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Urgent Care Urgent Care –– Case Case ReportsReports

Scott Allan MDScott Allan MD

Case #1Case #1

►► 21 year old male presents with a chief complaint 21 year old male presents with a chief complaint of a large, painful, erythematous bump on his leg.of a large, painful, erythematous bump on his leg.

►► He had been bitten by a spider several days He had been bitten by a spider several days earlier. Since then, the lesion has been growing in earlier. Since then, the lesion has been growing in size and is becoming increasingly painful.size and is becoming increasingly painful.

►► He denies any purulent drainage.He denies any purulent drainage.►► He also denies any similar events in the past.He also denies any similar events in the past.►► Review of systems is otherwise negativeReview of systems is otherwise negative

Case #1 Case #1 –– 21 year old male21 year old male

►►Physical Exam Physical Exam ––►►Vital signs stable.Vital signs stable.►►2cm x 3cm fluctuant, erythematous mass on his 2cm x 3cm fluctuant, erythematous mass on his

medial left thigh. Unable to express any drainage. medial left thigh. Unable to express any drainage. Very tender to palpation. No other significant Very tender to palpation. No other significant physical exam findings. physical exam findings.

Case #1: Abscess ManagementCase #1: Abscess Management

►► Incision and drainage remains the standard of Incision and drainage remains the standard of care.care.§§ Is there a type of incision that is most effective?Is there a type of incision that is most effective?§§ Are there options other than incision and drainage?Are there options other than incision and drainage?§§ Needle aspiration using ultrasound guidance?Needle aspiration using ultrasound guidance?

►► Following incision and drainage, there are widely Following incision and drainage, there are widely varying recommendationsvarying recommendations§§ Should we use packing?Should we use packing?§§ Should we prescribe antibiotics?Should we prescribe antibiotics?§§ Is primary closure an option?Is primary closure an option?

Case #1 Case #1 –– Abscess ManagementAbscess Management

►► Incision vs Needle aspirationIncision vs Needle aspiration§§ Annals of Emergency Medicine, 2011.Annals of Emergency Medicine, 2011.§§ A randomized controlled trial of incision and drainage A randomized controlled trial of incision and drainage

versus ultrasonographically guided needle aspiration for versus ultrasonographically guided needle aspiration for skin abscesses and the effect of MRSA.skin abscesses and the effect of MRSA.§§ 101 patients.101 patients.

►► Success rate Success rate §§ Needle aspiration 26% (CI 18%Needle aspiration 26% (CI 18%--44%)44%)§§ Incision and drainage 80% (CI 66%Incision and drainage 80% (CI 66%--89%)89%)§§ Overall success rate of both modalities worsened by MRSAOverall success rate of both modalities worsened by MRSA

►► Conclusion Conclusion –– Ultrasound guided needle aspiration is insufficient Ultrasound guided needle aspiration is insufficient therapy for skin abscesses.therapy for skin abscesses.


►► Following incision and drainage, should we use packing?Following incision and drainage, should we use packing?►► Pediatric Emergency Care, 2012.Pediatric Emergency Care, 2012.►► Randomized trial comparing wound packing to no wound Randomized trial comparing wound packing to no wound

packing following incision and drainage of superficial skin packing following incision and drainage of superficial skin abscesses in the pediatric emergency department.abscesses in the pediatric emergency department.§§ Looked at 57 subjects over 15 month period.Looked at 57 subjects over 15 month period.

►► Failure of therapy defined as requiring further intervention at Failure of therapy defined as requiring further intervention at 48 hours 48 hours (repeat I&D, change in antibiotics(repeat I&D, change in antibiotics

►► Overall failure rates similar:Overall failure rates similar:§§ 19 of 27 patients in the packed group (70%)19 of 27 patients in the packed group (70%)§§ 13 of 22 patients in the non13 of 22 patients in the non--packed group (59%)packed group (59%)

►► Limitations:Limitations:§§ Small sample sizeSmall sample size§§ Overall failure rate seems very highOverall failure rate seems very high


►► Should we use packing IIShould we use packing II►► Academic Emergency Medicine, 2009.Academic Emergency Medicine, 2009.►► Routine packing of simple cutaneous abscesses in Routine packing of simple cutaneous abscesses in

painful and probably unnecessary.painful and probably unnecessary.§§ Limited to simple cutaneous abscesses (<5cm)Limited to simple cutaneous abscesses (<5cm)§§ 48 subjects included in the final analysis48 subjects included in the final analysis

►► Requiring further intervention after 48 hoursRequiring further intervention after 48 hours§§ 4 of 23 in the packed group4 of 23 in the packed group§§ 5 of 25 in the non5 of 25 in the non--packedpacked

►► No significant differenceNo significant difference§§ Limitations:Limitations:

►► Small sample size. Cannot generalize the results.Small sample size. Cannot generalize the results.

