technology re t on its ability to direct appropri ate therapeuti c management. Given our limited sample size, our stud y wa unable to examine whether peni le NIRS ca n accurate ly di scern bl ood fl ow profil e di ffe rences between vasculogenic and non-vasculogcni c ED. Looking ahead, further studie are needed to establi sh diagnosti c ranges that identi fy p ychogeni c/neurogeni c (non-va cul ogeni c), mild vascul ogeni c, and severe vasculogeni c cau es of D. A we ll , more studi es are needed to correlate NIR te ting with Dopp ler studies 13 • Acknowledgements: Funding provided by niversi ty of Toronto provided by rodynamix Techno logies Ltd.

8

REFERENCES 1. Lue TF. "Erectil e Dy function " New England Journ al of Medicine. 2000; 342: 1802-1813 2. Johannes CB, Araujo AB, Feldman HA, Derby A, Kleinman K.P, McKi nlay JB . " Incidence of erectil e dy function in men 40 to 69 yea rs old : longitudinal res ults fro m the Ma achusens Male Aging Study" The Journal of Urology. 2000; 163; 460-463.

3. Spark RF. " val uation of male sexual dysfu ncti on" UpToDate. Retri eved December 12 20 I 0.

4. Da vi -Jo eph. B, Tiefer, L, Melman, A. "Accuracy of the in itial history and phy ical examination to establish the etiology of erecti le dysfunction". ro logy 1995 ; 45:498 .

5. Wespes E. Ama r E, Hatzic hristou D, Hatzimouratidis K, Montorsi F, Pryor J, Yardi Y. " AU Gu idelines on Erecti le Dysfu nction: An Update" European Uro logy. 2006; 49 : 806-8 15.

6. toth ers L. hadgan B. " rological applica tion of near infrared spectroscopy" The Canadian Journal of rology. 200 ; 15(6): 4399-4409 7. Rosen RC, Riley , Wagner G, 0 terloh I, Kirkpatrick J, Misbra A. "The Internationa l Index Of Erectile Function (li EF) : A Multidi mensional cale For Asse ment Erectil e Dysfu nction'' rology. 1997 ; 49 (6): 822-830 .

8. Levine LA . "Diagno i and Treatment of Erectile Dy function" American Journal of Medicine. 2000; I 09(9 ): 3 - 12 9. Koca 0 , ali kan , Met in I, OztUrk T, GU ne M. Kil1~og· G. "Ya culogenic Erecti le Dysfunction and Metabolic yndrome. Journal of Sexual Medicine 20 I 0;7:3997-4002 10. Fe ldman HA. Go ld tein I, Hatzichristou DG . " Impotence and its medi cal and p ycho ocial correlates: result of the Mas achu ens Male Aging rudy." Journal of rology, 151 : 54. 1994.

II . Jarow JP, ana-Sinkam P, abbagh M, kew A. "Outcome analy i of goal directed therapy for impotence." Journal of Uro logy 1996; 155 : 1609.

12. Hana h K. "Comparative re ults of goal oriented the rapy for erectil e dy function . Journal of rology 1997; 157: 2135 13 . Burnett L., Allen RP.. Da\ is DM ., Wright DC., True heart IN ., Chance B. " ear infrared spectrophotometry for the diagnosi of vascul ogeni c erectile dy function. " International Journal of Impotence Research. 2000; 12: 247-254

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Leamington D tslrict Memorial Hos pital is a 65·bed fully accredited community hospital offering a wide variety of programs and services to the community. The 24-hour Emergency Department

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gynaecological and obstelrical services and a va riety of visiting specialisls fro m the hospilals in W~nd sor provide a range of services. Diagnostic services are available including a CT scanner,

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For more information please contact Thomas He1nz, of Human Resources Manager, LDMH (519) 326-2373 ext. 4125 or Thomas.He1nz@ ldmh.org Dr. Ejaz Ghumman, Chief of Staff, LDMH (519) 326-2373 ext. 4190 or eghumman@ldmh .org

IR dev ice

UWOMJ I 80 :1 I Spring 2011

Surgical treatment for articular cartilage injuries in the athlete's knee Sandeep Dhaliwal (Meds 2013), Brennan Ballantyne {Meds 2014) Faculty Reviewer: Dr. Marie-E ve Lebel, MD {Department of Orthopaedic Surgery)

rticular cartilage injuri e of the knee are frequently observed in athletes partaking in hi gh-impact sports, particularly at the competiti ve collegiate, profess iona l, and world-class leve1. 1•2 Additionally, increas ing recreatio nal parti c ipation in pi voting sports such as footba ll , basketball , and occer has been associated with a rising number of sports-re lated arti cular cartil age injuries in the ge nera l popu lati on 3 .4 When left untreated thi s type of injury re ults in long- tenn dec line in athletic perfonnance 5 and predi sposes the The purpose of med ica l athl ete to earl y joint degenerati on 6 inte rvention, therefore, remains twofold: I) returning the athl ete to pre-inju ry perfo nnance; and 2) pre erv ing long- tenn knee function to ensure a healthy lifestyle can be maintained as the patient ages.

A

Artic ul ar cart ilage is a we ight-bea rin g connecti ve ti ss ue consi ting of chondrocytes w hose primary function is to secrete extracellular matri x. Due to the a neural and avasc ul ar nature of thi s ti ssue, damage caused by inju ry or pathogenes is res ults in very lim ited abi li ty for self-repa ir7 In this manner, treatment of arti c ular cartilage injuri es in the athl etic popu lati on presents a signifi cant therapeuti c cha llenge. Analgesics, anti-infl ammatory medi cati ons, activity mod ifi cati o n, change in body weight, rest and phys ica l therapy may provide partia l symptomatic re li ef, but they do not restore damaged cartil age to its natural state. Surgica l procedures such as total joint replacement may he lp re li eve joint pain , but pose significant limitations to yo un ge r patient w ishing to pursue vigo rou physica l activity.

Additi onall y, surg ica l debridement remains a potenti al option, but it too is not ideal as it fails to restore carti lage .

Therefore, substant ia l efforts have been devoted to the development of biologic methods for restoring degenerating artic ul ar cart il age.

Based on the source of the cartil age repa ir tissue, new techniques can be broadly c lass ifi ed as: 1) marrow stimul ati on-ba ed techniques; 2) osteochondra l transplantation techniques; and 3) cell -based repair techniques. Moreover, the development of new treatment regimens present prom ising scie ntifi c and clinica l excitement for the treatment of arti cu lar carti lage injury.

MARROW STIMULATION Developed in the earl y 1980s, a su rg ical technique known as mi c rofract ure is a cost-effective , minimally in vasive , a nd un complicated procedure wide ly used to treat ca rtil age inj ury in the ath lete's kn ee.

Microfracture hinges on the penetrati on of the subcho ndral plate w ith an aw l or drill a nd filling of the cartilage defect to take place by a blood c lot that contains pluripotent marrowderived mesenchyma l stem ce ll s.

These ce ll s pro liferate and differenti ate to produce a cartil ag ino us repa ir ti ssue that eventuall y fill s the chondra l defect. ¡9 The procedure is carried out by pl ac ing the pati ent in a supine positi on on the operating roo m table and admini stering a lower extremity or genera l anaestheti c. A femoral nerve block for postoperative pa in relief may also be used. 10 The leg is prepped, draped and has a to urniquet appli ed which can be inflated

if arthrosco pic vis ua lizati on becomes difficult due to intra-a rti cular bleedin g.

The orth opaed ic surgeo n ca rri es o ut a th oro ugh arthroscopic diagnostic exam inati on whereby the lesion is identifi ed and debrided of a ll loose or marg ina ll y attac hed ca rtil age using an arthroscopic sha ver and a curette.

This leaves a tab le rim of cartil age su rroundin g th e defect w hi ch is an idea l full-thickness border to provide a degree of protection to the regenerating tissue that w ill form in the treated les ion. 11 A ca lc ified cartilage laye r typ ica ll y remai n With anima l studi e showing that compl ete remova l is cru c ial to ensure proper repa ir, 12 the ca lc ified cartil age layer is removed by the u e of a curette or a burr. After preparati o n of the lesion i complete, an arthroscopic aw l is e mployed to make multipl e ho les (mi crofractures) in the exposed subchondra l pl ate.

Ho les are spaced 3-4 mm apa rt to ensure that the subchondra l bone maintains adequate structural integri ty, and a depth of 4-5 mm , or Until fat dropl ets are visibl y seen coming from the marrow afte r tourniquet de fl ati on, is typically achieved .

OSTEOCHONDRAL TRANSFER TECHNIQUES Osteochondra l gra fts of auto logo us or a ll ogenic ori g in rel y on transpl antati on of intact mature hya line cartil age conta ining viable chondrocytes attac hed to subchondral bone .

Although both a uto logous and a ll ogeni c modalities represent compl eme ntary paradi gms des igned to restore the characteri stics of nati ve ti ssue, each pose their own set of unique chall enges w ith regard to ti sue Generally, autografts are indi cated fo r ava il ab ili ty and safety. re latively sma ll (< 2cm) focal articu lar lesion of the femoral condy les . 13 Donor-site harvest is carried out from regions of less we ight-bea ring tructures in the knee such as the medial and lateral trochl ear rid ge, the intercond y lar notch, or the sulc us te1mina li s of the lateral femora l cond y le. 14 Hi storica ll y these areas were considered non-weight bearing, but recent reports have demonstrated that the e areas do bear significant weight and can lead to increased donor-site morbidity, such as osteoarthriti s . 13 Adva ntages of an auto logous ap proach inc lude immedi ate ava ilabili ty, relatively low cost, and nonanti ge nic and osteogeni c cartil age properties that res ult in uccessfu l osteointegration . However, auto logous graft sources are self- limited in th ei r maximal surface area, and donor-site morbid ity can add a sign ifi ca nt disease burden to the pati ent. On the other hand , osteochondra l all ografts are indi cated for the treatment of medium to large a11icul ar le ions and are hi ghl y versatil e in treating very compl ex or multiple lesions without inducing any donor- ite morbidity. 13 Draw backs to the allograft app roach incl ude scarcity of donor ti ue, potentia l ri sk fo r disea e transmi sion, a well as fin anc ia l and logisti ca l is ues regardin g graft procurement.

A utograft transplantati on can be perfonned arthroscopi ca ll y or throug h a tandard "open" arthrotomy approach. The patient's knee is prepped and a di agnosti c art hroscopy i undertaken to debride and

UWOMJ I 80:1 I Spring 2011

9

mea ure the cartilage defect. Donor grafts are extracted using a Thandled recipient harvester. Plug sizes fo r the harvester vary from 4 to I0 mm depending on whi ch com merc iall y ava ilable instruments are used during the operation. 14 After pl anning the number, size and placement of spec ifi c grafts, the harvester is aligned perpendi cular to the donor cartilage and tapped to an appropriate depth . Once tapped , th e harves ter chi se l is di engaged by rota tin g or " ge ntl y toggling" (depending on which system is used) the handl e in order to amputate the graft. The recipient ocket can be prepared using a core or drill. In general , a socket is created in the area of the defecti ve cartil age by u ing a slightly maller circumference T-handled harvester tapped to a depth of equal or greater length than the donor plug extracted.

Finally, the graft i implanted under direct visuali zation using a delivery tube and tapping the impactor with a gentle force. Once the graft is in pl ace, the delivery tube is removed and any resulting margin s on the articul ar surface should fill with fibrocartilage .

Converse ly, usi ng an open inci ion , osteochondral all ografting commences by establi shing the size of the host knee defect using a sizi ng cylinder. A sizer is placed over the entire les ion and a guidewi re i dri ven through the center of the sizer perpendi cu lar to the femoral cond yle su rface . The condyle is then scored to the subchondral bone usi ng an appro pri ately sized circumferenti al cutter (rea mer) placed over the guidewire. The reamer is typically drilled into the defect to a leve l of 8- 10 mm below the nati ve cartilage urface. 10 Employi ng the same sizer used on the host knee, the all ograft is sized and reamed in the same area of the cond yle where the ho t lesion is located. To avoid any height mi smatch, the graft is carefu lly cut with an osci llating saw to an appropriate height and the edges are sli ghtly bevelled to fac ilitate placement into the ho t defect. Final ly, a dil ator is impacted into the recipient site in order to achi eve sli ght dilati on (0.5 mm ) whi ch enables graft placement using di gita l pressure. Additional fi xation can be achi eved using screws or pins although it is usually not required with thi s method.

CELL-BASED REPAIR TECHNIQUES

Initi a ll y described in the mid-90s, autologous cho nd rocyte implantation (ACI) plays a major ro le in treating large full-thickne chondral injuri es. 15 AC I i a dual-stage procedure whi ch utili ze the first- tep to harvest chondrocytes, and then a second- tep to reimpl ant them following in vitro culture. The initi al-stage involves an arthroscopi c examinati on to enable full assessment of the inju ry to estab li sh the patient 's suitab ly for the procedure. If it i appropri ate to continue, sli ces of cartil age are harvested with a curet. The femoral trochlea and intercond ylar notch are recommended a harve t ites based on limited compli cati on and morbidi ty being associated wi th the use of those areas.16 After the sli ces are removed they are pl aced in a sterile vial and tran ported to the laborator; where chondrocytes will be cultured. The second-stage of A I i ca rri ed out u ing an arthrotomy to achi eve adeq uate exposure. The defect i debrided with care being taken to ensure that bleeding from the subchondral bone i minimal as it can introduce stem ce ll s and fibroblasts into the defect. The defect is measured and a template using steril e paper is made. A peri o Lea l fl ap from the proximal medial tibia is obtained using the templ ate. This fl ap is harve ted and then sutured to the cartilage rim of the defect and the border is sea led using fibrin glue.

The cultured chondrocytes are then aspirated into a syringe and are inj ected under the periostea l graft.1 7 CLINICAL OUTCOMES AND EMERGING TECHNOLOGY

Num erous systemati c studi es have elucidated improved knee function and increa ed activ ity scores for all three types of arti cul ar cartilage repai r strategies outlined above. Only recently, however, has m~ta-analysis comparing differen t repair techniques on returning the InJured athlete to sports participati on become available. Two

10

separate reviews sugge t better outcomes for patients undergoing autologous chondrocyte implantation and osteochondral transfer techniques versus microfracture. 18路19 Based on a review of 20 studies and 1363 patients, return to sports participation was observed in 73% of athl etes with the hi ghest occurring in those who underwent o teochondral autograft transplantation . On the other hand, 65% were actuall y deemed to have been able to return and perform at a pre-i njury level and thi s was best achieved with autologous chondrocyte. 19 As it pertains to adolescent athletes, evidence in the literature is scarce, but initial reports have suggested that better results are observed with autol ogous chondrocyte repair.20 It appears that numerous factor , uch a age, level of play, lesion size, and duration of symptoms, can impact the clinical outcomes observed in thi s pati ent popul ati on.

Several report depicting functional outcomes, 21 as well as return to athletic competiti on 22 following microfracture can be found in the Iiterature. Despi te initial improvements, however, there is confli cting evi dence regarding long-term results as some studies suggest that deterioration of knee function occurs in 47% to 80% of athl etes 24 month s following surgery.19路21路 23 These limitations have prompted inve tigation of new technologies to enhance the results of ex isting microfracture techniques . For examp le, the development of a dehydroepiandrosterone ulphate (D HEA-S)-releas ing rod that can be impl anted into the microfractures bas shown promi se in improving cartilage in animal model .24 Other efforts have revolved around the addition of growth facto rs to promote chondrogenic differentiation , or inhibiting the potential negative effects of cytokines 23 Final ly, the creation of a bioadhesive using choindroitin su lphate as a primary component ha yie lded promi sing re ults in clini ca l triaJs2s In an effort to improve clinica l outcomes, new and innovative techniques are rapidly advanci ng the field of articular ca rtil age repair.

For instance, to avoid the problem a ociated with osteochondral auto- or a ll ograft , yn th etica ll y manufactured bioresorbable caffolds have been developed a ubstitute grafts2J Principles of scaffolding have also been app lied to autologou chondrocyte implantation \ hich pro ide a mechanism of de li ve rin g chondrocytes into a lesi n during a ingle- tage procedure without nece si tating ex vivo chond rocyte cu lture and expansion.26 During th1 s procedure, the harve ted carti lage is fragmented and then embedded into a resorbable caffo ld which is then implanted into the knee. Other techniques currentl y being explored include the use of g~ n e th erapy to improve cartil age repai r by tran fecting chondrocytes w1th BMP-2, BMP-7 and IFG - 1 and neocartilage harvesting of JUVenile chondrocytes from prepuberta l and fetal human cartilage_27 REFERENCE I. Levy, ., Lohnes. J., cu ll ey, ., LeCroy. M., & Garrett, W. ( 1996).

Chondra l delamt natlon of the knee in soccer players. The American JOurna l of sports medicine, 24(5), 634-9.

2. Kaplan, L. D., churh off, M. R., e lesn ick, H. , Thorpe, M., & Uribe, J. w.

(2005) .. Magnetic re onance imaging of the knee in a ymptomati c profess tonal ba ketball ~l ayers . Arthro copy : the journal of arthroscop ic & related surgery : oflictal publt cat ton of the Arthroscopy Association of No rth Amenca and the Internati ona l Arthroscopy Association 2 1(5) 557-6 1. ' , 3. Arendt, E., & Di ck. R. ( 1995). Knee injury pattern among men and wo men 111 co ll eg tate basketba ll and soccer. NCAA data and rev iew of ltterature. The American journ a l of spo rts medi ci ne, 23(6), 694-70 1.

4. Jones, S .. J. , Lyo ns, R. A., ibert, J., Eva n , R., & Palmer, . R. (200 1). hanges tn sports injuri e to children between 1983 and 1998: compari on of ca e se n es. Joum al of Publi c Hea lth, 23(4), 268-27 1.

5. Me ner, K. , & Ma letiu.s, W. ( 1996). The long- term progno i for evere damage to .wetght-beanng ca rt ilage in th e knee: a 14-year clinica l and radt ogra pht c follow-up in 28 yo un g athl e te . Acta orth o pa edi ca Sca ndmav tca, 67(2), 165-8.

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c 6. Kuj a la, U. M., Kettun en. J., Paa nanen, H., Aa lto, T. , Batti e, M. C ., lmpi vaa ra, 0 ., et al. ( 1995). Kn ee o teoarthriti s in form er runn ers, occe r player , we ight lifter , and hooters. Arthriti s and rh eum ati sm, 38(4 ), 539-46.

7. Hun z iker, E. B. (2 002). Arti cul ar cartil age repair: bas ic sc ience and c lini cal progress. A rev iew of th e current statu s and pros pects.

O steoarthriti s and cartilage I OAR S, Osteoa rthriti s Resea rch oc iety, 10 (6), 432-63 .

8. Steadman , J R, Rodkey, W G , & Rodri go, J. J. (2001 ). Mi cro fracture : surg ica l technique and rehabilitati on to trea t chondra l de fects. C lini ca l o rth o paedi cs and re lated resea rc h, (39 1 uppl ), S362-9 .

9. Steadman , J Ri chard . Mill er. B. ., Karas , S. G ., Schl ege l, T. F., Bri ggs, Karen K, & Hawkin s, R. J. (2003). Th e mi cro fracture technique in the treatment of full -thi ckn ess cho ndra l le ion o f the kn ee in Na ti onal Footba ll League pl aye r . Th e j o urna l o f kn ee surgery, 16(2), 83 -6.

I 0 . Fee ley, B. T. , & Rodeo, . A. M. (2 009). Osteocho ndral All ogra ft Transp lantation . Technique in Kn ee Surge ry, 8( I), 22-28 .

II . Steadman, J. R., Rodkey, W. G ., & Bri ggs, K. K. (2008) . Mi cro fracture technique in the kn ee. In B. J. Co le & J. K. Seki ya (Eds.), Surg ica l techniqu es o f the ho ulder, e lbow, and kn ee in sports medi c in e (pp.

509-526). Phil ade lphia, PA : Elsev ier Inc. 12 . Frisbie, D. D., Ox ford , J. T. , Southwood, L., Trotter, G . W. , Rodkey, Willi am G, Steadman, J Ri chard , et a l. (2 003). Ea rl y events in cartil age repa ir a ft er subchondra l bo ne mi crofracture. C linical o rth opaedi cs and re lated research, ( 407), 2 15-27.

13. Go rtz, S., & Bug bee, W. D. (20 I 0). Osteoc hondra l gra fts: Di ago ns is. operati ve tec hnique , and c lini ca l o utco mes. In F. Noyes (Ed.), N oyes' kn ee di order : urgery, rehabilitati on, c lini ca l o utco mes (pp. 948-960).

Phil ade lphi a, PA : Elsev ier Inc. 14. Gomo ll , A. H., Farr. J., Gill og ly, S. D., Kercher, J., & M inas. T. (20 I 0).

Surgica l management of arti cular cartil age de fect s o f the kn ee. Th e Jo urn al o f bo ne and j o int surgery. Ameri can volume, 92( 14), 2470-90.

15. Brittbe rg, M., Lindahl, A., Nil ss on, A., Ohlsson, C., lsa kss on, 0 ., & Peters on, L. (19 9 4) . Tre atm e nt of de e p ca rtilage d e fe cts in the knee with a utologous chondrocyte tran s plantation. Th e Ne w England journa l of medicin e, 331(14) , 889-95.

16. Pe terson, L. (2010) . Autologo us chondrocyte impl a ntation. In F. Noye s (Ed.), Noyes' knee di s orders: Surgery, reh a bilitation, clini ca l outcomes (pp. 9 3 1-947) . Philade lphia, PA: Elsevier Inc. 17. Day, j ., & Gillogly, S. (2008) . Autologous chondrocyte implanta tion in the knee. In S. JK, with Cole BJ (Eds .) , Surgical techniqu es of the should e r, elbow, a nd kn e e in s ports medicin e (pp. 559-566).

