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Tres Difficile Stephen M. Brecher PhD Director of Microbiology VA Boston Health Care System West Roxbury, Massachusetts.

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Presentation on theme: "Tres Difficile Stephen M. Brecher PhD Director of Microbiology VA Boston Health Care System West Roxbury, Massachusetts."— Presentation transcript:

1 Tres Difficile Stephen M. Brecher PhD Director of Microbiology VA Boston Health Care System West Roxbury, Massachusetts

2 The opinions expressed in this presentation are those of the presenter and do not necessarily represent the views of the Veterans Affairs Health-Care System

3 The Dominant Species The human body has human cells and a minimum of bacterial cells

4 Overview Case reports Historical perspective Organism & key properties Changing epidemiology Disease Diagnosis Treatment Infection control

5 Case Study 1 60 yo male admitted to hospital for community acquired pneumonia, treated with levofloxacin and discharged 7 days later, seen at another hospital because of pound weight gain over last few days (“my abdomen has never been so big”) and hypertension (213/106) –Afebrile, WBC of 8.5, albumin 3.1, creatinine 0.9, no diarrhea noted –Admitted, treated for hypertension and ciprofloxacin given to complete treatment for CAP; discharged 3 days later

6 Case Study 1 (cont’d) Day 1Presents to ER 3 days after discharge Fever (101), diarrhea, generally feeling ill, no abdominal pain WBC 27.8K, albumin 2.9, creatinine 1.2 Admitted with C. difficile colitis listed as a possible dx, but not treated (except for levofloxacin) Day 210 stools/day, altered mental status C. difficile EIA positive; put on metronidazole 500 mg TID

7 Case Study 1 (cont’d) Day 3 Transferred to SICU, anuric, abdominal pain, distension, developed cardiac complications, ventilated, renal failure. Poor prognosis and colectomy ruled out following surgical consult Oral and rectal vancomycin added WBC > 30K, albumin 2.3, creatinine 3.1 Day 4WBC 59.6K, toxic megacolon Day 5WBC 88K, made DNI/DNR, died

8 Historical Perspective In the 1960s it was noted that patients on antibiotics developed diarrhea 1 –“staphylococcal colitis” Originally thought to be caused by S. aureus and treated with oral bacitracin Stool cultures routinely ordered for S. aureus Early 1970s, a new explanation –“clindamycin colitis” Severe diarrhea, pseudomembranous colitis, and occasional deaths documented in patients on clindamycin 1. Gorbach SL. NEJM. 1999;341:

9 “Antibiotic Associated Pseudomembranous Colitis Due to Toxin-Producing Bacteria” Bartlett and co-workers 1 demonstrated cytotoxicity in tissue culture and enterocolitis in hamsters from stool isolates from patients with pseudomembranous colitis –Isolate was C. difficile Bacillus difficilis (now confirmed as C. difficile) was cultured from healthy neonates (with difficulty, hence the name) in Bartlett JG, et al. NEJM. 1978;298: Hall JC and O’Toole E. Am J Dis Child. 1935;49:

10 Quiz Time Q. Why did it take so long to associate the organism C. difficile with the disease? A. Organism was (is) found in healthy infants Q. Why do antibiotics sometimes cause diarrhea (unrelated to C. difficile)? A. Disrupt the intestinal flora which plays a major role in digestion of food

11 Clostridium difficile Gram-positive, anaerobic, spore-forming bacillus Vegetative cells die quickly in an aerobic environment Spores are a survival form and live for a very long time in the environment Grows on selective media in 2 days and smells like horse manure (p-cresol)

12 Importance of Spores Resistant to heat, drying, pressure, and many disinfectants Resistant to all antibiotics because antibiotics only kill or inhibit actively growing bacteria Spores survive well in hospital environment Spores are not a reproductive form, they represent a survival strategy

13 Source of Infections Spores in hospital, nursing home, or long-term care environment associated with ill patients –Large numbers of spores on beds, bed-rails, chairs, curtains, medical instruments, ceiling, etc. Asymptomatic carriers in those same environments –Low risk compared to patients with active disease False negative lab tests (low sensitivity) Unknown in community based infections, but food has been implicated 1 1. Jhung MA, et al. Emerg Infect Dis. 2008;14:

14 Risk Factors for Infection Hospitalization or long-term care facility Antibiotics (some more than others) Increasing age (>65, >>80) Co-morbidity Surgery ? Proton-pump inhibitors Community-associated cases –Peri-partum –Close contact of CDI (C. difficile infection) case –Food

15 Case Study 2 31 yo pregnant female (14 weeks, twins) seen at a local ER with history of –3 weeks intermittent diarrhea –3 days cramping and watery diarrhea –Stool + for C. difficile toxin –Received T/S for UTI 3 months prior to ER visit –Admitted, treated with metronidazole and discharged –Readmitted next day with severe colitis –Treated in hospital for 18 days with metronidazole, oral vancomycin and cholestyramine, discharged

16 Case Study 2 (cont’d) Readmitted 4 days later –Diarrhea and hypotension –Spontaneously aborted her fetuses –Subtotal colectomy, aggressive therapy –Died on 3rd day –Post-mortem showed toxic megacolon with evidence of pseudomembranous colitis MMWR 54:(47);

17 What Can We Learn From Case 2? We know nearly nothing about community based CDI Testing for C. difficile is now both an in- patient and out-patient test Risk factors other than colonic imbalance mediated by antibiotics must be considered

18 Role of Antibiotics All antibiotics (including metronidazole and vancomycin) are associated with CDI High-risk group –Clindamycin –Cephalosporins/penicillins/beta-lactams –Fluoroquinolones Alteration of normal colonic flora thought to favor growth of C. difficile –Antibiotics do not know they are suppose to kill/inhibit only the “bad guys”

19 Pathogenesis Historical Perspective Most CDI were mild –Diarrhea was main symptom –Pseudomembranous colitis and toxic megacolon were rare –Discontinuing antibiotics worked in many cases –High response rate to metronidazole and vancomycin

20 Incidence of CDI United States –CDI is not a reportable disease so exact number of cases and deaths remain unknown –Based on discharge diagnoses, CDI cases have tripled over last 5 years United Kingdom –Deaths in UK ~ 9,000/year CDI = C. difficile infection.

21 Pathogenesis Toxigenic strains produce 2 large protein exotoxins that are associated with virulence –Toxins A and B –Mutants strains that do not make toxins A and B are not virulent –Some strains make a third toxin known as Binary Toxin By itself, not pathogenic May act synergistically with toxins A and B in severe colitis More common in animal strains

22 Asymptomatic C. difficile colonization Pathogenesis of CDI C. difficile exposure Antimicrobial C. difficile infection Hospitalization From Johnson S, Gerding DN. Clin Infect Dis. 1998;26: ; with permission.

23 Pathogenesis Changing Epidemiology Increasing morbidity and mortality noted beginning in 2000 Outbreaks in US & Canada (>200 deaths) Was this due to poor infection control, emergence of antibiotic resistance, or something else? A new, hypervirulent strain was detected

24 Epidemic Strain Strain typed BI/NAP1/027 1,2 Is highly resistant to fluoroquinolones 2,4 Binary toxin genes are present Produces large quantities of toxins A and B 1,3 Has a tcdC gene deletion 1 1.Warny M, et al. Lancet. 2005;366: Hubert B, et al. Clin Infect Dis. 2007;44: CDC Fact Sheet. July McDonald LC, et al. N Engl J Med. 2005;353: Adapted from McDonald LC, et al. N Engl J Med. 2005;353: ; with permission.

25 In Vitro Production of Toxins in Epidemic Strain From Warny M, et al. Lancet. 2005;366: , with permission.

26 Not So Fast 2 recent papers questioned whether this strain is more virulent –NAP-1 strain was detected around 25% of time in their hospital (BID in Boston) but was not associated with increased severity of disease (non-epidemic setting) 1 – 18 and 39 bp deletion containing strains were not associated with increased severity of CDI at the Mayo Clinic 2 Age >65 and prior NH stay implicated 1. Cloud, J. et al Cl Gastro and Hept. 7: Verdoorn, B. P. et al. Diag Micro and ID /j.diagmicrobio

27 Should You Treat the Patient or Treat the Strain? Routine diagnostics laboratory tests do not provide strain type Routine tests not always reliable Always treat the patient based symptoms, history, risk factors and markers of severe disease

28 Symptoms of CDI Asymptomatic colonization Diarrhea mild  moderate  severe Abdominal pain and distension Fever Pseudomembranous colitis Toxic megacolon Perforated colon  sepsis  death