Case #1 Abscess ManagementCase #1 Abscess Management

►► Traditionally, the incision is left open to heal by secondary Traditionally, the incision is left open to heal by secondary closure. Is primary closure an option?closure. Is primary closure an option?

►► Academic Emergency Medicine, 2013.Academic Emergency Medicine, 2013.►► Primary versus Secondary Closure of Cutaneous Abscesses Primary versus Secondary Closure of Cutaneous Abscesses

in the Emergency Department: A randomized controlled in the Emergency Department: A randomized controlled trial.trial.§§ Simple cutaneous infections. Those with systemic signs and Simple cutaneous infections. Those with systemic signs and

cellulitis greater than 5cm were excluded.cellulitis greater than 5cm were excluded.§§ 51 Adult patients51 Adult patients

►► Overall failure rate at 7 days similarOverall failure rate at 7 days similar§§ 7 of 23 treated with primary closure (30.4%. CI 15.67 of 23 treated with primary closure (30.4%. CI 15.6--50.9)50.9)§§ 8 of 28 treated with secondary closure (28.6%. CI 15.28 of 28 treated with secondary closure (28.6%. CI 15.2--47.1)47.1)

§§ Limitations:Limitations:►► Small sample size. Results not generalizableSmall sample size. Results not generalizable


►► Following incision and drainage, should we prescribe Following incision and drainage, should we prescribe antibiotics?antibiotics?

►► Annals of Emergency Medicine, 2010.Annals of Emergency Medicine, 2010.►► Randomized controlled trial of TMPRandomized controlled trial of TMP--SMX for uncomplicated SMX for uncomplicated

skin abscesses in patients at risk for community associated skin abscesses in patients at risk for community associated MRSA infection.MRSA infection.§§ 190 patients assessed for treatment failure after 7 days.190 patients assessed for treatment failure after 7 days.

►► Failure rates:Failure rates:§§ 15 out of 88 in patients receiving TMP15 out of 88 in patients receiving TMP--SMX (17%)SMX (17%)§§ 27 out of 102 in patients receiving placebo (26%)27 out of 102 in patients receiving placebo (26%)§§ Confidence interval (Confidence interval (--2% to 21%)2% to 21%)

►► However, fewer lesions were noted after 30 days from the antibioHowever, fewer lesions were noted after 30 days from the antibiotic tic group versus the placebo groupgroup versus the placebo group

§§ Limitations Limitations –– only studied healthy adultsonly studied healthy adults


►► Should we prescribe antibiotics IIShould we prescribe antibiotics II►► Annals of Emergency Medicine. 2010.Annals of Emergency Medicine. 2010.►► Randomized, controlled trial of antibiotics in the Randomized, controlled trial of antibiotics in the

management of communitymanagement of community--acquired skin acquired skin abscesses in the pediatric patientabscesses in the pediatric patient§§ Pediatric patients randomized to receive 10 days of Pediatric patients randomized to receive 10 days of

TMPTMP--SMX or placebo following incision and drainageSMX or placebo following incision and drainage§§ 149 children in the study149 children in the study

►► Failure rates:Failure rates:§§ 3 out of 73 in the antibiotic group (4.1%)3 out of 73 in the antibiotic group (4.1%)§§ 4 out of 76 in the placebo group (5.3%)4 out of 76 in the placebo group (5.3%)


►► Western Journal of Emergency Medicine, 2013.Western Journal of Emergency Medicine, 2013.►► The treatment of cutaneous abscesses: The treatment of cutaneous abscesses:

comparison of emergency medicine providers comparison of emergency medicine providers practice patterns.practice patterns.