Philadelphia, PA : Elsevier In c.

18. Harris, J. D., Brophy, R. H., Siston, R. A. , & Flanigan, D. C. (2010) .

Treatment of chondral d e fe cts in the a thlete's knee. Arthroscopy : the journal of arthro s copic & related s urge ry : official pub lication of the Arthroscopy Association of North Am e rica and the Internationa l Arthroscopy As sociation, 26(6), 841 -52 .

19. Mithoefer, K., Hambly, K., De ll a Vill a, S., Silvers, H., & Mandelbaum, B. R. (2009). Return to sports participa tion after articular ca rtilage repair in the kne e : scientific evidence. The American journal of sports medicine, 37 Supp11 , 167S-76S. 20. Micheli, L., Curtis , C., & She rvin, N. (2006) . Articular carti lage repa ir in the adoles cent athlete: is autologou s chondrocyte implantation th e answer? Clinical journal of s port me dicine : offi cial journa l of the Can a dian Academy of Sport Medicine, 16(6), 465 -70.

2l.Gobbi, A., Nunag, P., & Ma linows ki, K. (2005) . Trea tment of full thickness chondral le sions of the kn ee with micro fra cture in a group of athletes. Knee surgery, sports traumato logy, arthros copy : offic ial journal of the ESSKA, 13(3), 213-21.

22. Steadman, j. R., Rodkey, W. G., & Briggs, K. K. (2010) . Microfracture: Its History and Experience of the Developing Surgeon. Cartilage, 1 (2) , 78-86. SAGE Publications.

23.Mithoefer, K., McAdams, T. R., Scopp, j . M., & Mande lbaum, B. R. (2009) . Emerging options for treatment of articular cartilage injury in the athlete. Clinics in sports medicine, 28(1), 25 -40.

24.Shim, I. K., Yook, Y. ]., Lee, S. Y., Lee, S. H., Park, K. D., Lee, M. C., et al.

(2008). Hea ling of articu lar carti lage defects treated with a novel drug-rel e asing rod-type imp lant after microfracture s urg e ry .

jo urn a l o f co nt ro ll e d re lease : officia l jo urn al of th e Co ntro ll ed Re lease Society, 1 29 (3) , 18 7-9 1.

2 5. Wa ng, D.-A., Va rghese, S., Sha rm a, B., Stre hin, 1., Fe rm a ni a n, S., Gorh a m , j ., et a l. (2 00 7) . Multifun cti o na l cho ndro itin s ulph a te for ca rtilage ti ss ue- bi o m a te ri a l integ ratio n . Na ture m a te r ia ls, 6(5), 385-92 .

26 . Kon, E., De lcogli a no, M., Fil a rd o, G., Mo nta p e rto, C., & Ma rcacc i, M. (2 00 8 ) . Second ge ne ra tion iss ues in ca rtil age re pa ir. Spo rts me di cin e a nd a rthrosco py revi ew, 1 6(4), 22 1 -9.

27. Kess le r, M. W., Acke rm a n, G., Din es, ]. S., & Gra nd e, D. (2 008).

Em e rg in g te chn o lo gies a nd fo urth ge ne ra ti o n iss ues in ca rtil age re pa ir. Sports m edicin e a nd a rthrosco py rev iew, 1 6 (4) , 246-5 4 .

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Computed tomography (CT) based calcium scoring in the diagnosis and prognostication of coronary artery disease (CAD) Jai Pra shanth Jayakar (Med s 2013 ), Adrian Matth ew s (Med s 2013 ), Joshua Rosenblat (Meds 2014) Faculty Reviewe r: Dr. Aash is h Goela, MD MSc FRCPC (Depa rtmen t of Med ical Imaging)

nvented by Si r Godfrey Hounsfield in th e 1970 , computed to mograp hy (CT) has greatl y trengthened the arsena l of imagi ng tec hn o logies th at is ava il ab le to ph ys ic ia ns to detect, prog nosticate, and treat d isease. T he fund a menta l prin cip le underl ying CT cannin g is th e ex po ure of biological ti sue to rotatin g fin e beam X- rays, fo llowed by th e detecti on and process ing of the radi ati on th at th ese ti ssues attenuate to create a computeri zed image 1. The two majo r types of CT scannin g are heli ca l CT and conventio na l non-overl app ing CT. Since its introducti on, va riou enhancements have been made to T technology which has a llowed varied medi cal fie lds.

In cardi ac imaging, appl icati on aero coronary CT angiograph y has recentl y risen to the fo refront. A it i a newer techno logy, data in th e li te rature lags behind th e well -studi ed meth ods to qu anti fy th e amount of ca lc ium inside coronary arteri es using infonnati on obtained from cardi ac CT scans, kn own as cal cium scorin g 2 . ln th is arti cle, we ex plore th e use of thi s speciali zed CT techno logy and highlight its adva ntages and limitati ons in th e diagno i and prognostication of coronary artery di sease .

I

CT BASED CALCIUM SCORING In coronary arteries, CT based calcium corin g meth ods quanti fy ca lcium as a parameter tenned coronary artery ca lc ifi cati on (CAC) 3 .

Ca lc ium scoring is used to evaluate coronary artery di ease since calc ium bui ld up in pl aques is a key process in ath erosclero is. It sho uld be noted th at th ere is ev idence non-ca lc ified plaqu es area l o important , however, th ey are not eva luated by thi s meth od and are thus outside of the co pe of th is review. lectro n beam CT ( BCT) ha been a popul ar meth od fo r th e a e sment of coronary calcium since its development in th e 1980 . Nowadays, ca lci um scorin g can also be perfo rm ed with multidetector or multi s lice CT canners (MDCT and MSCT). There is some agreement that the ca lc ium scores obta ined from both meth ods are sim il ar, th ough thi has not Vari ous meth ods have been used to been extensively studi ed 4. compute ca lc ium scores ; for exa mple, th e Aga tston score ass igns a weighted va lue ba ed on th e hi ghest de nsity o f calc ifica ti on in the plaque and then multipli es thi s by th e area of ca lcifi cati on5. uch scores for all ca lcifi cations in all CT li ce taken are summed up to prov ide a CAC score for a ll th e coronary arteri es.

Due to certain limitati ons w ith Aga tston scorin g, mo t notabl y inconsistent inter-sca nner comparability, newer methods such a th e vo lume score and ca lc ium mass score we re developed and compared w ith th e Aga tston score. Some studi e indi cate that th ese meth ods m ay b e e qui va le nt t o th e Aga ts to n m e th o d in te rm s of reprod ucibility6 . A more recent meth od of ca lc ium scorin g is kn own as th e lesion specific calci um score in which more specifi c parameters related to each ca lcifi ed le ion are included in th e fin a l ca lcium score, such as w idth, density and di stance from maj or coronary arteries 7 . T here is emerg ing evidence to indi ca te th at the les ion-speci fi e ca lci um scorin g meth od may be more acc urate th an

12

the Agat to n method fo r some purpo es; for example, the sensitivity, specific ity, and accuracy of th e le io n specifi c calc ium score meth od were shown to be superior to the traditi ona l Agatston core in detecting angiographically con fi nned obstru cti ve coronary artery di ease 8

CORONAR Y ARTE RY CALCI FI CATION (CAC) AND CORONA RY ARTERY DISEASE Many stud ie have shown the associati on between CAC and coro nary artery d i ease a de tected by hi to path o logica l or ang iograph ic methods . For example, one hi stopatho logical study on auto p ied coronary arteri es showed th at th e EBCT ca lc ium scores correlated we ll wi th plaque area 9 . A clin ical study of more th an 700 pati ents showed that EBCT ca lci um coring had 95% sen iti vity in pi ckin g up ang iographica ll y ignificant coronary artery di sease 10.

CAC has also been tud ied in re lati on to myoca rdi a l ischemia.

Myoca rd ial i chem ia most often mani fe ts silentl y, and thi can be detected as stre -induced i chemia wi th stress testin g. One studyl 1 showed that the li ke lihood of tre -induced myocard ia l ischemia increa ed wi th a higher CAC core, a lthough the maj ori ty of patients (78%) w ith detecta ble CAC did not have stress-induced ischemia suggestin g a poor pos itive predictive va lue of prognosi with CAC corin g. A report from the pro pecti ve cohort study kn own as the multi ethni c stud y of ath e ro cle r os is (M E SA) eva lua ted the re lati o nship betwee n CAC a nd myoca rdi a l ische mi a in a n tudy showed that the coron ary asy mptomati c populati on 12. T hi va odil atory re ponse (myocardi a l bl ood fl ow w ith tre ) w a redu ced w ith a higher CAC, but the re ting myocardi al b lood flow was not affected by increa ed AC. These studi e provide some indicati on th at CA may be assoc iated w ith impa ired myocardia l perfu ion in a subclinica l ath eroscleroti c state . Ove ra ll , there is a good body of ev idence to uggest th at CAC i assoc iated with stru ctura l and fun cti ona l coron ary artery di sease .

PROGNO T IC VALUE OF CAC Studi es have a sessed the prognosti c value o f CA m both symptomati c and asymptomati c pati ent popu lati on . There i reasonable ev idence to indicate that AC has good prognosti c value in asy mpto mati c pati ents. For examp le, a stud y of more th an 5000 low- interm edi ate ri sk,_ midd le-aged adu lts over a 3 yea r fo ll ow up pen od found that h1 gher EBCT CAC sco res at ba eline w ere assoc iated with a hi gher ri sk o f developing cardi ac events later on in both gender 13 Anoth er study o f more than 1000 patients over a 19 month fo ll ow up period showed that higher cut-off leve l for EBCT CA . scores we re assoc iated w ith better specific ities for predi cting ca rd1 ac event 14 . Incrementa l progno ti c va lue o f EBCT CA C w a observed, in addition to that prov ided by conventio na l cardi ac ri sk factors.

UWOMJ I 80 :1 I Spring 2011

( One study in a symptomatic patient popul atio n con i ting of 49 1 parti ci pants referred for coronary angiography found that EBCT CAC scores were mode rately predictive of ang iograph ica ll y confirmed coronary artery stenoses and that hi gher scores were assoc iated w ith a hi ghe r incidence of coronary artery re lated card iac events 15. A simil a r study 16 on patients referred for coronary ang iography followed up after an average time of 7 years fo und that among conven ti ona l risk fac tors and EBCT CA , onl y EBCT CAC (ri sk ratio 1.72) and age (risk ratio 1.88) were predictive of future hard cardiac events (hard events include non-fatal myocardial infarction and cardiac death) . Furthermore, pati ents with an EBCT CAC score of less than I 00 had significantly hi gher event-free surviva l rates 16 . Taken together, the prognostic va lue of CAC has been shown to have a high negative predictive va lue and a moderate positive predicti ve va lue for major adverse coronary events (MACE).

Thus, CAC shows promise for a iding in ri k stratifi cation.

reduce treatment intensity of intermediate ri sk patients that had zero ca lc ium scores. Furthermore, the recommendations caution against extrapolating findings to populat io ns that have not been we ll studied ; the ev idence appear strongest for Ca ucas ian, non-Hispanic men.

CONCLUSION Despite some limitati ons m its spec ificity and concern s about its app licability to pati ents of varyi ng ethni c iti es and ri sk statuses, CT based ca lc ium cori ng of coronary artery ca lcificati on has emerged as a useful tool that provides added prognostic and screening va lue, especia ll y in asymptomatic patients with intermed iate coronary heart di sease ri k . G iven the preva lence of coronary a11ery di sease and its unpara ll e led impact on mortality and morbidity, better and innovati ve methods of cardi ac di sease screening and prognosti cation , inc luding ca lci um scoring, wi ll become increasing ly important in providing patient-centred care.

LIM ITATIONS OF CALCIUM SCORJNG

REFERENCES

Although the above di scuss ion has highli ghted the va lue of ca lc ium scoring in detecting and providing prognosti c information abo ut coronary artery di sease, certain caveats of ca lcium scorin g exist For exampl e, some results suggest that there is a threshold level of calcium accumul atio n beneath whi ch EBCT CAC is not predicti ve of plaque area or everity 17 â&#x20AC;˘ Furthermore, studies have reported that EBCT CAC has very good sensiti vity for pi cking up significant angiographic stenoses (g reater than 50%), but onl y moderate specificity 18. Thi s was confirmed by a consensus document re leased by the American Coll ege of Card iologyl 9 in which , based on a metaanalysis by the working gro up, the sensitivity and pec ifi city of EBCT in detecting coronary artery stenoses were 91 % and 47% re spectivel y. Studies have also evaluated whether treatin g asymptomatic pati e nt s with hi g h calcium sco res with pharmacotherapy improves outcomes. For example, the St. Francis heart stud y randomi zed controlled tria l showed that treatment of patients having high ca lcium scores with statins and antioxidants did not reduce the progression of coronary ca lcification or the rates of atherosclerotic cardiovascu lar disease events 20 .

I. McC ull ough H, Morin RL. Th e tec hni ca l des ign and performance of ultrasfa t co mputed tomography. Radi o! C lin North Am 1994; 32 (3): 52 1-26.

2. Ulzhe im er S, Kalendar WA . Assessment of ca lci um scoring perfonnan ce in ca rdi ac computed tomography. European Radio! 2003 ; 13 (3): 484-87.

3. American o ll ege of Cardio logy Foundation C linica l Ex pert Committee Task Force. ACCF/A HA 2007 clini ca l ex pert consensus document on coronary artery calci um sco ring by computed tomograph y in g loba l ca rdi ova cular ri k assessment and in eva luation of patients wi th chest pai n. JAm Co li Cardio l 2007; 47(3): 378-402 .

4. Horiguchi J, Yamamoto H, Akiya ma Y, Marukawa K, Hirai , Ito K. Coronary artery ca lcium sco ring using 16-M D T and a retrospective E G-gating reconstruction algorithm . Am J Roentgeno l 2004; 183( I): I 03-8.

5. Aga tston AS , Janowitz WR, Hildn er FG , Zu mer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery ca lci um usi ng ultrafast computed tomograph y. J Am Co li Ca rdi o l 1990; 15(4); 827-32 .

6. Rumberge r JA , Kaufman L. A rosetta stone for co ronary ca lci um ri sk stratifi cati on: Agatston, Volume, and Mass scores in II ,490 indi viduals.

Am J Roen tgenol 2003; 18 1: 743-74 8.

7. Liu Q, Qia n Z, Marva ty I, Rinehart S, Voros, S, Metaxas D. Lesionpecifi c coron ary artery calcium quantificati on for predicting cardiac events wi th multiple instance support vector machines. Lecture otes in Co mputer Science 20 I 0; 636 1: 484-492.

8. Q ian Z, Anderson H, Marvasty I, Akram K, Vazq uez G, Rinehart S, Voros S. Lesion-and vesse l-spec ifi c coronary artery calciu m scores are superi or to whol e-heart Agatston and vo lum e sco re in the diagno is of obstructi ve coronary artery disease. J Cardi ovasc Co mputed Tomograph y 20 I 0 ; 4(6): 39 1-99.

9. Rumberger JA, S im ons DB, Fitzpat ri ck LA, Sheedy PF, Shwartz RS .

Coronary artery ca lci um area by electron-bea m co mputed tomography and coronary athero c lerotic plaque area. A hi stopath ologica l corre lative study.

Ci rcul ation 1995; 92(8) : 2 157-62.

10. Budoff MJ , Geo rgio u D, Brody A, Agat ton AS, Kennedy J, Wolfkiel C, Stanford W, Shi elds P, Lewis RJ , Janowitz WZ, Rich S, Brundage BH. Ultrafast comp uted tomography as a diagnosti c modali ty in the detecti on of coronary artery di sease: a multi ce nter study. Ci rcu lation 1996; 93(5): 898-904.

II . He ZX , Hedri ck TD, Pratt CM , Verani MS , Aqu in o V, Roberts R, Mahmarian JJ . Severity of coronary artery calc ifi cation by e lectron beam co mputed tomography predicts sil ent myoca rdi al ischemia. Circulati on 2000; I 0 I (3): 244-51.

12. McC le ll and RL, Chung H, Detran o R, Post W, Kronmal RA . Di stributi on of coronary calcium by race, gender, and age: results from the MultiEthni c Stud y of Atherosc lerosis (MESA). Ci rcul ation 2006; 11 3( 1): 30-7.

13. Kondo GT, Hoff JA, Sevrukov A, Dav ig lus ML, Gars ide DB , Devri es SS, Chomka EV, Liu K. Electron-bea m tomography coronary artery ca lci um and cardiac even ts: a 37 month follow-up of 5635 initia ll y asymptomati c low-to intermediate-risk adults. Ci rcul ation 2003; I 07(20): 257 1-6.

14. Arad Y, Spadaro LA , Goodman K, Lledo-Perez A, Shennan S, Lerner G, G uerci A D. Pred icti ve va lue of electron beam computed tomography of the coronary arteries. 19-month fo ll ow- up of 1173 asymptomatic patients.

C ircul ation 1996; 93( 11 ): 195 1-3.

Interestingly, another randomi zed controlled tria l showed that using results from EBCT ca lc ium scores to moti vate behavioural change was not successful , as reflected by a lack of improvement in composite cardiac ri sk measured by I 0 year Framingham risk scores 2 1. Thi s rai ses concerns about the uti lity of EBCT calcium scoring in being an effective screening tool that affects outcomes, but more studies are required in thi s regard . In addition , there are practica l, unreso lved concerns about the application of EBCT CAC from a screening perspective ; for example, its cost effectiveness and the negati ve effects associated with false positi ve te ts and radiation exposure are potentia ll y worrisome.

CLINICAL RECOMMENDATIONS FOR USE OF CALCIUM SCORING The American Co ll ege of Cardiology Foundation (ACCF) publi shed a consensus document in 2007 to synthes ize the evidence and make recommendations regarding the clinical use of CT based calcium scoring 3 . For example, one of the recommendations states that it is helpful to use CAC to ri sk stratify asymptomatic patients that have an intermediate I 0 year ri sk of developing cardiac events (1 0-20%), since this may affect how aggressive ly patients are managed.

However, this use of calcium scoring is not recommended for low risk (< 10%) asymptomatic patients since these patients are likened to the general population and there is no evidence to support screening the general population with CAC. CAC measurements were also not recommended for high risk (>20%) asymptomatic patients since intensive medical therapy is already suitable for these patients. Also, owing to insufficient evidence, a recommendation was made to not

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) 15. Detrano R, Hsiai T, Wang S, Puentes G, Fallavo ll ita J, Shi elds P, Stanford W, Wolfkiel C. Georgiou D, Budoff M, Reed J. Prognosti c va lue of coronary calcificati on and angiographic tenoses in patients undergo ing corona ry angiograph y. J Am Coli Cardi ol 1996; 27(2): 285-90.

16. Keelan PC, Biel ak LF, Ashai K, Jamj oum LS, Denktas AE, Rumberger JA, Sheedy II PF, Peyser PA, Schwartz RS. Long-term progno ti c va lue of coronary calcificati on detected by electron-bea m tomography in patient undergo ing co ronary angiograph y. Circulati on 200 I; I 04(4 ): 41 2-7.

17. Baumgart D, Schm ermund A, Goerge G, Haude M, Ge J, Adamz ik M, ehnert C, Altmaier K, Groenemeye r D, Seibel R, Erbel R. Co mpari son of electron bea m computed tomograph y with in tracoronary ultraso und and coronary angiography for detecti on of coronary ath erosclerosis. J Am Coli Ca rdi ol 1997; 30( I): 57-64 . . Haberl R, Becker A, Leber A, Kn ez A, Becker C, Lang C, Broning R, Reise r M. teinbec k G. Correlation of coronary ca lci fi ca ti on and angiographica ll y documented steon es in pati ent with suspected coro nary artery di ease: re ults of 1764 pati ents. J Am Coli Ca rdi ol 200 1; 37(2): 451-7.

19. O' R urke RA . Brundage BH , Froelicher VF, Gree nland P, Grundy SM, Hachamo itch R, Poho t GM, haw LJ . Weintraub W . Winter WL Jr, Forrester J , Dougla P , Faxon DP, Fis her JD, Gregoratos G, Hochma n JS, Hutter AM Jr, Kaul . Wo lk MJ . Amercian College of Cardi ology/ Ameri ca n Hea rt A socia ti on ex pert con en us document on electron-beam computed tomograph y fo r the di agno i and prognosis of coronary artery di ease. ircul ati on 2000; I02( I): 126-40.

20. Arad Y. Goodm an KJ , Roth M, ewstein D. Guerci AD. Co ronary ca lci fi catio n, coronary disease ri sk factors, C- reacti ve protein, and ath eroscleroti c ca rdi ovascul ar di sease events: the St. Francis Heart Study.

J Am oil Ca rdi ol 2005 ; 46( I): 158-65.

2 1. O' Mall ey PG, Feuer tei n JM , Tay lor AJ. Impact of electron bea m tomog raph y, with or without case manage ment, on motiva tio n,

behav ioural change, and cardi ovascul ar ri sk profi le: a randomized controlled tri al. JAMA 2003; 289: 22 15-23 .

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UWOMJ I 80 :1 I Spring 2011

Direct-to-consumer genetic testing in Canada Laura Allen (Meds 2013}, Moska Hamidi (Meds 2013}, Niran Argintaru (Meds 2014} Faculty Reviewer: Dr. W. Liang, JD, MD

he goa l of this arti c le is to di scus DTC ge netic testing in tenns of the process of testing, the current regul ati on of the indu try in Ca nada and the effect the resu lting informati on can have on manag ing individual and populati ons in hea lthcare. This w ide-rangi ng and rapidly evo lv ing topic ex tends into the fie lds of ge netic , ethics, law and business, each of whi ch have been addressed in the following fash ion: the acc uracy of testing, the predi cti ve va lue of the results, the possib le effects that the test will have on the consumer and fina ll y the effect that the persona l ge neti cs indu stry w ill have on phys ic ian practice and soc iety. Due to the rapid evoluti on of the field , testing kits can now be purchased for a littl e as three hundred do ll ars, making persona l ge netic testi ng highl y affo rdab le and accessible.