29 Markers of Severe Disease Leukocytosis –Prominent feature of severe disease –Rapidly elevating WBC –Up to >100 K >10 BM/day Albumin < 2.5 Creatinine 2x baseline Hypertension Pseudomembranous colitis Toxic megacolon Severe distension and abdominal pain

30 Laboratory Diagnosis of C. difficile Infection (CDI)

31 Which Test Should I Use? Considerations –Accuracy –Time to detection –Prevalence in your population Screening tests followed by confirmatory tests In a low prevalence population, a screening test with a high sensitivity is useful (no/few false negatives) –Cost –Ease of use At this time, there is no perfect test for the diagnosis of CDI

32 What Should I do First? Make some rules Rule 1: Accept only liquid stools or soft stools –Why? Any Exceptions? Rule 2: Limit repeat testing once a patient is positive –Why? Any exceptions

33 The Specimen Fresh is best (test within 2 hours) Liquid or loose, not solid If unable to test within 2 hours, refrigerate at 4°C for up to 3 days Freeze at -70°C (not -20°C) if testing will be delayed Specimen quality will influence test results In: Manual Clin Micro. 9th ed. 2007;p. 897.

34 Laboratory Diagnosis of CDI Laboratory Diagnosis Enzyme Immunoassay (EIA) Glutamate Dehydrogenase (GDH) Cell Culture Neutralization Assay (CCNA) Toxigenic Culture (Culture and CCNA) Molecular Based (PCR Or LAMP) Stool Culture

35 Conflicting Results with EIA 1.Stamper PD, et al. J Clin Microbiol. 2009;47: Musher DM, et al. J Clin Microbiol. 2007;45: Sloan LM, et al. J Clin Microbiol. 2008;46: Gilligan PH. J Clin Microbiol. 2008;46: Ticehurst JR. J Clin Microbiol. 2006;44: Nice review by Planche T, et al Recently Published EIA Papers (1-6) ParameterRange Sensitivity32 – 98.7% Specificity92 – 100% PPV76.4 – 96% NPV88 – 100%

36 EIA Testing Advantages Rapid Inexpensive Relatively easy No costly equipment Batch or single test formats Disadvantages Great variations in published sensitivity and specificity Technologist error Contamination

37 Two-Step Tests 1-3 Screening Tests Glutamate dehydrogenase (GDH) –Detects nearly all true positives as well as false positives –Low PPV –High sensitivity Very few false negatives –Works best in a low- prevalence population EIA: Is it accurate enough to use as a screening test? Confirmatory test? Confirmatory Tests CCNA –Add 1-2 days CX followed by CCNA –Add 3-4 days PCR –Possibility of false positives due to colonization 1.Gilligan PH. J Clin Microbiol. 2008;46: Ticehurst JR. J Clin Microbiol. 2006;44: Planche T, et al

38 Most Recent Studies Cdiff Quik Chek Complete (GDH and EIA on one test card) 1 –Both + = + –Both - = - –13.2% discrepant, re-test. Use PCR PCR had very high S,S, PPV and NPV 2 PCR resolved low false positive EIA 3 1.Quinn, C. D J Clin Microbiol. 48: Novak-Weekley, S. et al J. Clin Microbiol.doi: /JCM Brecher, S. et al ICAAC Abstract D-1422

39 Molecular-Based Assays Polymerase Chain Reaction (PCR) 3 FDA Approved test kits 2 of them are less expensive but more labor intensive 1 is easy enough to do that even I can do it, but is expensive I recently switched from an EIA to the expensive PCR –The cost of a misdiagnosed patient is too great, especially for our Veterans

40 Treatment

41 Treatment of Mild to Moderate Disease Stop antibiotic(s) if medically reasonable Metronidazole –Oral or IV, 500 mg TID for days is standard therapy –5–20% failure rate –20% relapse rate –Can use a full 2 nd course for failure/relapse but beyond 2 courses, switch to vancomycin –Failures not due to metronidazole resistance

42 Initial Treatment Options for CDI Historical response (96%) and relapse rates (20%) similar between metronidazole and vancomycin 1 More recently, efficacy of metronidazole for severe disease called into question 2-4 Recent prospective trials report vancomycin to be superior to metronidazole in severe CDI Aslam S, et al. Lancet Infect Dis. 2005;5: Fernandez A, et al. J Clin Gastroenterol. 2004;38: Gerding DN. Clin Infect Dis. 2005;40: Musher DM, et al. Clin Infect Dis. 2005;40: Lahue BJ, Davidson DM. The 17th ECCMID Meeting, March 31 to April 4, 2007; Munich, Germany. Abstract 1732_ Zar FA, et al. Clin Infect Dis 2007;45: Louie T, et al. The 47th Annual ICAAC Meeting, Sept , 2007; Chicago, IL. Abstract k-425-a.