►► Data obtained via survey. 474 surveys sent, 350 Data obtained via survey. 474 surveys sent, 350 returned.returned.§§ 189 attending physicians189 attending physicians§§ 135 residents135 residents§§ 26 midlevel providers26 midlevel providers

Case #1 Case #1 –– Abscess ManagementAbscess Management►► Study resultsStudy results►► Irrigation Irrigation ––

§§ 48% did, 52% did not48% did, 52% did not§§ Of those that did irrigate, almost all (94%) used salineOf those that did irrigate, almost all (94%) used saline

►► Some used tap waterSome used tap water►► 1% used betadine1% used betadine

§§ Most irrigated under high pressure (66%)Most irrigated under high pressure (66%)§§ No agreement on the amount of irrigationNo agreement on the amount of irrigation

►► Incision type Incision type ––§§ Linear Linear –– by far most commonby far most common§§ Elliptical and Cruciate used much less frequentlyElliptical and Cruciate used much less frequently

►► Packing Packing ––§§ Most used packing (91%)Most used packing (91%)

►► 75% filled the wound cavity75% filled the wound cavity►► 24% used a small wick to keep the cavity open24% used a small wick to keep the cavity open

Case #1 Case #1 –– Abscess ManagementAbscess Management►► Instructions Instructions ––

§§ Follow up in 24 hours Follow up in 24 hours –– 15%15%§§ Follow up in 48 hours Follow up in 48 hours –– 32%32%§§ Follow up at 48 hours unless wound is concerning and needs furthFollow up at 48 hours unless wound is concerning and needs further evaluation er evaluation ––

47%47%►► Culture Culture ––

§§ Most did not Most did not –– 68%68%►► Antibiotics Antibiotics ––

§§ Rare after incision and drainage in healthy patients (only 17%)Rare after incision and drainage in healthy patients (only 17%)§§ Diabetic or immuneDiabetic or immune--compromised (58%)compromised (58%)§§ History of MRSA (24%)History of MRSA (24%)§§ Surrounding cellulitis (74%)Surrounding cellulitis (74%)§§ 33% used TMP33% used TMP--SMXSMX§§ 8% used cephalexin8% used cephalexin§§ 8% used clindamycin8% used clindamycin§§ 47% used a combination of two or more drugs for strep and MRSA c47% used a combination of two or more drugs for strep and MRSA coverageoverage

►► 99% did not close incision with primary closure99% did not close incision with primary closure

Case 1 Case 1 –– Abscess ManagementAbscess Management

Western Journal of Emergency Medicine. 2013;14(1):25

Abscess Management ReferencesAbscess Management ReferencesSchmitz, Goodwin, Singer, Kessler, Bruner, Larrabee, May, Luber,Schmitz, Goodwin, Singer, Kessler, Bruner, Larrabee, May, Luber, Williams, Williams, BhatBhat. Treatment of . Treatment of

CutaneousCutaneous Abscesses: A comparison of Emergency Medicine ProvidersAbscesses: A comparison of Emergency Medicine Providers’’ Practice Patterns. West J Practice Patterns. West J EmergEmerg Med. 2013; 14(1):23Med. 2013; 14(1):23--28.28.

Duong, Duong, MarkwellMarkwell, Peter, , Peter, BarenkampBarenkamp. Randomized, Controlled Trial of Antibiotics in the Management. Randomized, Controlled Trial of Antibiotics in the Management of of CommunityCommunity--Acquired Skin Abscesses in the Pediatric Patient. Ann Acquired Skin Abscesses in the Pediatric Patient. Ann EmergEmerg Med. 2010; 55: 401Med. 2010; 55: 401--407.407.

Singer, Singer, TairaTaira, , ChaleChale, , BhatBhat, Kennedy, Schmitz. Primary Versus Secondary Closure of , Kennedy, Schmitz. Primary Versus Secondary Closure of CutaneousCutaneous Abscesses Abscesses in the Emergency Department: A randomized controlled trial. Acain the Emergency Department: A randomized controlled trial. Academic Emergency Medicine 2013; demic Emergency Medicine 2013; 20:2720:27--32.32.

OO’’Malley. Malley. DominiciDominici, , GiraldoGiraldo, Aguilera, , Aguilera, VermaVerma, , LaresLares, Burger, Williams. Routine Packing of Simple , Burger, Williams. Routine Packing of Simple CutaneousCutaneous Abscesses in Painful and Probably Unnecessary. Academic EmergeAbscesses in Painful and Probably Unnecessary. Academic Emergency Medicine 2009; 16: ncy Medicine 2009; 16: 470470--473.473.