T

THE ACCURACY OF THE ASSAY

THE EFFECT OF THE TEST RESULT ON THE CONSUMER Whil e so me DTC co mpa ni es offer ove r-th e- ph o ne ge neti c co unse lling with the results, it is importa nt that a ll customers understand the information in a contextua li zed manner. Thi s require understand ing of concepts such a re lative and lifetime risk of di ease. Physicia ns have also ex pressed concern over so ca ll ed ' ge neti c determini m', w here the indi vidual negates environmenta l ri sk factors which are contributory to the di sease in favour of the test re ults8 . For exam ple, a pati ents' ri sk of heart di ea e is more re fl ecti ve of the ir weight, bl ood press ure and/o r cho lestero l than genetic factors 4 . A nother ethica l concern is testing for conditi ons where there is no viab le treatment or preventati ve measures.

Advoca tes of DTC testin g po int to studies such as the REVEAL study, w hich showed that di sclosure o f a genetic tra it predisposing patients to Al zheimer's di sease "did not result in s ign ifi cant shorttern, psychologica l ri sks" compared to those that were not tested 9 .

DTC gene testing compani es suc h as 23andme, deCO DEM E, Navigenics and K.no me (the ' main playe rs' in the current market 1) are private labs governed by the laws in their jurisdiction . In Ontario that licensing body is the Labo ratory and Specimen Co llection Centre Licensing Act ( LSCCLA). However, the majori ty of these corporat ions are Ameri can and are hence regul ated by the Centers for Medi care & Medi ca id Serv ices (C MS) under the C lini ca l Laboratory Improve ment Amendments (C L!A). Recentl y there ha s been concern s abo ut " fau lty lab data ana lyses, exaggerated c lini ca l claims, fraudulent d a ta , poo r c linical stud y d es ig n a nd a lack of tracea bili ty" 2. The United States Government Accountabi li ty Office recentl y reported that when samples of DNA were sent to four different DTC testing companies "different compani es often provide different res ults for identical DNA" 3 . Interestin g ly, the testing kits themse lves are not considered medica l dev ices and are hence not regulated by the Food and Drugs Act4.5. Additionally, the maj ori ty of genetic tests are offered as in-house laboratory serv ices and are simil arl y not regulated by the federal gove rnm ent throu gh the Hea lth Protection Branch or Therapeutic Products Program 6 .

Pri vacy concern s a lso ex ist abo ut third party di sclosure of data, e peciall y in regards to hea lth and li fe insurance, where thi s deta il ed inforn1ation could lead to ge netic di scrimination. Whil e company poli cy is ge nera ll y not to di sc lose information witho ut explic it consent of the custom er, the info nnation itse lf is not protected to the same standard as infonnatio n covered by the US Hea lth Insurance Portability and Acco untabili ty Act ( HIPAA) 10â&#x20AC;˘ 11 . If a custo mer di scovers that they are pos iti ve for a mutati on and fa il to di sclose it to the ir insurance company, it may serve a grounds for vo iding po licy if the insurance company finds a way to access the infonnation 8â&#x20AC;˘ 11 . Sim ilarl y, the Canadi an Human Ri ghts Act does not conta in a clause protecting aga inst geneti c di scriminatio n, thoug h an amendment i currentl y under considerati on in the Ho use of Commons (Bill C-536). On the other hand, Ame ri cans are protected from such di scrimination by the Genetic Info rm ation on di scriminatio n Act (G INA) whi ch doe not apply to Canadians using the US based compani es.

THE LINK BETWEEN TESTED GENES AND DISEASE

THE ROLE OF THE HEALTHCARE SYSTEM

In contrast to geneti c testing in a cli nica l context, pri vate genetic testing a lso exa mines mo re ' persona l' ge netics traits. According to the website fo r deCODEME yo u can "di scover your ge netic ri sk for 47 di seases a nd traits rang ing from Heart Attack and Diabetes to A lcohol Flush Reacti on and Male Pattern Ba ldness" 7 . However di sc la imers also state the results may have poor predicti ve va lue 1 and are not considered di agnostic, leading customers to questi on the finan c ia l va lue of uch test res ults. Nonethe less, the e compani es g ive the ir customers information about the research that links these polymorphi sms to increased probability of developing a g iven di sease.

Ontario's Regul ated Hea lth Profess io ns Act st ipul ates that a hea lthcare professiona l i responsib le for "communicating to the indi v idua l o r hi s o r he r perso na l representati ve a diagnos is identi fYi ng a di sea e or di sorder as the cause of symptoms of the indi vidua l in circumstances in which it is reasonabl y foreseeab le that the indi v idual or hi or her per ona l representati ve wi ll re ly on the di agnosis" 12 Does the genetic ri sk assess ment offered by these pri va te ly owned companies count as a diagnos is? The companies ex plic itl y state that their products are not diagnosti c o r are substitute for medi cal advice and that a ll concern s ari sing from the test should be referred to yo ur hea lthcare prov ider. The onus then lie on the

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15

fa mil y practiti oner to interpret the information, a burden that could become substantial accordin g to a study by McGuire et al where 78% of respondents sa id they would con ult their family doctor about results of commercial ge netic test4 . Thi s increased burden on the hea lthcare system is furth er complicated by the fact that famil y physic ians are often not trained in geneti cs coun se lling and may not be equipped to deal with thi s extensive genetic inforn1ation.

CONCLUS ION In 20 I 0, the FDA sent regul ation letters to five American commercial genetic testing companies stating that their device is regul ated " . . . under secti on 20 I (h) of the Federa l Food, Drug, and Cosmeti c Ac t (the Act), 2 1 U.S. C. 32 1(h) because it is intended for u e in the di ag nosis of di ease or other conditions or in the cure, miti gati on, treatment, or preventio n of di sease, or is intended to affect the tructure or function of the body."; it went on to state that the product is cia sift ed a a medica l device under the Medi ca l Device Act and as such require premarket approva l13 Increas ing regulati on has been occurring in both the United tates and many European countries out of concern for inaccurate or mi leadin g test results 14

11 . Wolfberg, Adam J. Ge nes on the Web - Direct-to-Consumer Marketing of Genetic Testing. ew England Journal of Medicine 2006;35 5(6):543-545.

12. Regulated Health Professions Act Section 27.2. 199 1, bttp://www.elaws.gov.on.calhtm Vstatutes/english/elaws_statutes_91r 18_ e.htm .

Accessed December 20 I0.

13. Food and Drug Admina tration : Letter to Industry. http ://www.fda.gov/ Medi ca iDevices!ResourcesforYou/l ndu try/ucmllll 04. htm . Accessed December 20 I0.

14. Hogarth , Stuart, Javitt, Gai l and Melzer, David. The Current Land cape for Direct-to-Consumer Genetic Testing: Legal, Eth1 cal, and Policy Issues.

Annual Review of Genomics and Human Genetics 2008;9: 16 1.

However, supposing the tests are accurate and re lati ve ly spec i fie the next logical question is whether the knowledge of ri sk factors will translate into better outcomes for patient : reduci ng risk, ea rli er creening, prophylactic measures and, in orne cases, influence on fa mil y planning6 . It i difficult to assess thi s as the industry is relatively new and there is no follow up after the company di close the re ult to the customer. Without counse lling it may be difficult to put the ri k into context for the indi vidual pati ent and an over or underesti mati o n could be de lete ri ous to a pati ents' hea lth4 Proponent argue these te t champion patient autonomy and to limit access to one's own genome is paternalistic whi le detractors are concerned the patchwork regul ation does not protect customers purchasing these products. With expanding use of these services the effects of thi s pl ethora of informatio n, both posi ti ve and negati ve, will be become more apparent.

REFERENCES I. Kaye, Jane. The regulation of direct-to-con umer genetic tests. Human Molecular Genetics 2008; 17(2):RI 80- R183.

2. Webster, Paul Christopher. Regulation of genetic tests unnecessary, government says. Canadia n Medica l Association Journal 20 I0; 182( 16): 1715- 1716.

3. Kutz, Gregory. Direct-To-Con umer Geneti c Tests: Misleading Test Results Are Further Complicated by Deceptive Marketing and Other Questionab le Practices. United States Government Acco untability Office 20 I 0 , Testim ony Be for('} th e ubcommittee on Over ight and ln ve tigati ons, Committee on Energy and Co mm erce, House of Representati ves.

4. Caulfield, T. , Ries, N.M., Ray, P.N., human, C., Wil on, B. Direct-toconsumer genetic testing: good, bad or benign? Clinica l Ge netic 2009; 1-5 .

5. Sarrazin, Patrice. Regulatory Over ight of Genetic Testing in Canada: Health Canada Perspecti ve. Hea lth Canada.

6. Cauldeild, Timothy A. , Burgess, Michael M., Wil liam-Jones, Bryn.

Providing Ge neti c Testi ng Through the Private Sector: A View From Canada. ISU MA 200 I :72-8 1.

7. deC ODEM E http s: //www.decode me.c om/com pl ete- ge neti c-s ca n.

Accessed December 20 I0.

McCabe, Linda L., McCabe, Edward R.B. Direct-to-consumer ge netic testing: Access and Marketing. Genetics in Medicine 2004;6( I}:58-59. upples L.A., Relkin N.R. , Whitehouse P.J ., 9. Green J., Roberts S., Brown T. , Eckert S.L. , Butson M., A., Sadovnick A.D. , Quaid K.A ., hen C., Cook-Deegan R., Farrer L.A . Di sc losure of APOE Genotype for Ri sk of Alzhei mer' s Di sea se. New England Jo urn a l o f Medi cin e 2009;36 1:245-254.

I0. Henegan Jr, John C. , Robin, Nathaniel H. Direct-to-consumer genetic testing. Current Opinion in Pediatrics 20 I0;22 :685-686.

16

SWOMEN

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Schulich MEDICINE & DENTISTRY

(

Improving healthcare with information technology Karline Treurnicht Naylor (Meds 2013}, Paul Kudlow (Meds 2013} Felix Li (HBA 2011} and Kevin Yuen (HBA 2011) Faculty Reviewer : Dr. Kellie Leitch MD, MBA, FRCSC

s healthcare costs escalate and the public maintains high expectat ions abo ut health ervice delivery, the sustai nabi li ty of our current public system ha become untenable. In 20 I 0, health expenditures compri sed 11.7% of Canada 's GOP and 192 billion dollar were spent on hea lthcare. 1 Furthermore, Canada 's oftcited agi ng popul ati on-which consumes 44% of a ll hea lthcare do ll ars-continues to grow. In 2005 , 13% of Canadians were age 65 or o lder; by 2036, that figure is expected to reach 24.5% 2 As policymaker struggle with broad healthcare reform, they are asking hard questions abo ut the margi nal returns of further spending on sickness care. For their part, c lini ca l managers and c lini cian- leaders are worki ng to reorgani ze the delivery of hea lth services, promote evidence-guided decision-maki ng, and create a culture of interprofessiona l co ll aboration and qua li ty improve ment.

A

There is increasing pressure to promote cost-efficiencie in the hea lthcare system, and hea lth information techno logy (IT) has enormous potential in that regard . Ev idence suggests that such innovations can enhance the effic iency, cost effectiveness, quality, and safety of hea lthcare delivery.3 A nd as the face of hea lth human resources c hanges, with the adopti o n of co llabo rative multidisciplinary models of care, sharing of health information between providers is all the more cru c ia l.

As of March 20 10, an e lectronic hea lth record is ava ilable for 22% of all Canadi ans, and by early 20 II , that proporti on is predicted to reach 50%. 4 Canada Hea lth lnfoway is an orga ni zation charged w ith managing the development, and promoti ng the adopti on of, electroni c health record systems in Canada; its goa l is fo r a ll Canadians to have an e lectronic hea lth record by the year 20 I 6.

When we compare o urselves to peers in other nati ons, it is clear that we are not keeping pace. In 2006, Canada ranked last amo ng seven countries based o n the use of hea lth IT by primary care phys ic ians.5 According to a survey of almost 1500 Canadian phys icians, onl y 37% use hea lth information technology. The statistic for our hos pital is more optimi stic: approx imately 65% have at least one e-hea lth compo nent. 4 What makes this task so daunting? The complex ity of hea lth informati on techno logy lies in the amount of data, the sensiti v ity (and need for pri vacy) of data, and the hi gh stakes in ensuring the accuracy of data. Banking is an indu stry with simil ar infom1ati on technology needs; according to data fro m 2004, US financial services spend 5.4% of their tota l budget on information technology. It is therefore no surpri se that we have a long way to go : the ave rage for Canadian hea lthcare IT spending was onl y estimated at 1.5-2 .0% 6 In thi s review arti cle, we will di scuss both the potenti a l benefits and challenges to widespread hea lth IT implementati on, a we ll as provide recommendations and future directi ons for the fi e ld .

BENEFITS OF HEALTH IT Hea lth in formatio n technology can deliver a wide range of benefits, including system-leve l effic iencies (reduced co t and increased productivity), better de li very of care, improved pat ient safety, more effective communi cati on between providers, and increased access to inform ati on. Whi le we have categori zed benefits for the sake of discussion in thi s arti c le, we recogni ze that these benefits are not truly di screte, and are actua ll y inter-re lated; for exam ple, when prov iders communicate mo re effective ly, the resulting decrease in ambiguity leads to improved patient safety, and ultimately, a costefficiency through do ll ars saved treating an adverse event.

Enhanced productivity and long-term cost savings: From an efficiency perspective, upgrades to healthcare IT can he lp minimi ze wasted time and reso urces in a c linica l setting. For example, the e limination of paper charts increases the amount of physica l space that can be used for patient care. Furthermore, computeri zatio n of medi cal records leads to reduced storage and transcription costs.

After a period of training and adj ustment, e lectro nic documentation of clinica l encounters wo uld be more rapid than hand written documentation in a paper chart; as such, the amo unt of time that c lini c ians spend on admini strative tasks is reduced, freeing up va luabl e time for producti ve c lini cal care. A sing le e lectronic pati ent record can res ult in smoother ha nd-offs and ti g hter connections between health providers along the continuum of care, leadin g to an overa ll more efficient care process . Furthermore, hea lth infonnation technology can be used to optimize the scheduling of procedures and diagnostic tests , reducing overbooki ng and bottlenecks, thus all ocati ng resources mo re accurate ly.7 The costs of imp lementing a hea lth infonnation strategy are hi gh. However, evidence suggests that the payoff can be equa ll y impress ive. In Canada, for exa mpl e, the estimated productivity gains and savings from a full y implemented electroni c hea lth record are estimated at 6 billion 4 There is a growing body of literature that presents detailed cost-benefi t analyses of hea lth IT impl ementation .

One study 8 used US data to demonstrate potential net efficiency and safety savings of $8 1 billion each year, after wi despread and effective e-hea lth adoption. These ga ins in efficiency wi ll ideall y lead to the transfer of labo ur to more producti ve activ iti es. The authors analyzed other industri es for productivi ty ga in s as a result of widespread IT implementati on, and estimated potential gai ns for hea lthcare between 1.5 and 4%.

Another paper9 assessed the va lue of a fully standardi zed and interoperable nationwide health IT system in the US. Des pite the hi gh co t associated with this ambiti ous task (estimated ten-year ro llout co t of $276 billion), the authors projected a net value of $77 .8 billi on annua ll y afte r implementation is compl ete. A third study 10 perfom1ed a cost-benefit ana lys is of an ambul atory care

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electroni c medica l record ystem, and e timated the net benefit for a 5-year period at $86,400 US per provider. Financial be n~ fit were largely realized from aving in drug and radi ology expenditures, and improve ments in reimbur ement (reduced bdlmg error and , accordingly, better capture of charges).

Enhancing the delivery of safe, high-quality patient care: The Canadi an Adverse Events Study tabul ated 70,000 adverse events that occur in our ho pitals each yea r, resulting in as many a 23 , ~00 death .1I British Columbia ha implemented a drug mformatwn ystem (DI ), wi th great uccess: if the e results are used to make projecti ons for all of Canada, we can ex p~ct an electromc DI S to reduce inappropriate pre cription by 55 million , and to 1dent1 fy 20 million drug interactions.4 Thi s positive impact on patient afety can al o translate into cost-savi ng . In one tudy, adverse drug event were a sociated with an increase in co t of $2,262, primarily due to a 1.9-day increase in length of stay. 12 Data cited in another rep~rt7 sugge t that drug-related event cost the average 200-bed h p1tal between 1.6 milli on and $3 milli on a year.

The potential for health in fo nnation technology to reduce er:ors i three-fold : by preventing the error upfront, by alertmg clmJCJan and all owi ng a more rapi d correction of the error, and by reportmg and generati ng feedback about the adver e event.D In a controll ed trial eva luati ng the effect of computenzed med JcatJ on o rd e~ e nt ~ by phy ician , the in e tigator found a 55 percent reduction 111 .s~ n o u medi cation errors; a follow-up tudy later eva luated the addJtJon of enhanced leve ls of clini cal deci ion support to the electromc appli cati on, and noted an 83 percent reduction in the overall medi cati on error rate. 14 A fundam ental advantage to electroniC health reco rd s is th e elimin ati on of i ue that pla gue written documentati on, such as ill eg ibl e handwritin g and in compl ete medi cati on orders. Communi cation breakdowns, most notabl y dunng poor "handoff" between clin ica l team members, are ano.ther common ri sk factor for adver e events. 13 Hea lth IT can facilitate effecti ve communication among providers, particu larl y wi th the u e of hand-held wire le s device wi th access to the electroni c patient chart .

The capaci ty fo r electronic information systems to facilitate effecti ve clini cal decision-making is increasi ngly being recogni zed.

Order entry system ca n limi t do age or route of admini !rat ion for potentially un afe medi cati on ; for exa mpl e, in patient with rena l dy func tion , com puterized ca lcul ati ons of safe drug dosage . are particularly beneficia l. 13 IT can peci fically improve pati ent monitoring. For exam pl e, IT y tern ca n alert clinic ians to potentially eriou lab atm rma liti e that may otherw i e be overlo ked , and promote earlier c rrection : in one trial, this strategy decrea ed the duration of dangerou patient cond itions by 29 percent.

15 In a related approach, technology-enabled remote monitorin g of inten ive care lead to a reduction in mortali ty of up to 68 percent, and a reducti n in average length of stay and associated costs of abo ut 33 percent. 16 Fin all y, hea lth informati on technology can increase linkage to clini ca l reference and best practi ce reco mmendati ons, all ow in g clini cians to make ev idence- inform ed dec ision .

Increased access to information: Increas ing acce s to informati on leads to myriad benefit , at th e leve l of patients, provi ders, and the hea lth y tem alike. Many of these benefits have already been rea li zed by prov incial initiati ves. 17 Fir tl y, provi ders ca n deve lop a common understanding of pati ent conditi ons, leading to more sea ml es care for patients. For example, ON Mail is an email erver that all w for transfer of pati ent medi ca l record back to the family physician upon di scharge from a hospital. Currentl y, 55,000 Ontari hea lthcare wo rker have ONE Mai l accounts. 17 Secondly, hea lth informati on technology ca n also facilitate communi cati on and co ll aborati on between prov iders, whi ch i parti cularl y relevant to the en hancement of rural hea lthcare deli very. One exa mpl e, Tele troke,

18

is an emergency telemedi cine app lication that uses..two-w.ay communication and digital imaging to connect local phys1c~an s w1th remote neurologi t located at large urban centers, to ob~m urgent di agno is and treatment reco mmendat.ions about the1r stroke . t Tllus •ar 1200 pati ents have rece1ved urgent care that saved pat Jen s. " ' . . d d d I t 1e11· . 1·1ves. 11 TJ1irdl y, when health informatiOn IS share · · ,bre un fi ·ancy 1 and the need for duplicate testing are decreased ; th1s IS ene JCJa . to patient , who wi ll no longer have to undergo. unnecessary repet1t1on of te ts, and a a ystem-wide co t-effic1ency s m~e additiOnal ex pen ive te ts can be avoided. A local s ~ ccess story 111 th1 s arena, the South Western Ontario Digital lmagmg . etwork (SWOD~) pro ides regional hea lthcare providers electroniC ac~ess to a pat1 e n~ s medical imaging result , when taken at any hosp1 tal 111 the network. 7 tories, there a.re other intriguing Beyond the e to at ucce potential outcome of increased access to health mform~t10n . In o~e cena rio, where patients are to rece1ve access to the1r electrom.c hea lth record, they could use this informat1on to manage the1r chro ni c conditi on on a day-to-day ba i , identi fy ri sk facto r , and for self-care . One important benefit that can be felt on both a systemand patient-level i reduced wait times . The u e .o f hea lt.h IT to ~a­ ord inate and manage wait lists, and to make \ a1t time mformatwn acces ible to the public in real time, i well document~d. In the UK, for examp le, their national health sy tem reports wa1t t1mes .data that uch, patient can make an mforme.d i le than one month old.18 deci sion about where to go for care. A related benefit of hea lth IT 1 the wea lth of data that are made readily avai lable; this is u efu l both for reporting of health tatu to the provi ncia l government, and for reporting of performance indicator (e.g. length of stay and mortality rates) to increa e h pita! accountab ili ty.

BARRJERS TO

UCCESS

One reviev 3 provided a uccinct classificati on of four types of barrier to the implementation of health information technology. ituational barrier include time and financial concerns; cogniti ve and/or phy ica l barrier include phy ical di sabi liti e and in ufficient comp ut er kill ; liabi lit y barriers include co ncerns a bout confidentia lity; and kno\ ledge and attitudinal barrier include apprehen ion about change or lack of awarenes of potential benefits.