43 Initial Treatment Options for CDI Metronidazole 250 mg QID or 500 mg TID May be administered PO or IV Development of resistance rare Historical first-line agent Vancomycin 125 mg QID Effective in enteral (oral or rectal) form only Typically reserved for severe disease, those failing to respond to metronidazole, or cases in which metronidazole is contraindicated IV=intravenously; PO=orally. Fekety R. Am J Gastroenterol. 1997;92: Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16: American Society of Health-System Pharmacists. Am J Health-Syst Pharm. 1998;55:

44 Metronidazole vs Vancomycin Zar et al 1 classified patients as mild or severe CDI In mild disease, vancomycin was slightly better than metronidazole (98% vs 90%) –Not statistically significant In severe disease, vancomycin was significantly better than metronidazole (97% cure vs 76% cure) 1. Zar FA, et al. CID. 2007;45:

45 Clinical Success by Disease Severity: Tolevamer Phase III Results Mild CDI 3–5 BM/day WBC ≤15,000/mm 3 Mild abdominal pain due to CDI Moderate CDI 6–9 BM/day WBC 15,001 to 20,000/mm 3 Moderate abdominal pain due to CDI Severe CDI ≥ 10 BM/day WBC ≥20,001/mm 3 ; Severe abdominal pain due to CDI Defining CDI Disease Severity Louie T, et al. The 47th Annual ICAAC Meeting, Sept , 2007; Chicago, IL. Abstract k-425-a. Any one of the 3 defining characteristics assigns a patient to the more severe category.

46 Metronidazole vs Vancomycin vs Tolevamer Patients stratified as mild, moderate, or severe Original goal of study was to evaluate tolevamer as a treatment for CDI Drug MildModerateSevere Tolevamer Metronidazole Vancomycin Louie et al. ICAAC AbstractK

47 C. difficile Infection: Case 3 79-year-old woman with multiple medical problems admitted to hospital for treatment of community-acquired pneumonia Responds slowly to levofloxacin 750 mg daily After 6 days –Develops diarrhea (9 loose BMs) –WBC count: 11,500/mm 3 Day 7–14 loose BMs, WBC count rises to 19,500/mm 3 Stool testing for C. difficile toxins A and B is requested Continued antibiotic therapy for pneumonia is deemed necessary How would you manage her care? A.Await stool test results and monitor her progress B.Empirically start metronidazole PO C.Empirically start metronidazole IV D.Empirically start vancomycin PO

48 C. difficile Infection: Case 3 79-year-old woman with multiple medical problems admitted to hospital for treatment of community-acquired pneumonia Responds slowly to levofloxacin 750 mg daily After 6 days –Develops diarrhea (9 loose BMs) –WBC count: 11,500/mm 3 Day 7–14 loose BMs, WBC count rises to 19,500/mm 3 Stool testing for C. difficile toxins A&B is requested Continued antibiotic therapy for pneumonia is deemed necessary How would you manage her care? A.Await stool test results and monitor her progress B.Empirically start metronidazole PO C.Empirically start metronidazole IV D.Empirically start vancomycin PO

49 Treatment of Severe Disease Follow definition of severe disease –>10 BM/day, high WBC, low albumin This is a life-threatening infection Surgical consultation recommended as patient may require a colectomy Oral vancomycin drug of choice –Dose varies based on severity –Can add metronidazole (oral or IV)