Kessler, Kessler, KrantzKrantz, , MojicaMojica. Randomized Trial Comparing Wound Packing to No Wound Packing . Randomized Trial Comparing Wound Packing to No Wound Packing Following Following Incision and Drainage of Superficial Skin Abscesses in the PediaIncision and Drainage of Superficial Skin Abscesses in the Pediatric Emergency Department. Pediatric tric Emergency Department. Pediatric Emergency Care. Volume 28. June 2012: 514Emergency Care. Volume 28. June 2012: 514--517.517.

Baumann, Russo, Baumann, Russo, PavlikPavlik, Cassidy, Cassidy--Smith, Brown, Smith, Brown, SacchettiSacchetti, , CapanoCapano--WehrleWehrle, , MistryMistry. Management of . Management of Pediatric Skin Abscesses in Pediatric, General Academic and CommPediatric Skin Abscesses in Pediatric, General Academic and Community Emergency Departments. unity Emergency Departments. Western Journal of Emergency Medicine. 2011; 12(2): 159Western Journal of Emergency Medicine. 2011; 12(2): 159--167.167.

Schmitz, Bruner, Schmitz, Bruner, PitottiPitotti, et al. Randomized Controlled Trial of , et al. Randomized Controlled Trial of TrimethoprimTrimethoprim--SulfamethoxazoleSulfamethoxazole for for Uncomplicated Skin Abscesses in Patients at Risk for CommunityUncomplicated Skin Abscesses in Patients at Risk for Community--Associated Associated MethicillinMethicillin--Resistant Resistant Staphylococcus Staphylococcus AureusAureus infection. Annals of Emergency Medicine. 2010; 56: 283infection. Annals of Emergency Medicine. 2010; 56: 283--287.287.

GaspariGaspari, , ResopResop, Mendoza, et al. A randomized Controlled Trial of Incision and, Mendoza, et al. A randomized Controlled Trial of Incision and Drainage Versus Drainage Versus UltrasonographicallyUltrasonographically Guided Needle Aspiration for Skin Abscesses and the Effect of Guided Needle Aspiration for Skin Abscesses and the Effect of MethicillinMethicillin--Resistant Staphylococcus Resistant Staphylococcus AureusAureus

Case 2 Case 2 –– 39 year old male39 year old male

►►Chief Complaint Chief Complaint –– red, swollen, painful area red, swollen, painful area at the base of his big toe. Started last night at the base of his big toe. Started last night and is getting worse. Has taken and is getting worse. Has taken tylenoltylenol with with minimal relief. Denies prior episodes.minimal relief. Denies prior episodes.

►►Review of systems otherwise negative.Review of systems otherwise negative.►►PMHxPMHx –– Hypertension, Obesity, Alcohol Hypertension, Obesity, Alcohol

Abuse, Cocaine abuseAbuse, Cocaine abuse►►Medications Medications -- HydrochlorothiazideHydrochlorothiazide


►► Physical exam Physical exam ––§§ Vital Signs: Vital Signs:

►► T: 98.6, P:102, R:16, BP: 138/82, P:10/10 SpO2: 98% on RAT: 98.6, P:102, R:16, BP: 138/82, P:10/10 SpO2: 98% on RA§§ ErythematousErythematous, swollen first MTP joint on left foot., swollen first MTP joint on left foot.§§ PE Otherwise unremarkable.PE Otherwise unremarkable.


►►LabsLabs–– CBC, BMP, ESR, Uric Acid levelCBC, BMP, ESR, Uric Acid level►►Results:Results:§§ ESR ESR –– 2525§§ Uric Acid Level Uric Acid Level –– 6.11mg/dL6.11mg/dL§§ No other outstanding lab abnormalities.No other outstanding lab abnormalities.