With re pect to financial concerns, it is no urpri se that wide pread hea lth information technology implementation come with a hefty pric tag. The co t of impl ementation include oftware and hardware, training, work Oow proce s redesign , hi torica l paper chart ab tracting, and ongoing maintenance and upport. There are al o indirect co t as a re ult of the transition from a paper to electronic y tem , uch a the temporary decrea e in provider producti ity after implementation, a they adjust to a new y tern . IO The creation of an electroni c hea lth record for all anadian is projected to co t 10 billion. 4 In Ontario alone, thee timated total cost of a three-year e- hea lth trategy- which focu e on diabetes management, medi cation , and wa it times- is over 2 billi on. 19 Compounding thi s hi gh co t is the fact that the pre um ed financial payoff is delayed: one rev iew including 82 studi es with co t-benefit analyse bowed the time to break-even on hea lth IT in ve tment wa between 3 and 13 year .3 In some cases, the fina ncial payoff may also be uncertain- particularl y for physicians operating in a mall group or olo practice, where the return on in vestment i le ub tantial, and there i no forn1a l organi zati onal upport for training and re tructuring.20 Moreover, the ta k of performing a co t-benefit analy i can it elf po e diffi culti e , given the chall enge of a igning do ll ar va lues to producti vity ga in or improvement in pati ent ca re.

With re pect to attitudinal baJTier , Poon et aJ21 noted the percepti on that hea lth informati on technology could have a negati e impact on clini ca l proce se . Thi s pea ks to the fact that technology ca nnot be applied to a clini ca l area without careful workO w analy es; where nece sa ry, updated protocol hould be implemented

UWOMJ I 80 :1 I Spring 2011

that are in sync w ith the new techno logy. The authors 21 a lso noted that product and vendor immaturi ty was a barri er; many c urrent software offerin gs were not compatibl e w ith hospita l needs, and va ri ous modifi cati ons were necessary to acco mmodate th e hospita l's current workflo w.

Hersh22 reported that system and data interoperability was a major concern , noting the " info rm atio n s ilos" pervas ive in manag ing healthcare data. Further to thi s, sma ller, pil ot proj ects are o ften more affordable, and thu s, des irabl e from a manage ment perspecti ve; this becomes a probl em when a hea lth system has multipl e incompatibl e e lectroni c medi cal records, and an ex pens ive standardi za ti on process must be undertaken. Hersh22 al o identified the need for a wo rkforce tra ined suffi c ientl y in c linica l in formati cs to ro ll -out such a compl ex implementati on process. A re lated cogniti ve barri er is the lack of IT kn ow ledge and tra ining in hea lth profes iona l edu cati on; thi s can certa inly impede fro nt-line c lini cian ' acceptance of techno logica l trends in their wo rkpl ace.

CONCL USIONS Recommendations: A n e lectroni c hea lth inform ati on system has a large impact on the day-to-day wo rk of both c lini c ians and hospita l admini strators. As such, there i a c lear need to engage, and ensure buy-in from , these stakeho lders ea rl y in the dec ision process 7 Health profess iona ls in particul ar should be con ulted in order to e lect and build an e lectroni c system that i compatible with clinica l needs and patient fl ow. One approach i to des ignate key phys ic ians as "champions" of the process, w ho can then help moti vate other clinicians and admini strators, and promote acceptance and adopti on o f the IT system 7 Often times, there is res istance among front-lin e staff when a change is seen as coming fro m admini strato rs who are not fa miliar with c linica l processes; if the process is supported by a res pected c linical co ll eague, however, other c lini cians tend to be less wary. It is also important not to underestimate the sca le o f such an implementation process . The process ma y inc lude modificati ons to the software architecture and the establi shment of new standards of care or changed medi ca l practi ces. C hange management itse lf requires reso urces and time; for exampl e, in one Canadian hospital system , app rox imate ly 30 percent of the tota l proj ect budget was allocated to thi s stage. 7 Another approach is to implement an infonnation technology ystem in a succes ion of phased pil ots; the proj ect team ca n identi fy lessons learn ed and apply them to subsequent ro llo uts. If pilots are successful , other clinical areas w ill be eager to undergo the same change. Increas ing education and awareness about the benefits of hea lth information techno logy w ill boost acceptance of change on the part o f the ge neral publi c and health prov iders alike. Data eluc idating these bene fits are required for such endeavours; c lini ca l settings w here IT systems have been implemented should be encouraged to co llect, analyze and publi sh data on the results. Finall y, hav ing di verse applicati ons and softw are platform s increa ses co mpl ex ity, ra ises costs, and le ngth e ns implementation timeframes. 7 As such, at a time of rapid adoption of health IT, it is crucia l to impl ement a simple, unifi ed system. It will be important to ma intain an integ rated e-H ea lth Ontari o strategy to facilitate this .

The path ahead: Health info rmation technology has created endless opportunities and has enormous potential to transfo rm the de livery of healthcare. The possibilities even surpass the bi o medi cal model: an e lectronic health record has the capac ity to link c linica l data to indicators of soc ioeconomi c statu s, a ll o win g a re ma rkabl e understanding of the impact of soc ia l determinants of hea lth .

However, this chang ing landscape has also challenged us with important questions. 18 Who will have access to thi s wea lth of infonnation? Will patients be able to v iew the ir own e lectro nic record? If data are anonymi zed, are they then ethica l for gove rnment reporting and public use? Will health info rmatio n techno logy be used

to increase transparency, by provid ing o utco mes data to the ge nera l public? Will c lini cia ns fee l comfortable operatin g in such a system, where the ir post-operati ve morta lity rate is wide ly publi shed? And perh aps most importantl y, will the myri ad stakeho lders em brace the opportuni ty to co ll aborate and use infonnati on fo r the ad va ncement of hea lth? We look forwa rd to leamin g the answers to such questi o ns, and hope that innovatio ns in hea lth in fo rm ati on techno logy w ill be embraced ac ros Canada.

REFERENCES I. Canadian Insti tute for Health Information . Nati onal hea lth ex pend itu re

trends: 197S-20 10 [In tern et). 20 10 Oct [ci ted 20 11 Ja n 10). Avai lab le f r o m : h ttp : // sec u re . c i h i . c a I c i h i web I produc t s I HEX_ Trends_ Report_20 I O_ fi nai_ E G_ web.pdf 2. Millman J, Bryan t M. South we t Ontari o Digital Imaging etwork.

Richa rd lvey Bu iness School Health Care Ma nagement Ca e Book .

Version (A) 2009: 11 -24.

3. Shekelle PG, Morton SC, Kee ler EB. Costs and benefi ts of hea lth information techn ology. Evid Rep Tech no! Assess. 2006;( 132): 1-7 1.

4. Canada Hea lth lnfoway. An nua l repo rt 2009-20 I 0: Repo rti ng to Ca nadia ns [I nternet). 20 10 [ci ted 20 11 Jan 10). Available from : S. ht tp s://www. in foway- in fo ro ut e.ca/tlash / la ng-en /a r2009-20 I 0/docs/ CHI An nua l Report 2009-20 I0 E G.pdf 6. Sch~en C, Osborn R, Huynh PT, et al. On the fron t li nes of ca re: pri mary care doctors' office systems, experi ences, an d views in seven co untri es.

Hea lth Aff(Mi ll wood). 2006;2S(6):wSSS-7 1.

7. Canada Health ln foway. 20 IS: Canada's next generation of health ca re at a glance [I nternet). 2007 [ci ted 20 11 Jan 9) . Avai lab le fro m: http :1/ www2 .in foway- in foro ute.ca/Doc umen ts/Vision _Summary_ EN .pdf 8. Lafl amme FM, Pietraszek WE, Rajadh yax NV Reformi ng ho pita ls with IT in vestm ent. 20 10 Aug [cited 20 11 Jan S). Avai lab le fro m: Im ps:// w w w. m c k i n s e y q u a r t e r Iy. c o mI H e a It h_ C a re I Reformin g_ho pita Is_ with_ IT_ in vestment_26S3 9. Hillestad R, Bigelow J, Bower A, et al. Ca n Electroni c Medical Reco rd System Transform Hea lth Ca re? Potenti al Hea lth Benefi t , Savings, And Costs. Hea lth Aff (Mil lwood). 200S ;(24)S : II 03- 111 7.

10. Walker J, Pan E, Johnston D, et al. The va lue of hea lth ca re inforn1ati on exc hange and interoperability. Hea lth Aff (Mill wood). 200S ;Suppl Web Exclusives: WS- 10-WS- 1 .

II . Wang SJ, Middleton B, Pro er LA , et al. A cost- benefit analys is of electroni c medi ca l reco rds in primary care. Am J Med. 2003 ; 11 4:397-403 .

12. Baker GR, No rton PG, Flintoft V et al. The Canadi an Adverse Events Stu dy: the incidence of adverse events among hospi ta l patients in Canada.

CMAJ. 2004 ; 170( II ): 1678- 1686.

13. Classen DC, Pestotnik SL, Eva ns RS, et al. Adverse drug events in hos pitali zed pati ent . Exce length of tay, extra costs, and attri butable mortali ty. JAMA. 1997 ;277:30 1-6.

14. Bate DW, Gawa nde AA . Improvi ng safety with information techn ology.

N Engl J Med 2003 ;348:2S26-34.

IS. Bates DW, Miller EB, Cullen DJ , et al. Patient risk fac tors fo r adverse drug events in hos pitali zed patients. Arch Intern Med. 1999; IS9:2SS3-60.

16. Kuperm an GJ, Teich JM , Ta na ijevic MJ, et al. Improv ing response to crit ica l laboratory res ults wi th automati on: re ult of a random ized controlled trial. JA m Med In fo rm As oc. 1999 ;6:S I2-22.

17. Rosenfe ld BA, Dorman T, Breslow MJ, et al. Intensive care unit telemedi cine: alternate paradi gm fo r prov iding continuous intensivist care.

Crit Care Med. 2000;28:392S-3 1.

18. eHea lth Ontari o. Wh at we've done [Internet). 20 I 0 [cited 20 II Jan 8).

Ava ilable from: http ://www.ehea lthontari o. on.ca/about/successStories.asp 19. Ca nadi an Institute for Health Inform ati on. Health ca re in Canada 2009: A decade in review [Internet). 2009 [cited 20 11 Jan S). Ava il able from:http :// secure.cihi.ca/cihi web/products/HCIC_ 2009 _Web_e. pd f 20. eHealth Ontari o. Ontari o's eHea lth Strategy 2009-20 12 [Internet) . 2009 [cited 20 11 Jan 10). Ava ilable from: htt p://www.ehealthontari o.on.ca/pd fs/ About/eHealthStrategy.pd f 2 1. Miller RH , Sim I. Phy icians' use of electroni c medi cal records: barriers and solutions. Hea lth Aff (Mill wood) 2004;23(2): 11 6-26.

22. Poon EG, Blumenthal D, Jaggi T, et al. Overcomin g barri ers to adopting and impl ementin g co mputerized ph ysician order entry ystems in U.S. hospitals. Health Aff (M ill wood). 2004 ;23(4): 184-90.

23 . Hersh W. Health ca re in fo rmat ion techn ology: progress and barri ers.

JAMA. 2004;292( 18):2273-4.

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)

Using texts for safe sex: technology in adolescent sexual health Stephanie Gottheil (Meds 2014), Paul A. Kudlow (Meds 2013) Faculty Reviewer : Dr. Lois Champion . Critical Care and Anesthesia

i ky sex ual behaviour among adole cents is a ignifi ca nt ca u e of infection and morbidity, as well as un wa nted pregnancy. In the United State , 25% of females between 14-1 9 have acquired a ex uall y tran mitted infection (STI) and adolescents between I0-24 account for more than 20,000 new cases of HIV/AIDS annually.1 While many ST I are eas ily treatabl e, they can also lead to pelvic infl ammatory di sease, chronic pain , or cervica l cancer and infertility.2 As we ll , there are over 745,000 teenage pregnancies in the US every year.1 Therefore, promoting se ual hea lth through yo uth - pec ifi c interventions is an important topi c of research and concern .

R

In the past, sex ual hea lth promotion interventi ons (S HPI ) have been provided through choo l programs and sexual hea lth clini cs.

Through thi s medium, informati on is typica ll y given face-to-face by hea lth care workers and is compl emented by print materi als. Whil e these trategies have hown moderate succe , they are limited by cost, time, and access ibili ty.3 Face-to-face HPI have not been hown to ub tantia ll y impact Tl in fecti on rate , unplanned pregnancy rates, or number of sex ual partners, although they have been shown to increase knowledge abo ut sex ual hea lth and condom u e.3 Th e introduction of new techn ology all ows for a less ex pensive and more effi cient way of pro moting sex ual hea lth to the largest number of peopl e. Th e most successful technology-ba ed SHPI to date have involved eith er internet-based interventions or tex t-messaging-based interventions. Since 93% of U adolescents have a computer at home and 85% of 14- 18 year olds own a cell phone,4 these media prov ide exce llent access to the adolescent popul ati on. Techn ology-ba ed SHPI have not onl y been shown to reduce ri sky ex ual behav iour and increase know ledge of sex t.ml hea lth ,3 •5•6 but ca n reduce co t and time spent by hea lthcare workers by shifting the burden to more automated technologies 7 Sex ual hea lth pro moti on con i ts of prov iding indi viduals with the too ls to make informed dec i ions about their ex ual we ll -be ing. 3 The overall goa l is to improve the sex ual hea lth of a popul ati on through commun ity- based interventi ons. In order to do so, however, one mu t first identi fy th e reason that ind iv iduals, espec iall y adolescents, engage in ri sky sex ual behavio ur. Recent research into adolescent moti vation fo und that the fo ur main factors that contri bute to these behaviours are: low percepti ons of ri sk, lack of confidence, the influence of social norms, and in accurate knowledge.s Most interventi ons ai med at adolescents focus on thi s last factor by providing information on Tl and contrace pti on; however the e strategies have show n onl y margin al ucces .2 Sex ual hea lth promoti on interventions must not onl y focus on bi ologica l outcomes, such as STI incidence rates or teen pregnancy, but on behav ioural and emoti onal outcomes - in creased self-e ffi cacy, moti vati on to change, and confident dec ision-making.

20

Technology-ba ed strategies can incorporate thi research by prov iding populati on- peci fi e interventi ons that touch on multiple a pects of ex ual hea lth . Studi es have shown that interventions are more effective when they are ba ed on behavioural theori es and address th e soc ial and p ychologica l cau e of risky sex ual acti vity.5 •8 lnte rn et-ba ed and text-me aging-ba ed interventi ons have the abili ty to promote behavioura l change by u ing the con venience, peed, and ubiq uity of these techn ologies to access at-ri sk adolescents . lnternet-ba ed HPI are promi ing because they a llow for anonymou , repeatable, con enient, and inexpensive interventi ons that can reach popul ati ons that are more res istant to mainstream medi ca l ca re 3 Almo t 50% of youth urveyed have already used the In te rnet to search fo r sexual hea lth in fo rmati on.5 A recent Cochrane Rev iew meta-analysis of interacti ve, computer-ba ed HPJ found igni fica nt effect n both behavioural measurements, uch a condo m use, and psychologica l mea urement , such a confidence and elf-efficacy3 . Fifteen RCT \ ith 39 17 part ic ipant were reviewed. In keeping wi th pre ious fi nding on the importance of moti vation and dec i ion- mak ing in behaviour modification5 , the review focused only on interventi ons that required user contribution and provi ded perso na lized fee dback. T he mo t ucce ful interventi on were tai lored to an indi vidual's leve l of know ledge and invol ed role-playi ng or ituational exerci es. 3·4.8.Q.JOStudi e that foc u ed specificall y on adole cents were also more ucce ful if they a oided negati ve me ages and scare tacti cs, and ta rgeted peci fi e behaviour . Many of the e interventi on exempli fy the principles of hea lth promoti on becau e they not onl y educate, but al o prov ide u ers with the confi dence and motivati on required to make safe dec i ion in the future. 1 Other we b ites prov ide user with anonymous and acce ib le way of improv ing sex ual hea lth ia mailin Tl te ts or onli ne contact-trac ing after Tl diagno i .1 Us ing text messag ing to promote adolescent sex ual hea lth has many adva ntages . Tex t mes ages are fast, co nveni ent , and inexpen ive; they can be sent to multiple indi viduals at the ame tim ; they. are very popul ar among adole cents, and text mes aging rate are unil ar bet~een socioeconomi c groups.6 Tex t me aging has been Incorporated 1nto ex ual hea lth ca re in numerous ways, with encouraging res ults: Sex ual hea lth clini cs in the UK have begun prov1d111g results of Tl tests via tex t mes age if des ired - 70% of adolescents preferred thi to booking a foll ow-up appointment. ? The UK ha . a l ~o . begun a text mes aging "G rab a Condom" campaign, where mdJ v1dual can request condoms and have them homedeli vered6 Other clini c have begun prov iding daily text mes age remmders to pat1 ent about taking oral contraceptives, and have seen a ignifi cant improvement in reported co mpli ance6 The most prom1 mg interventi on, implemented in an Franci co aiiO\ indi viduals to text " XINFO" from any mobile phone and r~cei e

UWOMJ I 80 :1 I Spring 2011

( infom1ation about sexual hea lth , relati onships, and nearby clini cs. In the fir t 6 month , SEXINFO rece ived more th an 4500 tex t mes ages and th ose who remembered seeing adverti sements for the ervice were ignifi cantl y more likely to be concerned about STI . 11 Wh ile not yet widely used, tex t messag in g shows promi se a an effecti ve SHPI that can be u ed to target adole cents directl y.

The use of technology-based HPI is relatively new, although their effectiveness has been demonstrated in numerous tudi es.

However, there are till concem that th ese strategies may be aving time and money at the ex pense o f acc uracy and hoi isti c care. A recent study of 177 sexual health website showed that 17% contained one or more medica l errors, and the number of errors was correlated with the complexity of the topi c at hand. 12 Sex ual hea lth web ites foc u strongly on ST is and contracepti on, but often only contain a cursory treatment of how to ex press sexuality, body image, and th e po iti ve aspects of sex. 13 A recent stud y of 30 " Positi ve Youth Development" interventions- tho e that foc used on empowerment of di adva ntaged youth - howed that all ucce sful in terventi on in vo lved a supporti ve environment containing pa rents, teachers, or hea lth ca re providers. 1 Can technology-based interve ntions provi de thi s ame level of support and intimacy? ea rl y half of teenager cited their parents a the people with the most influence in their sex ual dec isionmaking, yet very few of the intemet- or text mes aging-based interventi ons encourage parental in vo lvement. 5 Moreover, prov idi ng STI results via text messaging led to a decrease in foll ow-up visits, which wa hail ed a a succes by the UK sex ual hea lth clin ics invo lved . 14 Howeve r, if th e e in te rve nti o ns lea d to fewe r conversation between adole cent and their hea lth care prov iders, is this reall y omething to ce lebrate?

for global diffu sion. urr Opin Psyc hi atry. 20 I 0 Mar;23(2 ): 139-44.

8. Bull , Phibbs . Watso n , Mc Farl ane M. What do yo un g adu lts expect when they go online? Le on for development of an TD/HIY and pregnancy prevention web ite. J Med Sys t. 200 7 Ap r;3 1(2): 149-58.

9. Ki ene M, Barta WD. A brief indivi duali zed co mp uter-d eli vered ex ual ri sk reducti on intervention increa es HI Y/AID preventi ve be hav ior.

Journal of Adolescent Hea lth 2006 ;39( 3 ):404- 10.

I 0. Roberto AJ, Zimmerm an RS , Carlyle KE, Abner EL. A co mpu ter- based approac h to prevent ing pregnancy, STD. and HI V in rural ad ole cen ts.

Journal of Hea lth Co mmunicati on 2007 ; 12( I ):53- 76.

I I. Le vine D, McC right J, Dobki n L, Wood ru ff AJ, Klausner JD. EXTNFO: a se ·ual health text messaging service fo r San Francisco youth . Am J Pu blic Health. 2008 Mar;9 (3 ):393-5.

12. Buhi ER, Daley EM , Obeme A, Smith A, Schn eide r T, uhm1ann HJ .

Quality and accuracy of sex ual hea lth infom1 ati on web ites visited by yo ung peo pl e. J Adolesc Hea lth . 20 I 0 Aug;47(2) :206-8.

13. Ge rress u M, French RS. Using th e Intern et to promote ex ual hea lth awa reness among yo ung peo ple. J Fam Plann Reprod Hea lth Ca re. 2005 Oct;3 1(-I ):267 , 269-70.

14. Menon-Johansso n A , ohen E, Jones R. Interventi ons to increase acces to Tl se rvices: a stud y of England's high-i mpact changes across th ree ce nt ral London clini cs. ex Trans Infec t. 20 10 86:540-544 .

Medi a and communi cation techn olog ies, like Internet and text messaging, have the potential to be used as fa r-reaching and costeffecti ve method of promoting sex ual health among adolescents.

Initi al studi e demonstrate that the e intervention can successfu lly provide know ledge, motivate people to change behaviour, and encourage adolescents to seek medica l ca re when necessary.

However, few studies have measured their effect on long-term outcomes, uc h as ST I in fec tion or pregnancy rates. As we ll, some concem remains that technology-based SHPI cannot full y address the emoti onal needs of adolescent in the sa me way a face-to-face conversations with a hea lthcare provider. Neve11heless, it is th ought that reaching adolescents "on their own turf' , by using medi a th ey are comfortabl e and fa miliar wi th , may encourage them to seek care when nece ary and fee l more motivated to practice safe sex ual practices.

"MCI takes care of everything without telling me how to run my practice."