50 Management of Severe CDI Early recognition is critical –Initiate therapy as soon as diagnosis is suspected Manage as for mild CDI plus: –Oral vancomycin (125 mg QID for 10 to 14 days) as initial treatment If patient is unable to tolerate oral medication, consider intracolonic vancomycin instillation (by enema) –0.5–1 g vancomycin (IV formulation) in 0.1 to 0.5 L of normal saline via rectal (or Foley) catheter –Clamp for 60 minutes –Repeat every 4–12 hours Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16: Zar FA, et al. Clin Infect Dis. 2007;45: Louie T, et al. The 47th Annual ICAAC Meeting, Sept , 2007; Chicago, IL. Abstract k-425-a. Apisarnthanarak A, et al. Clin Infect Dis. 2002;35:

51 Potential role of intravenous immunoglobulin G (IVIG) 1-6 –Antitoxin A IgG predicts clinical outcome of CDI –Serum antibodies to toxins A and B are prevalent in healthy populations Recent studies in severe disease 5,6 –Well tolerated in small numbers of patients –Conflicting data regarding outcome improvement (mortality and need for colectomy) Often administered when surgery is considered imminent 1. Salcedo J, et al. Gut 1997;41: Beales ILP. Gut. 2002;51: Kyne L, et al. N Engl J Med. 2000;342: Kyne L, et al. Lancet. 2001;357: McPherson S, et al. Dis Colon Rectum. 2006;49: Juang P, et al. Am J Infect Control 2007;35: Management of Severe, Complicated CDI

52 Multiple Recurrent CDI Rates of recurrent CDI –20% after first episode 1 –45% after first recurrence 2 –65% after two or more recurrences 3 Metronidazole or vancomycin resistance after treatment not reported Repeated, prolonged courses of metronidazole not recommended (risk for peripheral neuropathy) Several empirical approaches have been advocated but most have no controlled data 1. Aslam S, et al. Lancet Infect Dis. 2005;5: McFarland LV, et al. Am J Gastroenterol. 2002:97: McFarland LV, et al. JAMA. 1994;271:

53 Treatment of Recurrent CDI First recurrence can be treated in the same way as a first episode according to disease severity 1 Metronidazole should not be used beyond first recurrence or for >14 days 2 –Concerns for hepatotoxicity and polyneuropathy Further recurrences can be treated with oral vancomycin taper and/or pulse dosing 2,3 1. Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16: McFarland LV, et al. Am J Gastroenterol 2002;97: Tedesco FJ, et al. Am J Gastroenterol. 1985;80:

54 Other Treatments * Patients who produce antibody to toxins A and B usually do well so IVIG has been tried. Probiotics Rifaximin Chasers Rifampin Nitazoximide IVIG*

55 Unproven Adjunctive Therapies for Recurrent CDI Probiotics Saccharomyces boulardii Lactobacillus GG May reduce the likelihood of further recurrences in some patients when added to and continued after treatment with metronidazole or vancomycin 1-3 RifampinEfficacy in one series (n=7) when added to vancomycin 4 NitazoxanideResponse demonstrated in patients (n=35) who failed prior metronidazole therapy 5 and similar response and recurrence rates when compared with metronidazole for initial therapy (n=110) 6 Rifaximin “chaser”Effective when used for 14 days after vancomycin therapy (n=8) 7 1. McFarland LV, et al. JAMA. 1994;271: McFarland LV. J Med Microbiol. 2005;54: Surawicz CM, et al. Clin Infect Dis. 2000;31: Buggy BP, et al. J Clin Gastroenterol. 1987;9: Musher DM, et al. J Antimicrob Chemother. 2007;59: Musher DM, et al. Clin Infect Dis. 2006;43: Johnson S, et al. Clin Infect Dis. 2007;44:

56 Saccharomyces boulardii for CDI Prevention* 1. McFarland. JAMA. 1994;271: Surawicz et al. Clin Infect Dis. 2000;31: P=0.04 *Metronidazole or vancomycin for 10–14 days plus placebo or S. boulardii 1 g daily × 4 weeks. Recurrent CDI S. boulardii

57 Recurrent CDI: Rifaximin Chaser Eight women with multiple recurrences –Rifaximin 400 mg BID for 2 weeks immediately after completing last course of vancomycin –Seven of eight patients had no further diarrhea recurrence –Single case of rifaximin resistance (identified after therapy) with recurrent CDI after a second course of rifaxmin Effective in interrupting recurrent episodes but resistance may become an issue Johnson S, et al. Clin Infect Dis. 2007;44:

58 Rationale: restoration of bacterial homeostasis Preparation of donor specimen –Fresh (<6 hours) –~30 g or ~2 cm 3 volume –Add 50 mL 0.9% normal saline, and homogenize with blender –Filter suspension twice with paper coffee filter Delivered by nasogastric tube following vancomycin Results –1 of 16 survivors had a single subsequent recurrence Recurrent CDI: Fecal Transplantation Aas J, et al. Clin Infect Dis. 2003;36:

59 Infection Control Wash hands with warm soap and water –Mechanical removal of spores –Alcohol does not kill spores –Stool is pre-treated with alcohol when growing C. difficile Contact and barrier precautions Private room Antibiotic stewardship

60 Efficacy of Hand Hygiene Methods for Removal of C. difficile Contamination from Hands CFU = colony forming units * Different from AHR (P<0.05). ** Different from AHR and AHW (P<0.05) * WWS = warm water and soap CWS = cold water and soap WWA = warm water and antibacterial AHW = alcohol hand wipe AHR = alcohol hand rub Decrease in colony counts compared with no wash Hand hygiene method Decrease in colony counts (log CFU/mL) WWSCWSWWAAH W AHR ** * Oughton M, et al. The 47th Annual ICAAC Meeting, 2007.

61 Alcohol Gels and Hand Hygiene Alcohol-based gels appear to be less able to remove C. difficile spores However, in general they: –Provide an excellent method of hand hygiene effective against many common nosocomial pathogens –Are convenient thereby increasing compliance –Have not been implicated in CDI outbreaks In the setting of a CDI outbreak or increased rates, visitors and healthcare workers should wash hands with soap and water after caring for patients with C. difficile CDC. Fact Sheet, August 2004 (updated 7/22/05). Oughton M, et al. The 47th Annual ICAAC Meeting, Sept , 2007; Chicago, IL.

62 Isolation and Barrier Precautions Patients with CDI and incontinence should be in private rooms or cohorted if private rooms are not available Contact precautions and isolation –Gloves and gowns required for direct contact and contact with environment –Discontinuation of isolation when diarrhea resolves Dedicated equipment when possible CDC Guideline for Isolation Precautions, Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16: Simor AE, et al. Infect Control Hosp Epidemiol. 2002;23:

63 Environmental Disinfection Removal/thorough cleaning of environmental sources can decrease incidence Use chlorine-containing agents (at least 5000 ppm available chlorine 10 minutes contact time) for environmental contamination, especially in outbreak areas Fogging Poutanen SM, Simor AE. Can Med Assoc J. 2004;171: CDC. Fact Sheet, July McMullen KM, et al. Infect Control Hosp Epidemiol. 2007;28: Mayfield JL, et al. Clin Infect Dis. 2000;31: Fawley WN, et al. Infect Control Hosp Epidemiol. 2007;28:

64 Antimicrobial Use Restrictions Practice antimicrobial stewardship Decrease duration of exposure and number of antimicrobial agents Best evidence for controlling C. difficile demonstrated with restriction of cephalosporin or clindamycin Recent reports of fluoroquinolone restriction helping to control outbreaks McNulty C, et al. J Antimicrob Chemother. 1997;40: Pear SM, et al. Ann Intern Med. 1994;120: Climo MW, et al. Ann Intern Med. 1998;128: Kallen AJ, et al. Infect Control Hosp Epidemiol. 2009;30:

65 Summary CDI is increasing in incidence, severity and poor outcomes Laboratory diagnosis is challenging –Carefully evaluate what works best in your setting No reasonable explanation for treatment failures Community based infections are not well understood Improved therapies are needed Extremely important to accurately detect and aggressively treat severe disease

66 q p Y Chromosome Testis Determining Factor (TDF) Gadgetry (MAC- locus) Channel Flipping (FLP) Catching and Throwing (BLZ-1) Self-confidence (BLZ-2) (note: unlinked to ability) Ability to remember and tell jokes (GOT-1) Sports Page (BUD-E) Addiction to death & destruction movies (MOV-E) Air Guitar (RIF) Ability to identify aircraft (DC10) Pre-adolescent fascination with Arachnid and Reptilia (MOM-4U) Spitting (P2E) Sitting on the john reading (SIT) Inability to express emotion over the phone (ME-2) Selective hearing loss (HUH?) Total lack of recall for dates (OOPS) Gitschier, J., Science, 1993 (261) p. 679

67 Thank you


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