Arthritis and rheumatism, 1996, 39(1):1


►►Gold standard Gold standard –– joint aspirationjoint aspiration§§ Rarely doneRarely done

►►Clinical diagnosis made of goutClinical diagnosis made of gout

Arch Intern Med. 2010;170(13):1120-1126. doi:10.1001/archinternmed.2010.196

Clinical score totalClinical score total00--4 : low probability 4 : low probability –– consider alternate consider alternate

diagnosisdiagnosis--rheumatoid arthritis, rheumatoid arthritis, pseudogoutpseudogout, , psoriatic arthritis, reactive arthritispsoriatic arthritis, reactive arthritis(2 of 72 patients with gout)(2 of 72 patients with gout)

>4 >4 –– 8 : intermediate 8 : intermediate –– consider analysis of consider analysis of synovialsynovial fluid for MSU crystals fluid for MSU crystals (17 of 63 patients with gout)(17 of 63 patients with gout)

>8 : high probability (gout was confirmed >8 : high probability (gout was confirmed in >80% of patients)in >80% of patients)(197 of 245 patients with gout)(197 of 245 patients with gout)

Case 2 Case 2 –– Acute Gouty ArthritisAcute Gouty Arthritis

►►Treatment should be initiated within 24 Treatment should be initiated within 24 hours of onsethours of onset§§ Symptoms will resolve on their own in 7Symptoms will resolve on their own in 7--10 10

daysdays

►►Do not start Do not start urateurate lowering therapy during lowering therapy during an acute attackan acute attack

►►Do not discontinue Do not discontinue urateurate lowering therapy lowering therapy during acute attackduring acute attack

Acute Gouty Arthritis Acute Gouty Arthritis --ManagementManagement

Acute gouty arthritis Acute gouty arthritis –– NSAIDS and NSAIDS and COXCOX--2 inhibitors2 inhibitors

•• IndomethacinIndomethacin (evidence A), Naproxen (evidence (evidence A), Naproxen (evidence A)A)•• IndomethacinIndomethacin –– 50mg, PO, q8hr for 350mg, PO, q8hr for 3--5 days5 days•• Naproxen Naproxen –– 750mg initially, then 250mg, q8hr until 750mg initially, then 250mg, q8hr until

attack subsidesattack subsides•• Extended release Extended release –– 10001000--1500mg once, then 1000mg daily until 1500mg once, then 1000mg daily until

attack subsidesattack subsides

•• CelecoxibCelecoxib –– option for acute gout in patients with option for acute gout in patients with a contraindication or intolerance to other a contraindication or intolerance to other NSAIDsNSAIDs(evidence B)(evidence B)•• Recommended dosing Recommended dosing –– 800mg once, 400mg on day 1, 800mg once, 400mg on day 1,

400mg BID x 1 week400mg BID x 1 week

Acute gouty arthritis Acute gouty arthritis ––ColchicineColchicine

Only recommended when initiated within 36 hours of onset Only recommended when initiated within 36 hours of onset (evidence C)(evidence C)§§ Loading dose 1.2mg followed by 0.6mg one hour laterLoading dose 1.2mg followed by 0.6mg one hour later§§ Continue with 0.6mg Continue with 0.6mg QdailyQdaily or BID until attack resolvesor BID until attack resolves§§ Requires dosing reduction with moderate to severe kidney diseaseRequires dosing reduction with moderate to severe kidney disease§§ High incidence of GI side effects before relief of symptomsHigh incidence of GI side effects before relief of symptoms

Acute gouty arthritisAcute gouty arthritisCorticosteroidsCorticosteroids

►► IntraIntra--articulararticular –– Consider if 1Consider if 1--2 large joints affected2 large joints affected§§ Dose dependant upon joint sizeDose dependant upon joint size

►► Systemic Systemic –– an option for all cases of goutan option for all cases of gout§§ Study Study –– Lancet 2008. Double blinded RCT comparing oral Lancet 2008. Double blinded RCT comparing oral

prednisoloneprednisolone to naproxen.to naproxen.►► 120 Patients120 Patients

§§ 35mg 35mg prednisoloneprednisolone QdailyQdaily vsvs 500mg naproxen BID500mg naproxen BID§§ Treatment for 5 daysTreatment for 5 days

►► Both equally effective, no difference in treatment.Both equally effective, no difference in treatment.§§ Prednisone 0.5mg/kg per day Prednisone 0.5mg/kg per day

►► For 5For 5--10 days and then stop (A) 10 days and then stop (A) ––oror——►► For 2For 2--5 days with a 75 days with a 7--10 day taper and then stop (C)10 day taper and then stop (C)

Acute gouty arthritis Acute gouty arthritis –– intraintra--articulararticularcorticosteroidscorticosteroids