MCI means freedom: I remain independent • No financial investment • Flexi ble hours and 34 locations

REFE RENCES

• Appointments or walk-in

I. Gavin LE, Catalano R.F, Dav id-Fe rd on C, Gloppen KM , Ma rkham CM . A review of po iti ve youth deve lopment programs th at promote adolesce nt sex ual and reprod uctive hea lth. J Ad olesc Healt h. 20 I0 Mar;46( 3 Suppi ):S75-9 1.

2. Dow ns JS, Murray PJ , Brui ne de Bruin W, Penrose J, Palmgren C, Fi chh off B. Interacti ve video behav ioral interve nti on to red uce ado lescent fe male ' TD ri sk: a random ized co ntro lled tri al. oc Sci Med. 2004 Oct; 59( 8): 156 1-72.

3. Bailey JV, Murray E, Rait G, Mercer H. Morri s RW, Peacock R, Cas ell J, Naza reth I. Interacti ve com puter-based interventi ons fo r sex ual health promoti on. oc hrane Database yst Rev. 20 I 0 Sep 8;(9): D006483.

4. Hassa n A, Fleegler EW. U ing technology to improve adolescent health care. Curr Opin Pedi atr. 20 I 0 Aug;2 2(4):4 12-7.

5. Delgado HM, Austin SB. Ca n medi a promote re ponsib le sex ual behaviors among adolescents and yo ung adu lts? Curr Opin Ped iatr. 200 7 Aug; 19( 4 ):405-1 0.

6. Lim MS, Hockin g JS, Hellard ME, Ait ken CK. MS Tl: a review of the u es of mobi le phone tex t messag ing in sexual health. lnt J T D AIDS. 2008 May; 19(5 ):287-90.

7. Swen deman D, Rotheram -Borus MJ . Inn ovati on in sex uall y transmi tted disease and HI Y prevention : intern et and mobil e phone delivery vehicles

• Trained , professiona l staff

r

MCI has over 20 years of experience managing family mE'dicine clinics in the Toronto, Calgary and Vancouver areas.

Toronto (416) 440.4040 x 433 Calgary (403) 269.1440 x 26 Vancouver (604) 323.1001 practice@mclmed.com www.mc1med.com

MCI Medical Clinics Inc. Toronto -Calgary -Vancouver Works for Doctors • Cares for Patients • Empowers Employees

UWOMJ I 80 :1 I Spring 2011

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PACS, SRR and the future of radiology Ashley Kim (Meds 2013}, Emma Farley (Meds 2013) Faculty Reviewer : Dr. Richard Rankin (Department of Medical Imaging)

he compl ex orga ni zation of the Canad ia n healt h care system has led to fragmen ted care, and cha ll enges in interdi sci pli nary communicati o n. Adva nce in techn o logy, however, are rapidl y e nh anc in g th e potenti a l fo r multipl e di sci plin es to communi cate and integrate infonnati on. Many of th ese adva nces have been fostered under th e leadership and influence of radi ology.

T

Innovati on i described as hav ing two components: th e development of new technologies, and th eir adoption into c lin ica l practice 1. Both are req uired fo r a rea l impact in med icine. Beginning with Roentgen 's discovery of x- ray , inn ovat ion in new imag ing techniques like ultraso und, CT and MRI ha pro pelled radio logy to th e fo refront of cutti ng edge med ica l science. Furthenn ore, leaders in radi ology have pi oneered efficient communicati on and electroni c storage strategies to more effi ciently adopt th ese imag ing modalities into c linica l practi ce, accessibl e to a large r group o f caregive r 2 Pi cture Archi ving and Communicatio n System (PACS) is ju t one example th at has now been implemented in hospita ls acros th e country and throughout the world .

The fi eld of radi ology has been exempl ary in using innovati on to fac ilitate multidi sc iplinary care. O ften, however, th e e innova ti ons are adopted or compl ete ly taken over by oth er pecialti es res ulting in " turf wa rs", whi ch create animos ity, hinderin g co ll aborati on on a fund amenta l level. In additi on, it is poss ible th at ince techno logy ha redu ced face- to-face time in non-medi ca l rea lms (e.g. Face book, online chat, bl ogs), it could a lso negati vely impact communicati on in medi c ine. Thi arti c le arg ues, however, th at an increase in compute ri zed co mmuni ca ti o n is a pos iti ve deve lopm ent fo r inte rdi sc iplin a ry co ll a bo rati o n owi ng to th e nature o f th e techno logies used . Thi s arti c le w ill a lso outline so me exa mpl es of current techno logy th at have co me to ymbo li ze th e concept o f computeri zed clini ca l integ rati on.

Despi te literature th at bemoa ns th e decrea ed c lini ca l pre ence of radi o logists caused by technology, its adva ntage to pati ent care ca nn ot be ignored . A radi ologist stated, " th e say ing 1empora mulantur is as tru e today as it was in th e day o f th e Roman : time change, and we must change w ith th em" 3 . Radi o logists have been pi vota l in deve loping these modern techno logies and now must adapt to best rea p th e ir rewa rds.

PICTURE A RC HIVING AN D COMMUN I CATI ON SYSTEM PACS re fers to the e lectroni c storage of multimoda l data in c lu din g imag ing studi es, repo rts and pati e nt identifi ca ti o n in fo rmat ion. PACS repl aces hard co py data ( film s and paper records) and all ows th e integratio n of imag ing with oth er systems such a th e Electroni c Medi ca l Record (EMR). There are severa l storage form at fo r PACS, whi ch a ll ge nerall y inc lude images (w hi ch can be T, MRI, US, PET, endoscopy, mammograph y, oph th almo logy, etc), a secure netwo rk, multip le wo rkstati on (w hi ch can ex ist at mu lti ple

22

ho pita ! si te ), and patie nt archives . PACS fac ilitates remote access, and is u ed by ra dio logists to perfonn te leradi o logy, or off- ite image in terpretation. Integrated into PAC is a wo rkfl ow management system, which a llows fo r an efficient a yn chrono u communicati on ys tem 4 . In other wo rds, once the image is acquired , pre liminary comments can be made by the technic ian or referrin g phys ic ian. In addi tion, if a diagnos is is made immedi ately and acted upon, say in the ED, thi is recorded and can be later re-eva luated by th e radi ologi t who can either agree or d isagree wi th the ori gina l imp ression. T his a llow for a ystem > here discrepanc ies can be recorded and later studi ed fo r particular patterns of error.

In th e tudy by Mate e / a/., an add iti o na l communicati on tool was impl emented a longs ide PACS, ca ll ed Co ll aborative N otificati on System (C ), w hi ch was used in th e setting of urgent or emergent radi o logy4 . C con i ts of a page r notifi cati on syste m between th e radi o logist and referri ng physic ian, and allows for image to be read immediate ly, and the d iagnosis paged to the referrin g phy ic ian w ho can then acknow ledge its receipt. The system was shown to improve documentatio n, and provided an exact record of th e communicati on, whi ch wo uld not be ava il abl e wi th per on-to-person communicati on.

CN is j u t one way in w hich PAC has been shown to fac ilitate radi o logi t wo rkfl ow.

Additiona l bene fits of PACS include an increase in 1mage ava ilab ility as we ll a a decrea e in time pent trave lling to the radi ology department 5 A nother report de monstrated th at PA CS enh a nced co mmuni ca ti o n betwee n radi o log i ts a nd re fe rrin g ph y icia n by decrea ing e rro rs re lated to in co rrect pati e nt identifi cati on, and increased the e ffi c iency of meetin gs by pro iding readil y ava ilable image and report 6 . Mo re managea ble w orkflow and increa ed effi c iency of inter-ph ys ician communi cation are und eni able here. Unfortun ate ly fo r radi ologists, however, more acces ibl e image data may lead to an increase in th e number of nonradi o logist ph ys ic ian w ho interpret radi o logica l studies.

SPEECH RECOGN ITION REPORTI NG Speech Recogniti on Reportin g ( RR) has been wide ly ava ilab le in hea lth ca re world w ide fo r the Ia t 15 or so yea r , but recentl y Improvements have been made such that the vo ice recognition sy.stems are more ophi sti cated, requirin g less voice-tra ining time w 1t~ 1ncrea ed word -recognition accuracy. Radi o logi t have been a maJor con umer o f S R~ as it ha been shown to sig nificantl y reduce th e .tun e between examJ.nation and report fin a li za tion 7路s. Tradi ti o na ll y, radiOl ogists wo uld di ctate report , w hi ch w ere record ed and t~a n scribed at a .later time: and fin a ll y veri tied by the radio logi t and s igned off for mc lus1on m th e patie nt chart or EMR. With RR vo ic e i converted directly to tex t a fter th e RR oftwa re ha bee~ trained to th e parti cul ar user 's voi ce. T he report th en appears unm ed1ate ly 111 th e EMR and as part of th e hospital 's PA S . The use

UWOMJ I 80 :1 I Spring 2011

( of SRR along ide PA CS ha been hown to ignificantl y reduce report completi on time a we ll a igni ficant ly inc rea e the number of reports which are avai lable with in 24 hourss.

Another benefit of RR, how n by Bh an et a/., is th e decrease in overall hospital operati ng costs8 The ame report, however, publi hed data bowi ng that RR actu all y increased the amou nt of time taken to produce indi vi dual reports, and was prone to inaccurac ies in certai n ettin gs, for exa mpl e, when used by practitioner for whom Engli sh was a econd lang uage. Speech Recogniti on Reporting wa hown to have no effect on the overall number of report produced. De pile some of it shortcomings, RR has recently hO\ n a t improvement and wi ll undoubtedl y cont inue to do so. It has become a main tay for many radio logi ts and other specialties alike and ha the unique ability to be combined with to provide a more comp lete compo ite of ystem such a P patient data, benefitting all member of the interdi ciplinary team.

THE FUTURE OF RADIOLOGY

ince many technologie have improved the efficiency and accuracy of radiological reporting, there has been a parall el increase in the adopti on of radio logical technique by other spec ialti e . Thi s i known to many a radio logy "turf war ". The most prominent example over the pa t 40 year are in va cular urgery and coronary angiography. One author specu lated that the rea on for the total ces ation of radiologi t perfom1ing these procedure was their lack of specific knowledge in the clini ca l as pects of coronary artery di ea e (e peciall y electrocardiology and ca rdio pharmaco logy) a well as the ability of cardiologist to se lf- re fer 9 Palma notes that since radiologists are not trained in the catheter lab and do not conduct research in coronary disease, they are less adept to perform coronary angiography. Thu s, radiologi t have largely abandoned thi practice. One study showed that the tota l number of intravascul ar procedure perfom1ed by radi ologist fell from 63 .6% to 49%, whi le those perfom1ed by ca rdiolog i ts ro e from 25% to 36% from 1997 to 2002 10 . Radiologists, however, have longer and more high ly speciali zed education that include in-depth radiati on sa fety training, familiarity with all imaging modaliti e , and ability to detect incidental findings " , whi ch suggests that they are better suited for these procedures. The previous ly mentioned ph enomenon of se lfreferral has also been explored and shown to lead to an increas ing and unnecessary utilizati on of radi ologica l se rvices by nonradiologists1 2.

The high le el of technical ability inherent in radio logy ha led to a real or perceived weakening of the clini cal re lationship between radiologist and pati ent. Therefore, there ha been a recent pu h towards ol uti on termed "clini ca li sation ", wh ich reinforce the clinical role of radiologists and their technol ogies 3路9 路 13 . Clini ca li ation also seeks to help radiologi ts better communicate wi th other discip lines by recommendi ng training for radiology resident in spec ific organ patho logies, and upports the ph ys ician-pati ent re lationsh ip by encouraging radiol ogists to maintain contact with the patient in all phases of treatment 13. Additionall y, centers in the Un ited States ha ve exp lored the po sibi li ty of using online im ages to increase patient access . Thi wa found to increase pati ent sati sfaction , and support the relation ship with and identificati on of the radiol ogist a a profe sional responsib le for diagnosis and treatment 14 .

or intemati onall y i po ible. 15 Telemedicine and vidoecon ferencing wi ll also enhance large- ca le com muni cati on. The next few decade wi ll ee further adva nces in nanotechn ology, molec ul ar imaging, and new forms of percutaneous treatm ent. Radi ologists who have ex perti e in electroni cs and informati c , a foundati on of specialized clini ca l pathology and exce ll ent bed ide man ner will help shape th e way innovation i impl emented in da y-to-day med icine.

REFE RENCES I. Gund erman RB , Meesa IR. The adop ti on of Innova ti on. Radiology 200 246 ( I ):659-661 . was developed an d old .

2. Wiley G. The Prophet Mot1ve : How PA I 111 a g i 11 g E co 11 o 111 i c s M a y 2 0 0 5 . A c c e s s e d a t h t t p : // www.imagi ngeconomi c .c m/ i ue /arti cles/2005-05 _0 l .a p.

3. Margu lis AR. The Con tantl y hang ing Field of Radio logy: ain ta1nmg Professionali m in an ra of Electronic ommun ication . Radio logy 20 I 0.

257 ( I ):22-23.

4. Mates J, Branstetter BF, Morgan MB, Lionetti DM , Chang PJ . 'Wet Reads' in th e age of PA S: techni ca l and workflow considerati ons for a preli minary report system. J Digit Imagi ng. 2007 ep;20(3):296-306.

5. Bryan S, Weatherburn GC, Watkins JR, Buxton MJ . The benefit of hospital-wide picture arc hivi ng and comm uni cati on systems : a urvey of clinica l u er of rad iology ervice . Br J Radio!. 1999 May;72(85 7) : 469-78 .

6. Dunca n LD, Gray K, Lewi JM , Bell JL, Bigge J, McKinney JM . Clini cal integration of picture arc hi vi ng and com mun icati on y tems wit h pathology and ho pita! informati n ystem in oncology. Am Surg. 20 10 Sep;76(9) :982-6.

7. Hart JL, McBride A, Blunt D, Gishen P, Stri ckland N. Immediate and sustained benefits of a "total" implementati on of speech recogniti on reportin g. Br J Rad io!. 20 I0 May;83(989):424-7. Epub 20 I 0 Mar II .

8. Bhan N, Cob lentz L, Norn1an R, Ali H. Effect of voice recognit ion on radi ologi t reporting tim e. an A c Radi o! J. 2008 Oct;59(4) :203-9.

9. Palma DL. Tomorrow's radi ologist: what future? Radi o! Med. 2006 Aug; Ill (5):62 1-33. Epub 2006 Jun 29 .

I 0. Levin DC, Rao VM , Parker L, Bonn J, Maitino AJ, Sunshine JH . The changing roles of radi ologist , card iologists, and vasc ul ar urgeons in percutaneous peripheral arte ri al interventi ons during a recent five-year interval. J Am Co li Radio!. 2005 Jan;2( I ):39-42.

II . Levin DC, Rao VM . Turf wa r in radiology : introducti on . J Am Coli Radio!. 2004 Jan; I ( I ):23-5 .

12. Levin DC, Rao VM. Turf war in radiology: th e overutili za ti on of imaging res ulting from se lf-refe rral. J Am Coli Radi o!. 2004 Mar; I (3 ): 169-72 .

13.Margulis AR, ostm an l-ID . Rad io logistpat ient co ntact during th e performance of cro - ecti onal exa min ation . J Am oil Radi o! 2004 ; I (3) : 162 - 163 .

14. Johnson AJ, 1-lawkin H, App legate KE. WEB-based re ults distribution : ne\\ chan nels of communication from radiologi sts to patient . JAC R 2005, 2: 168- 173.

15. Arenson R. The practice of medicine and radiology in 2020. Radiology 1997 ;203 :43A-46A.

CONCLUSION: WILL TECHNOLOGY HELP OR HI NDER RADIOLOGISTS?

Innovation in radio logy is influencing many as pects of medi cine that include comm unication, management, diagnost ics and therapy.

The future of radiology undoubtedly in vo lve furt her development of PACS and SRR systems and their becoming so widespread that transmi ssion of images and report to pati ent mart cards, nati onally

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Lab-on-a-chip technology: the future of pointof-care diagnostic ability Me lissa J. MacPherson (Meds 2014}, Mayoorendra Rav icha ndiran (Med s 2013} Faculty Reviewer : Dr. Cyrus Hsia, MD, FRCPC (Departm ent of Med icine, Divis ion of Hematology)

ne of the greate t cha ll enges in modem medi c ine is th e ability to provide acc urate diagnosti c laboratory te t in developing co untries and in remote areas where conve nti ona l analytica l laboratori e are lack ing. Imag ine running a cli ni c in a remote area o f rural Africa, the Canadian arctic, on a military fi e ld ba e or even in a small rural community in Ontario and hav ing th e ability to provide acc urate, rapid, po int-of-care di agnosti c lab tests wi th out the infrastructure of a full ana lyt ica l laboratory ' There 's no need for a cumbersome or ex pens ive mass spectromete r, a spectrophotometer, a fl ow cytometer or even a centrifuge beca use th e applicati on o f mi cro fluidi cs eng ineerin g to medi ca l di agno ti cs ha enabled labo ratory tests to be performed on a ma ll microchip th e size of a credit card that you can carry around in your pocket and may onl y require th e use of a battery as a power so urce for analys is!

As futuri sti c as this idea seems, th e appli cati on of mi crofluidi cs engineerin g to th e deve lopment of medical diagnostic te ts is very much a rea li ty.

0

Mi crofluidic s eng inee rin g is a multidi c ip linary fi e ld of eng ineerin g where th e intersecti on of th e fie ld of ph ys ics, chemi stry, eng ineering and biotechnology have come togeth er to deve lop chips on which the ana lys is of fluids can occur on a microsca le leve l. A parti cular ly interestin g application of micro fluidi cs eng ineerin g technology is th e deve lopment of a lab-on-a-chip ; a pl atform on whi ch one or more laboratory te ts are integrated onto a sma ll chip a few squ are centimetres in ize th at uses a very sma ll volume of fluid for anal y is. Severa l mi cro!iters of a va ri ety of biologica l fluid in cludin g bl ood, cerebro pinal fluid , urine, feces or sa li va ca n be add ed to th e lab-on-a-chip fo r analys is. 1 The e chips utili ze a wide va ri ety of techniques for analys is. The most succes fu l lab-o n-a-chip applicati ons integrate all aspects of sa mpl e preparati on, ample se parati on, signa l amplifi cati on and signa l detecti on on a sing le chip .

1 These chips ca n be ea ily adapted for use in remote regions since pecialized laboratory personnel are not needed for ana ly i - yo u simply need to appl y th e sampl e to th e chip and th e tec hno logy take care o f the rest. In additi on to th e ir sma ll ize and portability , th e appli cati ons of lab-on-a-chip platforms have a wide va ri ety of adva ntages to the fi e ld of medi ci ne and are li sted in Box I (adapted from references ( 1-3)) . A va ri ety of mo lec ul ar biology, immuno logy and biochemi ca l techniques ha ve been adapted for use on lab-on-achip platfo rms inc ludin g protein assays, nu c leic ac id as ays, cell sorting, and biological analyte detecti on. '.4 Since lab-o n-a-chip techno logy has a wide variety of applications in medicine we w ill now fo cus on two areas o f interest where we fee l the techno logy will be rapidl y appli ed ; th e detecti on of infecti ous mi croorga ni m from biological amples i.S路 6 and the microsca le detecti on of bi o logica l ana lytes 7 Arguably, one of th e most important and exciting app lica tions of th ese devices is in the ea rly and acc urate diagnosis of infecti ous

24

di sease in th e developing world .1.3 5 路 6 The ability to rapidl y detect an infecti on, a ess an infected patient 's health status and the appli cati on of this techno logy to epidemio logica l studies in the field are in va luab le. In order to be a useful tool in the developing world severa l de ign challenge need to be overcome; the reagents and the chip itself need to be stable at a wi de va riety of temperatures since refrigerati on of the component may not a lways be feasible in the de elop ing wo rld , th e cost of the chips needs to be low and the chips need to have a small power ou rce for operat io n ince re liable electri ca l infrastru cture is not found in a ll parts of the world. '路3 Re earch and deve lopment work is being undertake n to adapt lab-ona-ch ip technology for th e detection of many microorganisms from biological amples including; HJV (reviewed in (8)), ma laria (rev iewed in (9-1 0)), tubercu lo i 11 路 11 , di arrheal di seases 6 , pertussis 13 , and dengue fever. 14 One exciting lab-on-a-chip application for the detection of enteric infection i the Di sposa ble E nterics Card (DEC) which i able to detect the presence of Campylobacter jejuni, Escherichia coli 0 157: H7, Shigella dy enferiae, Shiga Toxinprodu cing Escherichia coli ( TEC) and Salmonella from a amp le of feces a ll on one microchip.6 The D EC lab-on-a-c hip techno logy combines evera l laboratory assays to detect th e bacte ri a (see Figure I and Figure 2 for a chematic of the chip). Bri e fl y, a ampl e of feces i appli ed to th e chip an d bacteria from th e sa mp le are captured on the chip by using pecific antibodie to each bacteria of interest.

The e antibodie are located in severa l different areas of th e chip.

Th e bacteria are ubseq uentl y ly ed u ing buffer and the bacterial DNA i captured on a silica resin co nta ined within the chip. The purifi ed bacteria l ON is ubsequently amplifi ed u ing a tandard mo lecu lar biology technique ca ll ed the po lymera e chain reaction ( PC R) w ith ON primers spec ifi c for a gene in each bacteria l pec ies of mterest. The end of each primer ha been de igned to contain a flu ore cent mo lec ul e. Afte r th e amplificati o n of the bacterial 0 A using P R, flu ore cent mo lecule are now found at th e ends of each

Figu re I. A Schemati c Di ag ram of th e Di sposa b le Enteric (DEC) lab-on-a-c hip Techno logy.

UWOMJ I 80 :1 I Spring 2011

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amplified mol ecul e of bacteri a l DNA . The next step in the process is to detect the amplified bacterial DNA . To do thi , a laser li ght is The fluorophore em its flu orescent li ght directed at the ample. which can be detected if the sample is positive for the bacteria .

Unfortunate ly, the DEC testing till require the use of a sma ll machine for the PC R reacti on and PC R product detecti on whi ch limits its abi lity to adapt to fi e ld conditi ons. Thi s techno logy wo uld be useful in a sma ll ana lytica l laboratory or c linic but it u efu lne would be limited under fi e ld conditi on .

A second appli cation of techno logy to lab-on-a-c hip capabi li ty is the detection of ana lytes uch as e lectro lytes fro m a sma ll sa mple of blood. The iSTAT, a device manufactured by Abbott Di agnostics, has the capab ili ty of rapidly ana lyzing ana lytes in a few drops of blood.7 The developers of the iSTAT have mini aturi zed e lectrodes by depo iting electrode arrays onto sili con cartridges to create a bi osensor. A few drops of bl ood depos ited into a sample chamber are able to enter the caitri dge by capi llary action. Once the sample is in the cartridge it can be treated w ith chemi ca l reagent prior to ana lysis. At the ana lytica l stage the cartridge is inserted into a handhe ld e lectromechanica l read-o ut device that prov ide a power source and controls the temperature of the chip. The electrode arrays depos ited on the s ilicon membrane can then be used to measure the concentration of va rio us blood e lectro lytes, gases, and other ana lytes using potentio metry (measuring the e lectri c potential),

Feces Sample applied to sample chamber

I':\

Antibody Capture \,:;) of Bacteria

~

Box 1: Advantages oflab-on-a-chip technology • • • • • • • • • • • •

Small size (credit card or smaller), portability s mall sample volumes, less invasive rapid analysis, short processing times low cost no need for highly trained laboratory technicians to perform the test may run using a battery for power (no need for electrica l infrastructure) reduced reagent consumption due to small volumes high reproducibility reduced exposure to hazardous materials or infectious agents due to small volumes minimal risk of sam ple contamination convenient disposal elimination of human error (you add the sample to the chip and the chip takes care of the rest)

Adapted from references (1-3} .

@ ooift;eo;o

Bacterial Cell Lysis and DNA Purification

~

DNA is Eluted from Resin and enters PCR Amplification Chamber

>-

I':\

A Bacterial Gene is Ampl ified by PCR using \,:;,) Primers Linkedto a Fluorescent Molecule

0

~ Amplified Fluorescent Bacterial DNA

•

•

I'::\

,, ,,,,.

Laser Used to Detect \::;) Amplified DNA

-/,

Figure 2. Biochemi cal steps of the anal ysis in the chip. (A) Feces sample is appli ed to the chip and enters the sampl e well. Various types of bacteria in the sample are represented by different ova ls. Different surface prote in s on each type of bacteria are denoted by rectang les and tri ang les. (B) Antibodies speci fie to surface prote ins o n the bacteria of inte rest capture the bacteri a in the chip. Thi s exampl e shows bl ack coloured bacteria captured in the upper chamber a nd grey coloured bacte ria in the lower chamber. Bacteria whose surface prote ins are not bound by the antibodies are washed away. (C) Captured bacteri al ce ll s are lysed in bu ffe r and bacterial DNA is purified on sili ca resin . (D) Purified bacteria l DNA is e luted from the res in and enter the PC R amplifi cati on chamber. (E) A bacteria l gene of interest is amp lifi ed using a standard mol ecul ar biology technique ca lled PCR. Sma ll DNA mo lecules (primers) specifi c for the gene of interest are found in thi s chamber. Primers are denoted as arrows in the di agram and are linked to a fluoroph ore (a flu o rescent mo lecule) denoted by a star. (F) The ge ne of interest is amp li fi ed exponentia ll y (there are many copies) and now conta ins flu orophores on each end. (G) Amp li tied bacterial DNA fluoresces when laser li ght is shone on the sampl e giving a readout, thus, leading to the di agnosis of the infecti o n.

UWOMJ I 80 :1 I Spring 2011

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amperometry (measuring the fl ow of an electri ca l current) or conductimetry (mea uring the conductance) of the sample. 7 These values are then di spl ayed on a screen. Different chips are u ed for different analyti ca l application and each chip is dispo ed of after one use. All the chips use the sa me handheld electromechanical read-out device.

We have only focused on two application of lab-on-a-chip technology; however, there are numerous u e for this technology and many approaches to the miniaturi zation of biochemi ca l, molecular biology and chemical a ays for u e on microchip . The miniaturization of medical technologie may very well revolutionize the deli very of medical care in the near future. I your pocket ready for the lab-on-a-chip?

REFE RENCES I. Chin CD, Linder V, ia SK. Lab-on-a-chip devices for globa l hea lth : past tudie and future opportun ities. Lab hip2007 Jan;7( I ):41-57 .

2. Ziober BL, Mauk MG, Falls EM, hen Z, Ziobe r AF, Bau HH . Lab-on-achip for oral cancer creening and diagnosi . Head Neck200 Jan ;30( I) : 111-21.

3. Yager P, Edwards T, Fu , Helton K, Ne lson K, Tarn MR, Weigl BH .

MicroOuidic diagno tic technologies for global public health. ature2006 Jul27 ;442(7101):412-8 .

4. Hou , Herr AE. Clinically relevant advance in on-chip affinity-ba ed electrophoresi and electrochrornato-graphy. Electrophore i 200 Aug;29 ( 16):3306-19.

5. chul ze H, Giraud G, Crain J, Bachmann TT. Multiplexed optical pathogen detection with lab-on-a-chip de ices. J Biophotoni cs2009 Apr;2 (4):199-21 1.

6. Weigl BH, Gerdes, J., Tarr, P., Yager, P., Dillman, L. , Peck, R., Ramachandran, ., Lernba, M., Kokori , M., Nabavi, M., Banrell, F.,

Hoekstra, D., Klein, E.J ., Denno, D.M. Fully integrated multiplexed labon-a-card a ay for en teri c pathogens. Proceedings of the SP!E-The International Society for opti cal Engineering 2006;6112:611202611-11 .

7. Lauks IR. Microfabricated Biosensors and Microanalytical Systems for Blood Analy i . Ace hem Res 1998;31: 317-24.

8. Wang S, Xu F, Demirci U. Advances in deve loping HIV-1 viral load assays for re ource-limited ettings. Biotechnol Adv20 I 0 Nov-Dec;28(6): 770-8 1.

9. Antia M, Herrick T, Rathod PK. MicroOuidic approaches to malaria pathogenesis. Cell Microbiol2008 Oct; I 0( I 0) : 1968-74.

10. Gascoyne P, atayavivad J, Ruchirawat M. Microfluidic approaches to malaria detecti on. Ac ta Trop2004 Feb;89(3):357-69.

II. Cooksey R , Limor J, Morlock GP, rawford JT. Identifyi ng Mycobacterium pecie and train typing using a microfluidic labchip instrument. Biotechnique 2003 Oct;35(4):7 6-94.

12. orstjen PL, Chen Z, Zuiden ijk M, Bau HH , Abram WR, Malamud D, Sam iedbala R, Tanke HJ . Rapid assay format for multiplex detection of hum oral immune re ponse to infectious di ease pathogen (HIV, HCV, and TB). Ann Y Acad ci2007 Mar; I 098:437-45.

13.de Ia Rosa , Tilley PA , Fox JD, Kaler KY. Microfluidic device for dielectrophoresi manipulation and e lect ro-disru ption of respiratory pathogen Bordetella perru i . IEEE Tran Biomed Eng2008 Oct;55( I0) : 2426-32 .

14.Zaytseva V, Montagna RA , Baeurnner AJ . Microfluidic bio en or for the serotype- pecific detection of dengue virus A. nal hem2005 Dec I ;77(23 ):7520-7.

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UWOMJ I 80 :1 I Spring 2011

1.866.362 .3331

An Interview with Dr. Ting-Yim Lee, PhD Lauren Sham (Meds 2014), Abdul Naeem (Meds 2014), Joyce TW Cheung (Meds 2013}

hysicians are often limited by techno logy in the ir pursuit of patient we llbe ing. Take fo r exampl e a pati ent sufferin g from stroke among a myri ad of other d iseases. Having the capac ity to measure blood flow to va rio us organs and to specifi c regions within those organs - vita l for proper bodi ly fun ctions - can have prodigious impli cations o n dec iding w hich treatment pl an to fo llow.

Fortunately, measuring fun cti ona l bodi ly processes with respect to hemodynami cs has been a specia lty of Dr. Ting-Yim Lee. Dr. Lee 's research on blood fl ow has contributed substantiall y in allowing physicians to apprec iate a more comprehensive picture of some of the most severe di seases. But the journey there has not been easy.

P

Winston Churchill once sa id, "Continuous effort is the key to unlocking our potenti a l. " Thi quotati on best exemplifi es the dri ving fo rce behind Dr. Ting-Yim Lee's research endeavours.

Having grow n up in Hong Kong, Dr. Lee travell ed to Lo nd o n U ni ve r s i ty in England to pursue graduate degrees in Radiati on Physics i n th e D e p a rtm e n t of N u c lea r M e di c in e . To furth er hi s research interests, he immigrated to Canada in 1983 . Dr. Lee exemplifi es the qualiti es of a committed, ambiti ous scientist who manages to go above and beyond the typ ica l protoco l. He is hard wo rkin g, humbl e and extreme ly kn ow ledgea bl e in hi s research deri ving fun ctional and physio logical info rmati on from contrast CT images. The Uni versity of Western O nta ri o has been fo rtunate enough to have him fo r well over two decades now. Whil e at Western, Dr. Lee quickl y emerged as a leader by deve loping a renowned fun ctional CT Imaging program. Hi s as pirati o ns are to study fun cti ona l processes in the human body us ing CT imaging, spec ifi cally those w ith respect to hemodynami cs. Hi s hallmark is in pi oneerin g a method of using x- ray dye and CT scanning to measure bl ood fl ow. Thi s intri cate research is making substantial contributi ons to severa l di seases including stroke, cancer and ca rdiac di sease.

In stroke, clots or injury to bl ood vesse ls can prevent proper delivery of oxygen and substrates (ma inl y g lucose) to the brain. The standard treatment is thrombo lysis. However, thi s must be done in a narrow time frame to meet current treatment criteri a. Dr. Lee is develo ping too ls to improve the time li mitation cri teria fo r treatment . He has developed

so ftw are, whi ch can measure fu nctional as pects of bl ood fl ow to the bra in (see Fi g ures I ,2) , in c ludin g ri s k fo r he m o rrh ag ic tran sfo rmati on. Takin g into acco unt ischemi c brain changes after a stroke can lead to more inclusive treatment criteria for thrombo lysis.

As such, thi s could lead to reduced di sabili ty fo ll owing stroke, therefore poss ibl y miti gating other severe treatment co mpli catio ns.

Fig ure I - Patient # I (A) admi ss ion non-contrast CT image, ( B) cerebral bl ood fl ow map (sca le 0- 150 m l/mi n/ 1OOg), (C) cerebra l blood vo lume map (sca le 0-8 ml/ 1OOg) obta ined 7 hours after stroke onset. initia l CT hypode nsity corres ponds to area of reduced C BF and CBV (solid arrow) whil e the dashed area shows an area of decreased CBF w ith normal/e levated C BV. Without recana lizati on, entire ischemi c area at admi ss ion (CBF = 16.48, CBV = 1. 8 1) progressed to infa rcti on on the day 5 non-contrast CT (D). Subtle stripes of isodensity surro unded by the low density of in fa rcti o n are typi cal fo r petechiae in cortex. Patient #2 (E) Admi ss ion non-contrast CT image, (F) cerebra l blood fl ow map (sca le 0-1 50 ml/mi n/ 1OOg), (G) cerebra l blood vo lume map (sca le 0-8 m l/ 1OOg) obtained 157 minutes after stroke onset. Large ischemi c area on th e admi ssion C BF (das hed arrows) w ith an area of severe ly reduced C BV in the deep grey matter (so lid arrow).

Spontaneous recana lizatio n occurred pri or to the 24 hour fo llow-up CTA. (H) 5-day NCCT co nfinns infarct in the deep grey matter (matched decrease in CBF and CBV at admi ss ion) w ith progression of some surrounding ti ssue to in fa rcti on. A large porti on of the mi smatch area at admi ss ion (decreased CBF, nonna l/e levated CBV) recovered and did not show in fa rctio n on the 5day no n-contra t CT. lsodense region central w ithin the low density infa rcti on is typical for a hemorrhagic region.

UWOMJ I 80 :1 I Spring 2011

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to 7000 copies are curre ntly in use, ~ ot onl y in orth ~merica: but 路 As ia , Europe and Australi a. He also has mternat10nal aI o m 路 f coll aborations as a resul t of hi ex perti se i_n CT perfuston . 0 ne o these is with the Ameri ca n Co ll ege of RadiOlogy lmagmg Network (AC RIN), an organizati on funded by the National Ca n~er Institute (US). One of hi main research commitments was pushmg through an appli cation of imaging biomarkers m cancer m a n ageme~t, lookm_g at treatment efficacy, treatment response, and earl y detectiOn . H~ ts now in vo lved with a trial u ing CT perfusion to look ~t ovana_n cancer, which will hopefully be approved as the_ first maJor multicentre tri al of its kind with over 20 ites in the Umted States. Dr. Lee al 0 con tantly ha in fo rrnal co ll aborations ?ccurring, fr~m working with Ita lian re earchers on analysi of thetr stroke pattent data to getti ng hi oftware into hospi tals in China, tho u~h he co ~ fesse ,~hat that i go ing slowly. " Havi ng the right contacts ts very dtfficult, he admits. " It seems a though it's till not onl y what you know, but al so whom you know."

Figure 2. Pati ent #3. (A) Cerebral blood fl ow (C BF ) map hows evere decrea e in bl ood fl ow in left MCA territory. (B) Cerebral blood vo lume (C BV) map hows similar severe decrease in bl ood vo lume a blood fl ow in the same left MCA territory. The concurrent decrea e in CBF and CBV sugge t that the tissue in the left MCA territory was already infracted with di rupted blood-brain barrier (BBB ) as shown by the increase in BBB pern1eability in (C). This pati ent went on to develop hemorrhage in the left MCA territory as hown by the ' light haze' in the region in the non-contrast CT scan (D) acquired 5 day later In many type of cancer, hypoxic tumours are resi tant to treatment. Furthermore, they may undergo genetic alterati on re ulting in increa ed res istance to treatm ent, rapid proliferati on and advancement to metastasis. Dr. Lee' resea rch undertaking i to des ign a new methodology of imaging tumour hypox ia using P T/ CT cans as an alternative to bi op y or urgery. If successfull y validated, Dr. Lee's resea rch ca n Iran late to ph ysicians specifi ca ll y targeting hypox ic area witll higher do e of radi ation and/o r u ing drugs to enhance the effect of radi ati on in order to achi eve a cure.

Si milarl y, T can of hypox ic tumour can help ph y ician monitor effecti veness of treatment. Also, hypox ic imaging of tumours can be used to defin e selecti on criteria for pati ents that may benefit from genetic therapy.

Whil e Dr. Lee deli ver superi or results at the laboratory leve l, he does admit to facing chall enges in translating research from the bench to th e pati ent bedside. There i always the confli ct between what is best for research and what is practi cal in a clini ca l environment. A good exa mpl e is how to use CT scanners in the hospital optimall y for resea rch. He has to des ign imaging protoco ls that will acquire the necessary data but more importantly are acceptabl e to pati ents and does not slow dow n the workflow of a bu y T scanner. After all , T scanners are the workhor es of modern imaging department ; the demand for their use is far greater than the time ava il abl e.

Fi nally and particul arl y, the golden questi on: h o:V . does he manage to do it all? Dr. Lee didn 't try to sugar coat tt: tt ts always very tressfu l, and everyone who wants to do well in hi s or her profes ion \ ill have this kind of tress. In the past, ht s strategy wa to th ink: "If onl y I could get through thi one cri i , I will be happy."

Unfortu nately, he woul d have one crisis after another, and thi s became a prob lem. Recently he ha come to the rea lization that " Happiness i a journey, not a destination." Thi s statement, which he now ha taped to the wa ll in fro nt of hi s de k, wa a wakeup ca ll for him . He reali zed that he could not constantl y li ve fro m one crisis moment to the next. "You can' t rea lly do thi s for long without burning out. You have to enj oy each step of the journey whil e you ' re trying to get to your de tination. Fortunately, being a scienti st or a clinician, you can have thi luxury." He now approache each day not onl y a a new probl em, but a new learning experience, never hav ing to repeat what he had to do before. He reli hes hi s "Aha!" moments tho e that he can refl ect on to remind him ofl earning omething new.

Havi ng th i mind et allow him to enjoy hi s journey every tep of the way, not j ust at the end . ltimately, what doe he want in the end? " I just want to tran late what i goi ng on with my pencil and paper and animal re earch. It ' nice if ometh ing comes out of all the pipe dreams you have, ifyour methodol gy i adopted the world o er. If you can ee that the impact of \ hat you' re doing means omething in a clinical en e." Dr. Lee chuck led a he bared that ometime he find s he' not even acknO\ !edged in paper when hi s softwa re i being used. " But I can't complai n becau e the product ha been commercialized and th i j u t mean peop le are u ing it. When what you ha e toiled fo r bea r fruit, if it is a tuall y helping patient , it make it ea ier to enjoy the journey." Dr. Lee al o has the quotation "Genius i onl y [a great capaci ty fo r] great patience" by Georges-Loui Leclere Buffon di pl ayed on hi de k. He ex plained that he was "a pl odder, a late deve loper." ccording to him , he wa never someone who wa a tar upon graduating from hi PhD program. Jokin gly, he uggests that thi BurTon quotati on is something to remember in keeping yourse lf out f depre ion. But it i al o important to keep in mind: per everance rea ll y matters. That is something to keep in mind a we stri ve to achieve happines during our own journeys.

There is no doubt that the fun cti onal CT imaging software has had an internati onal impact. Since GE Hea lth ca re has li censed it, it has been di tributed all over th e world . At Dr. Lee's last count, clo e

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UWOMJ I 80 :1 I Spring 2011

Molecular genetics in clinical practice for the rapid identification of pathogenic organisms Rom an Sh apiro (M eds 20 14) Facu lty Reviewe r: Dr. Carol in e Hamm (Depart m ent of On cology, Divisi on of M edi cal Oncol ogy)

A

50 yea r o ld ma le pre ents to the c linic w ith a hi story o f feve r

and cough lasting a wee k. He has recentl y immi grated to Canada, and ca nnot co mmuni cate we ll . Upon exa minati on, he is found to be hypotens ive w ith an e levated heart rate. A chest xray is ordered, and it indi cates pu lmonary infiltrates. Thi s findin g, along with the clin ical presentati on, suggests that the pati ent has communi ty-acquired pneumonia. He needs treatment, but w hat is the infection that brought about thi s epi sode? What sho uld the clini cian do when there is a limited amount of time to find the pathogen?

It is establi shed that timely admini strati on of antimi crobi a l therapy i criti ca l for good pati ent outcome.l.2· 3 Unl ess the c lini ca l features and hi story are very suggesti ve o f a particul ar causati ve agent, the therapy must be empiric. The recommendations in thi s case are to begin with broad-spectmm antibioti c therapy, and to adjust the treatment regimen o nce laboratory cultures identify the best antibiotics to use .2 Thi s approach, a lthough logical g ive n the current potential of identi fy ing the causati ve age nt, is fraught wi th problems. For one, inappropri ate initi a l empi ric therapy is an independent ri sk factor for increased patient morta li ty and durati on of hospitalization.4 Furtherm ore, the use o f a vari ety of antibioti cs may promote the deve lopment of antibi oti c resistance amo ng pathogenic orga ni sms. Idea ll y, once the c lini ca l picture is suggesti ve of an infectious cri sis, rapid identificati on o f the causati ve agent would a llow fo r targeted therapy that optimizes outcome w hile minimizing the ri sk fo r the deve lopment of antibi oti c resistance.2 While current medi ca l techno logy does not have th e rapid identification capacity in a ll cases of infecti o ns, it is progress ing steadil y towards thi s goa l with the applicati o n o f mo lecular geneti cs in the clinica l environment.

GENOTYP l NG The di stinguishing characteri sti c of every organ ism must li e in its genes. Two pathogenic bacteri al o rga ni sms may appea r a like in presenting clinica l symptoms, on gram sta in , and in the ir growth characteri stics, yet be di stinctl y di ffe rent and require di ffe rent treatment. The differences betwee n these organi sms that cannot be seen based on culturing and stai ning a lo ne w ill be re fl ected in the ir geneti c make-up . Gene sequenc ing, there fore, is an excell ent approach for the identifi cati on of a parti cular infectio us orga ni sm from a slew of poss ibi liti es .5 As sequenc ing techno logy becomes more e ffi cient, the approach will not onl y be hi ghl y sensiti ve and specifi c, it w ill be rapid and inexpensive. Befo re thi s can happen, however, hurdles must be overcome. One i specific ity - there must be an identi fy ing geneti c seque nce for every path ogenic o rga ni sm.

Thi s is no easy task g ive n the large va ri ety of known pathogeni c species as we ll as newly evo lving o nes . But the a uto matio n of ge ne sequencing coupled with co mputer process ing power a llows for the a lignment of who le genomes fro m di ffe rent pathogeni c spec ies in order to identi fy key differences that can be u ed to di sting ui h one

in fection from another. 6 As these geneti c d iffe rences are ide nti fied, it rema in s for highl y sensiti ve tools to be developed that ca n assay fo r the di ffe rences in clini ca l specimens.