►► Cochrane review 2013Cochrane review 2013►► Started with 182 records identified through database searchingStarted with 182 records identified through database searching►► 32 records excluded as duplicates 32 records excluded as duplicates -- 150 records remain150 records remain►► 148 records excluded148 records excluded

§§ Incorrect study type: 101Incorrect study type: 101§§ Wrong population: 28Wrong population: 28§§ Wrong intervention: 19Wrong intervention: 19

►► 2 full text articles remain2 full text articles remain►► Both remaining articles excluded as neither were RCT/CCTBoth remaining articles excluded as neither were RCT/CCT►► Result Result –– No published No published RCTsRCTs or or CCTsCCTs that the efficacy and safety of that the efficacy and safety of

intraintra--articulararticular glucocorticoidglucocorticoid therapy versus placebo in people with therapy versus placebo in people with acute goutacute gout

Acute gouty arthritis Acute gouty arthritis –– Off label Off label therapies in developmenttherapies in development

►► Biologic ILBiologic IL--1 inhibitors1 inhibitors§§ ILIL--1B 1B –– recognized as key cytokine driving the recognized as key cytokine driving the

inflammation of acute gouty arthritisinflammation of acute gouty arthritis§§ CanakinumabCanakinumab, , rilonaceptrilonacept, , anakinraanakinra

►► AnakinraAnakinra currently used for rheumatoid arthritiscurrently used for rheumatoid arthritis§§ Expensive Expensive –– but significantly less expensive than the othersbut significantly less expensive than the others

§§ None currently FDA approved for use in goutNone currently FDA approved for use in gout§§ Lack of long term safety data and expenseLack of long term safety data and expense

►► These should only be considered in patients with refractory These should only be considered in patients with refractory gout who have failed standard therapiesgout who have failed standard therapies

Acute Gouty Arthritis ReferencesAcute Gouty Arthritis ReferencesKhannaKhanna D, D, KhannaKhanna PP, Fitzgerald JD, et al. 2012 American College of PP, Fitzgerald JD, et al. 2012 American College of

Rheumatology guidelines for management of gout. Part 2: therapy Rheumatology guidelines for management of gout. Part 2: therapy and and antiinflammatoryantiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken) 2012; 64:1447.(Hoboken) 2012; 64:1447.

WechalekarWechalekar MD, MD, VinikVinik O, Schlesinger N, O, Schlesinger N, BuchbinderBuchbinder R. IntraR. Intra--articulararticularglucocorticoidsglucocorticoids for acute gout. Cochrane Database for acute gout. Cochrane Database SystSyst Rev 2013; Rev 2013; 4:CD009920.4:CD009920.

JanssensJanssens HJ, Janssen M, van de HJ, Janssen M, van de LisdonkLisdonk EH, et al. Use of oral EH, et al. Use of oral prednisoloneprednisolone or or naproxen for the treatment of gout arthritis: a doublenaproxen for the treatment of gout arthritis: a double--blind, blind, randomisedrandomisedequivalence trial. Lancet 2008; 371:1854equivalence trial. Lancet 2008; 371:1854..

DrDrHeinHein JEM JEM JanssensJanssens MD, MD, MatthijsMatthijs JanssenJanssen PhD, PhD, EloyEloy H van de H van de LisdonkLisdonk PhD, Prof PhD, Prof PietPiet LCM van RielLCM van Riel PhD, Prof PhD, Prof Chris van Chris van WeelWeel PhD. Use of oral PhD. Use of oral prednisoloneprednisolone or or naproxen for the treatment of gout arthritis: a doublenaproxen for the treatment of gout arthritis: a double--blind, blind, randomisedrandomisedequivalence trial. The Lancet, equivalence trial. The Lancet, Volume 371, Issue 9627Volume 371, Issue 9627, Pages 1854 , Pages 1854 -- 1860, 31 1860, 31 May 2008. doi:10.1016/S0140May 2008. doi:10.1016/S0140--6736(08)607996736(08)60799--00

DariaDaria B. Crittenden and Michael H. B. Crittenden and Michael H. PillingerPillinger. New Therapies for Gout. . New Therapies for Gout. Annu. Rev. Annu. Rev. Med. 2013. 64:325Med. 2013. 64:325––3737

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