Let us return to the pati ent w ith pneumonia symptoms. He i recentl y immi grated, meaning the infec ti on could have been picked up at hi s pl ace of ori g in . One of the most common g loba l human in fec ti ons is w ith members of the fa mily Mycobacteriaceae.7•8 They ca n be mi ssed as causes o f communi ty-acquired pneumoni a because o f the absence o f readi ly ava ilabl e rapid di agnosti c tests.9 Recent techno logica l adva nces have made progress in recti fy ing thi s probl em. In identi fy ing a myco bacteri a l causati ve age nt, it would be important to di stin g ui sh tubercul ous mycobacteri a from no ntu berculous myco bacteri a (NTM ) 8 · 1 Furthermore, it wo uld be impo rtant to determine the parti cular subspec ies as this can be critical in identi fy ing the source of the infecti on 8 Takin g adva ntage of kn ow n genomic data for the myco bacteri al orga ni sms, multipl ex PC R is one assay that can be used.

°

MULTI PLEX PC R The princ iple o f the po lymerase chain reactio n (PC R) is to specifica ll y amp li fy a target DNA sequence using thennostab le enzymes such as Taq po lymerase or Pfu . 11 The sequence to be amplifi ed is loca lized between two DNA primers that hybridi ze to the target DNA. The maj or adva ntage of thi s technique in clinical di agnosi is that it requires very littl e startin g mate ri a l for amplifi cati on. 12 For in fec tions w ith mycobacteri a, thi s could allow for identifi cati on without the culturing step that i so timeconsuming.13 Unlike traditi onal PC R techniques whereby a sing le target sequence is amplifi ed, mu ltiplex PC R is able to specifica ll y a mpli fy severa l target sequences in o ne reacti on.8· 14 Thi s poses severa l technica l cha llenges because every sequence in the reactio n requires an optima l temperature and buffer for amplification i 4 Furthermore, once the reaction conditi ons are optimized it is necessa ry to di sting ui sh one amplified sequence from another. Whe n these cha llenges are overcome, it is possibl e to ampli fy severa l species-specific ge neti c sequences, including testing fo r the presence of a ntibi oti c-res i tance genes. 15.16,17 In the case o f mycobacteria l infectio ns, mul tipl ex PC R can di tingui sh between M tuberculosis complex (MTC) and NTM based on kn own ge netic differences. 1 ·19 These have been tested on clini cal spec imens, yie lding hi gh sensiti vity and specifi c ity.B. I9.l0,21 Other multiplex PC R assays ex ist that can di stingui sh between the TM ub pec ie , in partic ul ar those of the Mycobacterium avium compl ex .

8 The maj or adva ntage of a ll of these assays is the sensiti vity and rapidity of PC R, a ll ow ing for very sma ll amounts of DNA sequences to be detected w ithin severa l ho urs. 12 However, res ults must be interpreted w ith caution, as the poss ibility of fa lse negati ves is con ide rabl e w hen runn ing severa l PC R amplifi cati on reactions at

UWOMJ I 80 :1 I Spri ng 2011

29

once 14 In additi on PCR may be prone to fa lse positi ve results since very .minute amou~ts of DNA may be amplified considerabl y. 12· 14 •21 SPOLIGOTYPI NG

Whereas multiplex PCR has found a use in di stinguishing. MTC from NTM and identifying subspecies of the NTM group, spoli gotypmg IS a method that has been deve loped and used to identi fy and genotype strains of bacteri a in the MTC group 22 •23 The method is ba ed on the presence of conserved direct repeat (DR) sequences separated by non-repeating spacer regions in the genomes of these bactena.

Di ffe rent strain vary in the number of such DRs as well as the length and sequence of the space r regions 22 By des igning oligonucleotide primers that hybridi ze to conserved regions within the DRs, it is poss ibl e to run a PCR reacti on that yield a large variety of amplified D A sequence of different sizes (Figure IA) .

The pattern of the e amplified D sequences is characteristi c of a strain of MTC bacterium (Figure I B)22

restnct 1on fragment length pol ymorphi sm (RFLP) a?alysis. 26 The latter method is based on the digestion of mycobatenal DNA With endonucleases, and the reso luti on of species-spec ific fragments by compari on of their migrati on patterns on a geJ.2 8 rtPCR is a technique that allows for the rapid, quantitative amplifi cati on of DNA using PCR. As the P.CR reaction is run, the PCR product generated during each cycle IS bound by a dye that flu oresces at a particular wave length when ~ound to double-stranded DNA. The resulting flu orescence is quantified dunng each cycle, yielding a rea l-time DNA amplifi cati on. curve . 12 The amplification product is then subjecte? to HRM analys is, whereby a .known am ~~ ~! of D A i melted by ra1 mg the temperature m fi xed mcreme~ts . · Since the melting temperature (Tm) of double-stranded D A IS very ensiti ve to equence 29, a ignifi cant difference in Tm may be ob erved between Beiji ng and non-Beijing trains of Mycobacterium by virtue of a ingle P. rt PCR wi th HRM analy i wa appl ied to clinical specimens and B

A

...

..

Figure 1. The bas ic principles invo lved in spoli gotyping. A Two juxtaposed blue rectangle indi cate a conserved direct repeat (DR) in the genome of a parti cul ar strain of Mycobacterium tuberculosis compl ex . Onl y a ubset of DRs are shown fo r clarity, whereas there would be many more in the actual organi m. PCR primers are des igned to hybridize at particular locations within the DR a shown by the arrows. An arrow pointing to the ri ght i a forward primer, whil e one pointing to the left i a rever e primer. The primers may hybridi ze at any of the DRs, and the resulting pos ibl e PCR products are indicated. The red square indicates a specifi c equence in the fir t pacer region, whil e the yellow rectangle indi cate a pecifi c equence in the econd space r region.

B The PCR products fro m A are hybridized to an array containing immobili zed oli gonucleotides whose sequences COITespond to a spacer region. Examples of thi arc demon trated with the red square and yellow rectangle from A, whereby the equence in each of the co loured rectangle is recogni zed by a spe ific oligonucleotide probe on the array. Hybridizati on between a PCR product and the array is ind icated by a bl ack circle on the spoli gotype. Each row on the array corre pond to hybridizati on signals from a single train . poli gotyping has been appli ed to clini ca l spec imens23 •24 It is a rapid a ay becau e it relie on PCR, and studies have shown that it is sensiti ve and speci fi c to MTC infections. 22 ·23 It has the additi onal advantage of bei ng abl e to di tingui h train s of M. bovis fro m those of M. tuberculosis, a di ffi cult task with traditi onal techniques 22 Much of the u e of poligotyping has in vo lved contact tracing in instances of u pected MTC infecti ons so a to limit the spread of infec ti on.22 •25 Fu rth er studi es are und ergo in g to definiti ve ly determine its use in clini ca l di agnos is and genotyping of MTC infecti ons.

REAL-TIME PCR (rtPCR) WITH MELTING ANALYS I S (HRM)

HI GH-RESOLUTION

A spoligotype performed on clini ca l isolates from the pneumoni a pati ent revea led a pallern co nsistent with a hi ghly virul ent spec ies of Mycobacterium belonging to the Beijing lineage. 26 Thi s lineage is known to be hi ghl y tran mi ss ibl e and often drug-res i tant, requiring spec ifi c treatment reg imens that differ from other mycobacteri al infecti ons 27 For th e purpo es of rapidl y confinning an infecti on with thi s pathogen, one a say that can be used is rtPCR with HRM analysis. Thi assay reli es on the presence of a single-nucleotide polymorphi m ( NP) corresponding pec ifi ca ll y to the Beijin g lineage that was identi li ed u ing methods such as spoli gotyping and

30

re ulted in nearl y 100°o ensiti vity and spec ificity as long a there was a uffi cient load of bacterial orga ni sm in the sputum .2 6 It ha the additi onal ad antage of being very rapid and relati ve ly inex pensive to perform .29 When clin ica l iso lates from the patient with pneumoni a ymptoms were subjected to the a ay, the pre ence of the Beijing lineage of M. tuberculosi was confirmed.

CONCLU ION

The assays menti oned here in the context of a poss ible infecti on with a member o f th e famil y Mycobacteriaceae are intended to demon trate the utility of the gene sequence in rapid clinical di agno i . Improvements in the effi ciency of gene sequencing a well as bioinformatics analys i are generating a large amount of data rega rding pecifi e geneti c target for each pathogenic organi sm that could be as ayed by techn iques based on PCR. Some of these technique , including multip lex PCR, spoligotyping, and rtPC R with H RM demonstrate that assays can be des igned and implemented in a clini ca l setting to identi fy parti cular infectious organi sms. A the e as ays become less ex pensive and standard in all microbiological laboratori e , their rapidity will all ow for the u e of appropriate targeted therapy in order to optimize patient health whi le minimizing the nsk of th e development o f antibi otic res i tance.

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2. Tenover, F.C. 201 0. Potential impact of rapid di agnosti c te t on improving antimicrobial use. Annal of th e New York Academy of Sciences. 12 13 : 70-80.

3. Kollef, M.H. 2008. Broad-spectrum anti-mi crobials and th e treatment of seri ous bacterial in fec ti ons: getting it ri ght up front. Clinical Infecti ous Disea e . 47: S3 - 13.

4. Lynch, J.P. 200 I. Hospital-acquired pneum oni a. Chest. 11 9(2) : 373S-384S 5. Myint, . 2002. Recent advances in th e rapid di agnosis of respiratory tract infecti ons. Briti sh Medi cal Bulletin . 6 1( I): 97-11 4.

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Sensiti ve, specific polymorphism di covery in bacteri a using ma sively parallel sequencing. Nature Methods. 6: 67-69.

7. Lonnroth , K. & M. Lav igri one. 2008. Global epidemi ology of tuberculosis: prospects for control. Seminars in Respiratory and Cri ti ca l Care Medi cine. 29: 48 1-9 1.

8. Shin. .J ., Lee, B.. , Koh, W.J ., Manning, E.J ., Anklam, K., Sreevat an, S., Lambrecht, R.S., & M.T. Coll ins. 20 I 0. Effi cient differentiation of Mycobacterium avium comp lex species and subspecies using a fi ve-target multiplex polymerase chain reacti on. Journ al of Clini ca l Microbiology. 48 ( II ): 4057-62.

9. Dooley, K.E., Golub, J., Goes, F.S., Merz, W.G., & T.R. Sterling. 2002.

Empiri c tr eat me nt of co mmunit y-ac quir ed pn e um o n ia w it h flu oroquin olones, and delays in th e treatm ent of tubercul osis. Clinica l Infectious Diseases. 34( 12): 1607- 12.

I 0. Ameri can Thoracic Society. " Better and Faster: Distingui shing Non-TB Pulmonary Disease from TB ." ScienceDail y 4 Apri l 2008. 3 Janu ary 20 II <http://www.sciencedail y.com /releases/2008/04/08040 I 08 1920. htm> II . Cline, J., Braman, J.C. , & H.H. Hogrefe. 1996. PC R fid eli ty of Pfu DNA pol ymerase and other th erm ostabl e DNA polymerases. Nucleic Ac ids Research. 24( 18): 3546-355 1.

12. Espy, M.J., Uhl, J.R., loan, L.M ., Buckwa lter, S. P., Jones, M.F., Vetter, E.A., Yao, J.D.C., Wengenac k, N.L., Rossenblatt, J.E., Cockerill Ill , F.R., & T. F. Smith . 2006. Real-time PCR in clinical microbiology: applicati ons fo r routine laboratory testing. Clinical Microbiology Reviews. 19( I): 165-256.

13. Shinni ck, T.M. & R.C. Good. 1995 . Diagnosti c myco bacteri ology laboratory practi ce . Clinical Infecti ous Di seases. 2 1(2): 29 1-299.

14. Edwa rds, M.C. & R.A. Gibbs. 1994. Multipl ex PCR: adva ntages, development, and applicati ons. Genome Research. 3: S65-S75.

15. Herrera- Leon, H., Molina, T., Sa iz, P., Saez-Nieto, J.A., & M.S. Jimenez.

2005. New multiplex PCR fo r rapid detection of isoniazid-resistant Mycobacterium tuberculosis clini cal i olates. Antimicrobi al Agents and Chemoth erapy. 49( 1): 144- 147.

16. Martineau, F., Picard, F.J ., Grenier, L. , Roy, P.H., Ouellette, M. , Bergeron, M.G. , & the ESPR1T Tri al. 2000. Multiplex PC R assays for detecti on of clinica ll y relevant antibiotic resistan ce genes in staph ylococci isolated from pati ents infected after ca rdi ac surgery. Journ al of Antimicrobial Chemotherapy. 46(4): 527-534.

17. Ramachandran, D., Bhanurnath i, R., & D.Y. Singh. 2007 . Multiplex PC R fo r the detecti on of antibioti c res i tance genes and th e SXT element: appl icati on in the characteri zati on of Vibri o cholera. Journal of Medi cal Microbiology. 56: 346-35 1.

18. Mokaddas, E. & S. Ahmad. 2007. Development and eva luati on of a multiplex PCR for rapid detection and di ffe rentiati on of Myco bacterium tuberculosis complex members from non-tuberculous myco bacteria .

Japanese Journal of Infec ti ous Diseases. 60: 140- 144.

19. Perez- Martin ez, 1. , Ponce-De-Leo n, A., Bobadi ll a, M., Vi ll egasSepulveda, N., Perez-Garcia, M. , Sifuentes-0 orni o, J., Go nza lez-yMerchand, J.A ., & T. Estrada-Garcia. 2008. A novel identifi cati on scheme fo r genus Myco bac te rium , M. tuberculos is compl ex , and seven mycobacteri a species of human clin ical impact. European Journal of Clinica l Microbi ology & Infecti ous Diseases. 27 : 45 1-459.

20. Ri chardson, E.T. , Samson, D., & N. Banaei. 2009. Rapid identifi cati on of Myco bacterium tuberculosis and nont uberculous myco bac teri a by mu ltiplex, real-time PCR. Journal of Clinical Microbiology. 47(5) : 1497- 1502.

2 1. Gupta, S., Bandyo padhyay, D., Paine, S.K., Gupta, S., Banerjee, S., Bhattacharya, S., Gachhu i, R., & B. Bhattac haarya . 20 I 0. Rapid Identi ficat ion of Mycobacteri um specie wi th th e aid of multipl ex polymera e chain reactio n (PCR) from clinical isolate . The Open Microbiology Journal. 4: 93-97.

22 . Kamerbeek, J., Schoul s, L. , Ko lk, A. , van Agterve ld, M., van oolingen, D., Kuijper, S., Bunschoten, A., Mo lhuizen, H., haw, R., Goyal, M., & J. va n Embden. 1997 . imu ltaneous detecti on and strain di ffe rent ia ti on of Mycobacterium tubercul osis fo r di agnosi and epidemiology. Journ al of Clin ical Mi crobiology. 35(4): 907- 14.

23. Gori , A. , Bandera, A., Marchett i, G., Degli Esposti, A., Catozzi, L. , Na rd i, G. P., Gazzola, L., Ferrari o, G., va n Embden, J.D., va n Soolingen, D. , Moroni , M. , & F. Franzetti . 2005 . Spoligo typing and Mycobacterium tuberculosis. Emerging lnfecti ou Diseases. II (8) : 1242-48.

24 . Abadi a, E., Zhang, J., dos Vultos, T. , Ritacco, V., Kremer, K., Aktas, E. , Matsum oto, T. , Refregier, G., va n Soolingen D., Gicquel, B., & C. Sola.

20 I0. Reso lving lineage ass ignation on Mycobacterium tubercul os is clinica l isolate class ified by spoligoty ping wi th a new hi gh-th roughput 3R SN Ps based method. Infecti on, Genetics, and Evoluti on: Journal of Molec ul ar Epidemi ology and Evoluti onary Geneti cs in Infecti ous Di seases. I0(7): I 066-74.

25. Song, E.J ., Jeong, H.J ., Lee, S.M., Kim, C. M., Song, E.S., Park, Y. K., Bai, G. H., Lee, E.Y., & C. L. Chang. 2007. A D A chip-based spoligotype method for the strain identificati on of Mycobacterium tubercul osis iso lates. Journ al of Mi crobi ologica l Meth ods. 68(2): 430-33.

26. Alonso, M., Nava rro, Y. , Barletta, F. , Martinez Lirola, M., Gotuzzo, E., Bouza, E., & D. Garcia de Viedma. 20 I0. A novel meth od fo r the rapid and prospecti ve identificatio n of Beijing Mycobacterium tubercul osis strains by hi gh-resolution meltin g analys is. Clin ical Microbiology and Infecti on. 17(3): 349-57.

27 . Lillebaek, T. , Andersen, A. B., Dirksen, A., Glynn, J.R., & K. Kremer.

2003 . Mycobacterium tuberculosis Beijing genotype. Emerging Infec ti ous Di eases. 9( 12): 1553 -7.

28. Das, S., Paramas iva n, C.N., Lowri e, D.B., Prabhakar, R., & P.R. Na rayanan. 1995. IS6 11 0 restri ction frag ment length polymorphism typing of clini ca l isolates of Mycobacterium tuberculosis from patients with pulmonary tubercul osis in Madras, south India. Tubercle and Lung Disease. 76(6) : 550-4.

29 . Reed, G.H., Kent, J.O., & C.T. Wittwer. 2007 . High-re oluti on D A melting analys is fo r simpl e and effi cient molec ular diagnosti cs .

Pharm acogenomics. 8(6): 597-608.

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The application of three dimensional laser surface scanning and imaging in a case of total nasal reconstruction Michal Brichacek (Meds 2013) Faculty Reviewer: Dr. Douglas C. Ross, MD MEd FRCSC (Department of Plastic Surgery)

he earli est reports of reconstru cti ve surgery are presented in an ancient Egyptian medi ca l text datin g back to 1600 B.C. th at describes the treatment of nose, ear, lip, and chin injuri es . 1 However, it was Indi an surgeons who are credited with empl oyi ng the first de finiti ve plasti c surgery techniques, w ith spec ifi c report describin g Sushruta performin g th e fir t rhinopl asty in 500 B.C .2

T

Pl asti c surgery developed at a time when th ere was a tremendous need for reconstru cti ve correcti on o f catastrophi c deformities : after World War 1_3 Never before had surgeo ns been presented w ith such extensive injuri es that required compl ex and innovati ve reconstructi ve procedure . The Greek work plastikos, meanin g to be capable of bei ng molded, wou ld become used to describe a fi eld where surgeo ns molded th o e devastated by th e injurie of wa r4 As technologica l adva nce have improved protecti ve gea r and medi cal advances have improved adva nced trauma care, th e proportion of soldi ers dy ing in combat a a result of thei r injuri es has markedl y decreased . Soldiers are currentl y survi ving injuries th at wo uld have kill ed them in any prev ious conflict, but as a res ult th ey are survi ving with mass ive facia l and crani a l injuri es th at require compl ex reconstru cti on.

PATIENT PRESENTATION

flap would still be intact, whi ch means th ere was a significant chance of it fai ling and becoming necroti c.

Despite th ese risk , the patient fe lt very strong ly opposed to a nasa l prosthesis and exp resses hi desire for surg ica l reconstruction .

Bei ng awa re of the igni ficant ri k of com plicati ons and the need for multiple stage , th e patient elected to proceed with urg ica l reconstruction.

TECHNOLOCICALPLA

The no e is a complex three-dimen ional obj ect that must be in harm ony wi th the rema inder of the face . The cha ll enge with thi s case was to create a new nose from nothin g. In extensive facial soft tissue injures th e surgeo n can use the remnants of th e nose as a guide in ord er to create a new nose. In thi s case, even th e cartil age, which serves as a framewo rk fo r the no e and co uld act a a guide, was absent.

It was deci ded that technology could he lp with thi problem by providing th e s urgeo n with two types of guides to a id him in the reconstru cti on: a two-d imen iona l template showing the complex area of kin that must be taken a a fl ap from the forehead, and a three-dimensional plastic mo ld bowing the fin a l shape that th e surgeo n should tri ve to achi eve during the creati o n o f the ubsurface framework of th e nose.

M.F. is a 2 1-yea r- old African American wa r veteran who sustained signifi cant facia l and body trauma in Iraq. He was in vo lved in a situation where a ve hi cle ex ploded and he ultimate ly rece ived multipl e oft ti sue injuries and facia l fractures . This resulted in amputati on of hi s left arm and left him with an ex treme ly fl attened nose. He presented to John s Hopkins Ho pita! seek ing nasal reconstru ction.

Nasa l reco ns tru cti o n wo uld have to be perform ed through a midline forehead flap, where a large fl ap o f skin is taken from th e middl e of th e forehead, rotated, and fold ed dow n to create a new nose.5 Due to th e lack of underl y ing ca rtilage to prov ide support for th e nose, rib ca rtil age wo uld have to be harvested and a nasa l subsurface wo uld have to be recreated. Additiona ll y, a radi al forearm free ti ss ue transfer would need to be perform ed to provide a vasc ulari zed interna l skin lining for the di sta l half of th e nose.

However, the patient was informed th at he was not a good candidate for thi s procedure du e to the need for multip le stages and hi s elevated ri sk for failure . Due to hi s signifi ca nt fac ial oft ti ss ue injuri es, it is unlikely th at th e bl ood suppl y to thi s

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I C

Figure I. Three-dimen sional laser scannin g is used to create a di g ital model of th e pati ent's face in the orig ina l conditi o n.

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The Art as App li e d to M edicin e di vision at Johns Hopkins bega n by taking a plaster mo ld of th e ex istin g condition of the patient' face. U ing thi s and photographs prov ided by the patient 's fa mily, a wax model wa created of the patient ' nose be fore hi s injury. This wax mode l wa th en ca t in pi a ter and sent to Direct Dimen ions Inc. (Owings Mill s, Maryland) for surface scannin g and digital manipu lation of the re ulting 3-dimensiona l mode l.

The mold is scanned usi ng a laser urface scanner (Perceptron Laser Scanning Sy tems, P lymouth, Michigan) that creates a three-dimen sional point c loud of data that i converted into a resulting three-dimen ional computer model usin g Poly Works oftware (lnovmetric Software Inc, Quebec City, Quebec, anada). In the same manner, th e patient ' injured face was th en Ia er smface canned and created into a three-dimens iona l computer model (Figure 1).

DI SC lJ SS I0 N

Figure 2. A th ree-di mensio na l tra nslucent plastic mode l served as a guide for the nasa l tructure du rin g the procedure, while the two-dimensional shaped served as a gu ide fo r harvesting of the fl ap fro m the fo rehead.

The three-dimensiona l mode l of the pre-mj ury nose wa then superimpo ed into the proper pos itio n o n the patient 's inj ured face, show in g a three- dim e ns io na l re nditi o n of w ha t th e id ea l reconstruction would achi eve. F rom thi s combined mode l engineers were able to determine the dimensions of a three-dimensiona l mode l molded in clear plastic to be used as a surg ica l guide, a nd usi ng complex mathematica l si mulatio ns engi neers were abl e to unro ll the complex shape of the three-d imensiona l pre- inj ury nose onto a fla t two-dimensional surface. (Figure 2) Th is served as a guide to the surgeon du ring the procedure for both the shape and size of the fl ap of tissue to be harvested from the forehead.

Ultimately, the patient req uired six separate procedu res to complete hi s reconstruction. Hi s recovery was complicated by an MRSA infec tion as well as a sma ll degree of d ista l fl ap necrosis.

Fortunately, total fl ap necrosis did not occur and the rema inder of the flap was salvaged. The patient was extreme ly pleased w ith the result and was extremely satisfied that he was abl e to have both the fo m1 and func tion of hi s nose restored (F igure 3).

More recent ly, the implementation of threedimensional object canning and vi sualization ha been applied in the medical field to provide great benefit to both surgeons and patients a like. By app lyin g this techn o logy, a rad iation shi e ld was created to protect adjace nt tissues in the treatment of head and neck cancers.6 The creation of threedime ns iona l breast mode ls through imaging has become possib le in order to he lp guide surgica l manageme n t 7 In more of a mai nst rea m applicati on, surgeo n ca n show patients expected res ul ts after s urge ry in a dy na mi c th reed imensiona l view usi ng imaging systems such as the Canfie ld Vectra M3 (Canfie ld Scientific Inc, Fa irfie ld, ew Jer ey) or the Ax is T hree XS200 (Ax is T hree Inc, Boston , Massachusetts) .

T he patient in thi s case presented with an extreme ly cha ll eng ing defect due to a co mbinati on of signi fica nt facia l soft tissue tra uma, multi ple facia l fractures, as well as the absence any ubsurface nasa l fra mework. Ca es of total or subtota l nasa l reconstructi on are particu larl y cha llengingly as the reconstructed structure must be vasc ular in order to hea l predictably, stable in order to with stand the scar contracture and maintain symmetry, yet at the a me time be fu nctio nal enough to be acceptab le to the pati ent 's li festy le. 8

T he construction of an abstract th ree-d imensiona l obj ect such a the nose from a fl at segment of ti ss ue is extremely di ffic ult in the absence of a subsurface fra mework. By using novel techno logical inn ovations invo lving three-dimensio na l laser surface scanning and imaging, the li ke lihood of achi eving a favo rable resul t is potenti all y increased. The creati on of a custom made translucent template fo r use durin g the procedure is achieved by the combined efforts of the patient, the anaplasto logist, and the surgeo n.8 The templ ate is created such that it anti cipates the thi ckn ess of the skin that w ill be provided by the fo rehead fl ap and serves as a surgica l guide for the surgeon in the c reatio n of the subsurface framework of the nose.

T he applicati on of three-dimensional lase r surface scatming and mode ling is a powerful tool that can be utili zed in order to aid in the visua li zati on of c ha ll eng in g defect as he lp in th e surgica l reconstructi on of the e defects. A lthough still in its in fa ncy, as thi s tec hno logy evo lves and its fu ll potentia l becomes rea li zed, it w ill ure ly fi nd many more ap pl ications in medic ine and particul arl y in the fie ld of reconstructive plasti c surgery.

REFERENCES

Figure 3: The pati ent shown from a side-view preoperative ly (a) a nd postoperati vely (b).

I. Brea ted J.H. The Edw in Smith Papyrus. Chicago, Uni versity of Chicago Pre , 1930.

2. Ei senberg I. History of Medici ne: A History of Rh inopl asty. SA Medical Journal. 1982 ;62 :286-292.

3. Haube n D.J ., onneveld .J . The influence of war on the deve lopment of plastic surgery. Ann Pia 1 Surg. 1983 ; I0:65-69.

4. McCormack RM . "P lastikos"- capable of being mo lded. Pfost Reconstr Surg. 1969;44:29 1-292 .

5. Men ick FJ. Nasa l reconstructi on. P/asr Reconsrr Surg.

20 I0; 125 : 138e- 150e.

6. Zemnick C, Woodhou e SA, Gewanter RM , Raphael M, Piro JD. Rapid prototyping techn ique for creating a radiation shield. J Prosrher Dent 2007 ;97 :236-4 1.

7. Tepper OM , Sma ll K, Rudo lph L, Choi M, Karp . Virtual 3-dimensional modeling as a valuab le adju nct to ae thetic and recon tructive breast surgery. Am J Surg. 2006; 192:548-5 1.

8. Byrn e PJ, Garcia JR. Autogenous nasa l tip reconstruction of complex defects . Arch Facial Plasl Surg. 2007 ;9:358-364

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Candles to computers: the story of minimally invasive procedures Pencilla Lang (Meds 2011) Faculty Reviewer: Dr. Terry Peters, PhD (Department of Medical Imaging, Medical Biophysics, and Biomed ica l Engineering)

or many peopl e, the words "min imall y in vas ive surgery" conjure up vision of medica l ro bots, MRJ machines and nanotechnology. Although we frequentl y herald minimall y invasive procedures as the fu ture of surgery, the concept is much older than most of the technology it is associated with . It is an ancient vision enabl ed by many tec hn olog ica l deve lopm ents unrelated to medicine - the introduction of electric ity, digital video, video game graphics, and industri al robots have all pl ayed major roles in shaping the way surgery is practi ce today.

F

John D. Fi sher ( 1798 - 1850), and Antonin J. Desormeaux ( 18 15 1894). Desorn1eaux was the fi r t to use an endoscopic instrument for therapeuti c purposes when he used his endo cope to remove a papilloma from the urethra.4 Eventuall y, it was reali zed that "to light up a room one mu t carry the lamp inside2, and the idea of the endoscope it elf as a Iight source was born .

WORKlNG IN THE DARK

The first documented attempt to "look inside" the internal organs was described by Hippocrates (460-375 BCE) in a pa sage referring to a rectal speculum (Figure I ). 1 Roman medicine also describes simil ar instruments, including a three-bladed vaginal peculum from the ruin of Pompeii .3 The initial attempts to make a di agnos is by examin ing internal body orifi ces all faced the sa me probl em: inadequate lighting. Almost all of the earl y too l were designed to max imize the amount of external ambient li ght avail abl e for direct visuali zati on of internal structures.

Figure 2. Construction drawing of the " Bozzini scher Lichtleiter".

Image courte y of the Medica l Univer ity of Vienna, Department of Hi tory of Medi cine .

Figure 1. xampl e of a rectal speculum simil ar to the one described

by Hippocrates. Image courtesy of the Hi storica l Co llecti ons & Servi ces of the Hea lth Science Li brary, Uni versity of Virgini a.

The first attempt to design a tool pecifi ca ll y guiding li ght to the target was an instrument call ed the " Li chtl eiter" des igned in 1806 by Phillip Bozzini ( 1773 -1 809), a young obstetrician (Fi gure 2). Thi s device was an elongated thin funnel that could be passed into an orifi ce. The end of thi s dev ice wa a stand carrying a candl e for lighting. Re fl ectors directed candl elight down the funn el. Many funn el of different sizes could be u ed, and it co uld help examine the bladder, rectum , vagina and naso pharynx. Although Bozzini is now. credited with creating th e first endoscope, the dev ice was poorl y received. The candl e produced heat and smoke leading to burns, the device co uld be painful to introduce, and lighting was stil l inadequate. 2â&#x20AC;˘3 In the foll ow ing years, attempts were made to improve the des ign by many peopl e in cluding Pierre ega las (1 792 - 1874),

34

. With the invention of the incande cent light bulb by Thomas d1 son ( 1847- 1.9.3 1), endoscopy bega n to be taken more eriously by med1 ca l practiti oner . Th ere were imultaneo us deve lopments ~ystosco py, thoracoscopy, and gastroscopy. Many modificati on and ~mprove m e nt s were made to endo cope des igns in the 20'h century, 1ncludmg the u e .of insuffl ati on by Georg Kelling, and the deve lopment of fl ex ible fibre-opti c in truments pi oneered by Bas il Hirschow itz ( 1925)5 ' FROM OLAGNO IS TO TREATMENT

While therapeuti c applicati on of laparoscopy began in the 1930 , the deve lop~1 e nt of the computer chip televi sion camera was a key piece of en a b1J~1 g tech.nology for. the u ~ of endoscopy to guide surgery and therapy 111 additi on to di agnostic uses. Video-endo copy allowed endoscop ic surgeon s t~ tand upri ght and u e both hands to carry out the proce~ure. In addition , the entire operating tea m was able to vi ew th e magnifi ed 1mage on a monitor. In the 1980s, CCD cameras became small enough that it became po sibl e to integrate them into too ls. In conjuncti on with these changes was the deve lopment of spec ialJ.zed tool s for ~~do scop1 c procedures. The e typically had a form . sm~llar to traditional too l , but with a long straight shaft all owmg Ill erllon Into the body cavity.

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( SEEING "WITHIN" Whi le endoscopes all owed surgeons to see inside body cavi ti es, their vision was till limited to the outer surface of organs. Frequent ly tumour and other abnonna l ti ssues were buried under a layer of normal tissue. Physicians had to "hunt" around for their targets, usually in a trial-and-error process that could result in the remova l of large sections of normal ti ssue. The discovery of X-ray in 1895 by Wi lliam Rontgen allowed physicians to ee in ide ti ssues for the first time. X-rays were immediately used for diagnosti c purposes, including the planning of surgica l interventi ons: 8 day after the publication of Roentgen' first paper, J. H . Clayton a surgeon in England used an x-ray print to remove an industrial ew ing needl e from a woman's hand .6 However, an actual x-ray guided intervention did not occur until 1963, nearly 70 year later when Charl es Dotter percutaneousl y dilated a tight tenosis of the superfi cial femora l artery 7 Today, fluoroscopy-guided interventions seem intuiti ve and a natural app lication of x-ray images. However, early images could take up to two hours to produce, and continuous imag ing was not possible.8 An explosion of new techniques and procedures followed the key deve lopment of video-endoscop y and inte rve ntional fluoroscopy as these technologies were applied to a range of different problems. While these modalities conti nue f01m the main stay of image-guidance for minimally invasi ve procedures, recent years have seen the exploration of many other modaliti es for the guidance of intra-operative procedure . Some example include: intra-operati ve MRJ for brai n tumour remova l9, epilepsy surgery 10, ca th eter-b ased aortic va lve pl ace ment 11 , catheterizations 12, and stenting of aorti c co-arctation l 3 intra-operati ve CT for brain les ion and sinu surgery 14

estimate the location of interna l structures. A paper published by Hor ley and lark ( 1908) described a stereotactic device that cou ld be affi xed to a subj ect's head and aligned using ex terna l landmark such as the auditory . canals and orbital rim (F igure 3 ).16 Thi s al1 gnm ent dev1ce prov1ded a coordinate system that co uld be used to guide the introducti on of electrodes into the kull. Thi s was the first time an attempt was made to correlate a model of the internal anatomy with the patient in phys ical pace. Horsley and Clark as um ~ d that brains pos essed a con tant tru cture and that every bram IS the sa me as another, and that spec ifi c internal structures ~o uld be targeted by simpl e coordin ates. Although this assumption is mco rrect, the des ign of the stereotactic frame was a maj or br.ea kthro~ g h that would later allow pre-operati ve images to be ali gned w1th the patient for procedure guidance (The in venti on of stereotacti c frames actuall y preceded the invention of CT and MRJ 1). ~he abi lity to bring models and image into the patient's coordmate sy tem was an important step in allowing model s to be used for pl anning and guidance of procedures. With the in venti on of CT sca nners in 1973 (Hounsfield , 1919 - 2004), CT stereotactic surgery beca me possible. The use of pre-operat ive images to guide mtervent10n s IS a current area of research of research and growth (F1gure 4). xamples of clinicall y used sy tem in clude the Carto XP E P Navigat ion System ( me rges CT o r MRI with electroanatomi ca l information for catheter ab lati ons) and the Medtronic Stealth Station (merges pre-operat ive CT and MRJ images w1th tracked surg1ca l too ls and intra-operati ve images) .11.18

ultrasound-guided breast surgery 15 Cost, acquisition speed and diffi cul ty in making the imaging sy tems OR compatible remain barriers to intra-operative CT and MRI guidance of surgical procedures. As real-time imaging has grown in popularity, it ha become increasi ngly important to develop new surgical tools that do not introduce artifacts into the images. This requires changes in both the mechanical design and the materia ls used.

ROADM APS There were also early attempts at minimall y invasive surgery wi th out the use of any real-time imagi ng to locate interna l structure . In lieu of direct visualizati on, a model was used to help the physician

Figure 4. Exa mpl e of multimodality imagi ng showi ng overl ay of CT and U image of the aortic root.

MOTION AT A DI STANCE

Figure 3. Horsely - Clark stereotactic frame. Image courtesy of the Sc1ence Museum , London , UK.

With minimall y invas ive access to internal structures through sma ll ports, too ls became more diffi cult to control and navigate. In respon e to these chall enges surgical robots were developed . Adapted from industri al des igns, the first medica l robots were desi gned to hold a fixture at a specific location in space. 19 The first robot used in surgery was an indu tri al robot called the PUMA 560 that held a fixture next to a patient's head to locate a bi opsy tool in neurosurgery (Figure 5).20 However, shortl y after thi s initial breakthrough, the company that manufactured the PUMA 560, Unimation Limited, was sold to Westinghouse Limited, which refused to all ow the robot to be used for surgica l purposes on the bas is that it was un afe.21 Soon

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Figure 5. Photo of th e PUMA 560. Image co urtesy o f Unm ann ed So luti o ns Inc. compani es began deve loping roboti c systems specifica ll y fo r medi ca l appli cati ons. The first to be tri ed on hum an pati ents was develo ped at l.BM and ca ll ed the Robodoc. It was used to ho ld a rotatin g c utter that reamed o ut the prox ima l fe mur to take a prostheti c impl a nt. 22 Today, medi ca l robots are used ro utine ly for many procedures, inc ludin g coro nary artery bypass g ra ftin g and tra nspubic radi ca l prostatecto my.

Surg ical robots can provide man y adva ntages, inc ludin g th e abi lity to move in predefin ed 3D pa ths, th e abi lity to ho ld too ls fo r long periods of tim e ri g id ly a nd without tremor, th e abi lity to ma ke precise mi cromoti on a nd th e abili ty for te le-operati on. However, s urg ical robots can a lso be bu lky, expensive, and diffi c ult to nav iga te.

Today it is sti ll unc lea r w hether surg ica l ro bots prov ide c lini ca l ad va ntages ove r comp ute r a ided surgery, in w hi ch nav iga ti o n a nd placement o f surg ica l tools are a ided by images and meas ure me nts pro vided o n a comp uter, but th e too ls re ma in ma nu a ll y co ntro ll ed by the surgeo n.

LOOKrNG FORWARD S ince th e 1980s th ere has bee n an ex plo ive interest in minim a ll y mvas tve procedures and the tec hno logy be hind it. As ph y ic ia n become mo re co mforta ble and co nfid e nt w ith th e new tec hn o logy, they a re attemp t!ng inc reas ing ly co mp lex procedures minim a ll y mvastve ly - spurnng o n the e ng inee ring o f new dev ices a nd yste ms.

Mea nwhil e, th e stud y o f inte rac ti o ns be twee n surgeo ns a nd th ese too ls has deve loped into a resea rc h a rea o f its ow n. Wh at d es th e futu re ho ld? M ul timoda lity imag ing platfo rm , teera ble ro bot , nanobo ts and a ug me nted rea lity?

5. Harrell , A.G ., Heniford, T. , Minimall y in vasive abdom inal surgery: lux et verti as pa t, present and future. Th e American Journal of Surgery 2005; 190: 239 - 243 .

6. Burrows, E., Pioneers and Early Years: A Histoty of British Radiology.

1986. Colop hon Press, Aldern ey.

7. Rosc h, J. , Keller, F.S., Kaufman, J.A., The Birth, Early Years, and Future of Jn tervent iona l Radi ology. J Vas e lnterv Radio/2003 ; 14 : 84 1 - 853.

8. Krohm er, J .S., Radi ograph y and Fluoroscopy, 1920 to the Present.

RadioGraphies 1989;9(6): 11 29- 1153 .

9. Bradl ey, WG ., Ach ievi ng Gross Total Resecti on of Brain Tumors: Intraoperative MR Imaging Can Make a Big Difference. American Journal ofNeuroradiology 2002 ; 23 : 34 - 349 10. Ke ll y, J.J ., Hader. W.J ., Myle , S.T., Sutherl and, G.R., Epilepsy urgery with in traoperative M RI at I. ST. Neurosurg Clin N Am. 2005 ; 16( I): 173183.

II. McVeigh et al. Rea l-Time In te ractive MRJ-Guided Cardiac Surgery: Aorti c Valve Replacement U ing a Direct Apical Approach. Magn Reson Med. 2006; 56(5): 958 - 964.

12. Dick AJ, Raman VK, Ra al AN, Gu ttman MA , Thompson RB, Orzturk C, Peter DC, tine AM , Wri ght VJ, Schenke WH , Lederm an RJ . In vasive hum an magnet ic reso nance imaging: Fea ibi lity during reva cularization in a combi ned XMR uite. Catheter Cardiova c lnten • 2005 ; 64(3), 265 274 13. Raman, V.K., Karm arkar, P.V., Guttman M.A., Dick, A.J ., Peters, D.C., Ozturk, ., Pe sa nh a, B.C., Thompson, R.B.. Rava l, A.N., DeS il va, R., Av ile , R.J., Atalar, E.. McVeigh. E. R., Lederman, R.J. , Real-time mag netic re o nance-g uided e ndo ascu lar repai r of ex perim ental abd omin al aorti c aneurys m in wi ne. JAm Col/ Cardia/ 2005 ; 45( 12), 2069 - 2077 14. Jac kman, .H.. Palmer. J. . , Chiu, .G .. Kennedy, D.W. Use of intraoperati\ e T canning in endoscopic sinu surgery: a preliminary report. Am J. Rlunol. 100 ; 22(2): 170 - 174. .M.A. et al. ltraso und-guided breast- paring surgery to 15. Kreka l, imprO\ e cos metic outcome and quality of life. A pro pec tive multicentre randomised controlled clin ica l tri al comparing ul trasound-guided surgery to traditional palpation-guided urgery (CO BALT trial). BMC Surgety 20 II ; II ( ).

16. Horsley, lark. R., The tructu re and fu nctions of the cerebellum examined by a ne\\ meth od. Brain 190 ; 3 I, 45-1 24.

17. C RTO P EP a\ igation y tern (Intern et]. Biosen e Web ter lnc; [upd ated 20 I 0: c ited 20 II Apr I I]. Ava il abl e from: http :// '' ,,,,, .biosen ewebster.corn/products/na vigationlcartox p.aspx .

18. Med tronic teal th tati on-R Treatmen t Gui dance ystem Fact Sheet [Internet]. ledtroni c Inc; (updated 20 11 ; cited 20 11 Apr II ]. Ava ilable from : http ://\''''' p.medtron1 c.co m ew room/ Lin kedlt em Details.do? itemld= 11 0 1832 66677&i temType= fact_ heet&lang=en_U 19. Da ie . B., Medi cal Robotics - a bright future. The Lancet 2006; 368, 53 - 54.

20. K, oh. Y. .• !-l ou. J .. Jonckhce re, E. A. and Haya ll , . A robot with improved ab olute po itioni ng accuracy fo r CT guided stereotacti c brai n surge ry. /£££ TrtlltS. Biomed. Eng ng, Febr11ary 19 8; 35(2),: 153- 16 1 2 1. Davies. B. Review of roboti c in urgery. Proceeding of the Institution of lechanical Eng ineers. Plwrt H: Journal of Engineering in Medicine 2000; 2 14( I): 129 - 140.

22. Taylor, R.H., Paul, H. . , Mitte lstadt, B.D.. Glassman, E., Musits, B.L., Bargar, W. L., Roboti c To tal Hip Replacement urgery in Dogs. In Proceedings of IEEE EMB lntem ationa/ onf erence 19 9; 7 - 8 9.

REFERENCES I. Rosin D. History. In Rosin D ed. Minimal Access Medicine and Surgery Oxfo rd: Radcliffe Medical Press, 1993 : 1- 9. · 2. Shah, J. Endoscopy through th e ages. BJ U Intern ational. 2002·89·645 _ 652. , .

3. Berci, G., Forde, K.A., History of Endosco py: What lessons have we learned from th e past? Surg. Endosc (2000) 14:5 - 15.

4. Desorm eau x AJ. The endoscope and its app lica ti on to th e di agnosis and trea tment of affect1 ons of the genitouri nary passages. Ch · , M d J 1867; 24: 177 - 194. tcago e

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