1. GEORGE D. COMERCI, JR., MD,FACP, DAAPM PROFESSOR OF INTERNAL MEDICINE CO-DIRECTOR: PROJECT ECHO PAIN HEADACHE CLINIC, UNM PAIN CONSULTATION AND TREATMENT CENTER Update in Outpatient Internal Medicine for the Outpatientalist: 2013

2. Financial Disclosures NONE

3. What to expect…. Discussion of New Studies pertinent to the internist Update on New Disease Prevention Recommendations New Drugs, New uses for old drugs, News about drugs

4. Objectives Describe the clinical features of the H7N9 flu Discuss the relationship of statins to diabetes Discuss the emerging knowledge of the relationship of the human microbiome to disease Describe the possible relationship of exercise on dementia prevention Discuss the importance of mammographic breast density as this relates to mammography frequency Describe the indications for the PCV-13 vaccine Discuss new information about drugs

5. Clinical Findings in 111 Cases of Influenza A H7N9 [N Engl J Med.2013.368:2277-85] Novel avian-origin influenza virus appeared in China Data on 111 cases evaluated H7N9 virus identified by RT-PCR assay Clinical FindingsLab Findings Pneumonia: 97.3 %lymphopenia ARDS: 71.2%Inc. CK and AST Shock: 26.1% Death: 27%

7. Origin of the Novel Avian Influenza A H7N9 Virus. Morens DM et al. N Engl J Med 2013;368:2345-2348.

8. 3 factors a pandemic make…. A substantial portion of the population should not be immune The virus should be capable of causing human disease Efficient human-human transmission*

9. Human Microbial Biosphere (Microbiota) The microbiota represents the communities of microorganisms that resides within (and on) us 10 times more microbial cells than human cells The microbiome is the genetic content of the microbial communities and is far more complex than the human genetic content Our symbiotic relationship to our microbial biosphere is usually commensal or of mutual benefit, but occasionally the relationship is pathologic We Are One with our Microbiota!

10. The Human Microbiome [Nutr Clin Pract.2012;27:201-214] The Microbiome is studied via gene sequencing techniques not by culture techniques The Microbiome is most similar in twins, differing some degree within family members and further differing amongst unrelated family members Infant gut microbiota resembles that of an adult by three years of age The microbiota is dramatically influenced by environment, foods, antibiotics, etc.

11. Microbiota of different body surfaces [Harrisons Principles of Internal Medicine.18 th ed. 2012]

12. Pharacometabonomic identification of a significant host- microbiome metabolic interaction affecting human drug metabolism [PNAS.106.2009] Can a host’s metabolic phenotype (their microbiota) influence drug metabolism?  Acetaminophen Acet Sulfate Acet Glucuronide Acet N Acetylcysteine  P-cresol is produced by certain gut microbes and competes for sulfation with acetaminophen  Patients who were high producers of p-cresol had reduced sulfation and reduced metabolism of acetaminophen

13. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. [Nature.2013;499:99-103] Senescent cells develop a secretory profile consisting of inflammatory cytokines, chemokines and proteases (senescence associated secretory profile-SASP)  Some of these SASP promote cell clearance but others promote tumorigensis Dietary changes that promote obesity change the gut of mice microbiota in such a way that production of deoxycholic acid (DCA) was increased which in turn increased SASP phenotype in hepatic cells favored tumorigensis and increased HCC This effect was reduced by administration of vancomycin which reduced DCA production

14. Energy-balance studies reveal associations between gut microbes, caloric load and nutrient absorption in humans. [AmJClinNutr.2011;94:58-65.] Indigestible carbohydrates and proteins account for 10-30% of total ingested energy The ability to “harvest” this energy is highly dependent upon the gut microbiota The microbiota of obese individuals is different than that of lean individuals. This study showed that a high caloric diet (3400 kcal/d) increased Firmicutes sp. and decreased Bacteriodetes sp. resulting in a net increased caloric absorption of 150Kcal/d

15. Duodenal Infusion of Donor Feces for Recurrent Clostridium dificile. [N Engl J Med.2013;368:407-414.] Question: Is duodenal infusion of donor feces effective for the treatment of recurrent Clostridium dificile infection. Methods: 43 patient who had failed a course of vancomycin for C dif colitis  17 received vancomycin 500qid x 4 D and subsequent colon lavage followed by infusion of donor feces  13 received vancomycin 500 qid x 14 D with bowel lavage  13 received vancomycin 500 qid x 14 D

16. Rates of Cure without Relapse for Recurrent Clostridium difficile Infection. van Nood E et al. N Engl J Med 2013;368:407-415

17. Microbiota Diversity in Patients before and after Infusion of Donor Feces, as Compared with Diversity in Healthy Donors. van Nood E et al. N Engl J Med 2013;368:407-415

18. We (our genome) and the microbiome are One! Variations in gut microbiome are affected by our immediate surroundings, our diet and drugs. Variations in gut microbiome can affect drug metabolism Variations in the gut microbiome may increase the risk of certain cancers Re-establishment of a damaged gut microbiome can eliminate disease

19. Meta-Analysis of Impact of Different Types and Doses of Statins on New-Onset Diabetes Mellitus [Am J Cardiol2013;111:1123e1130] Question: What is the specific the specific risk for developing DM associated with one statin compared with another and is there a relationship to dosage and DM Methods: Meta-analysis of RCTs between 1994-2012 Studies need have >1000 patients who were followed for > 1 year Endpoints New onset DM

20. Meta-Analysis of Impact of Different Types and Doses of Statins on New-Onset Diabetes Mellitus [Am J Cardiol2013;111:1123e1130] Results: 17 studies: 14 compared statin to placebo 3 compared high dose vs. moderate dose statin 11,3394 patients represented Rosuvastatin 20 mg/day: 25% relative increase in the risk for developing new-onset DM. Pravastatin 40 mg/day: lowest risk for DM, almost comparable with placebo treatment. Simvastatin 40 mg/day: approx. = Rosuvastatin 20 mg/day.

23. 1 case of diabetes for every 4 cardiovascular events prevented. [Circ.2012.126;e282-284]

24. The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia: A Cohort Study [Ann Intern Med. 2013;158(3):162-168] Question: Is there an association between midlife fitness and all cause dementia? Methods: Study Center: Cooper Center Longitudinal Study Study Cohort: 19,458 persons who had an exercise treadmill test between 1999-2009 Exclusion Criteria: MI, stroke, chronic illness leading to disability, age>65. Fitness Level: quintiles according to METs on ETT

25. The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia: A Cohort Study [Ann Intern Med. 2013;158(3):162-168] Methods (cont.)  Quintile 1: 8.1 METS  Quintile 2: 9.4 METS  Quintile 3: 10.4 METS  Quintile 4: 11.3 METS  Quintile 5: 13.3 METS Assessment at ages 70, 75, 80 and 85 years Dementia identified ICD-9 codes (primarily for Alzheimer- type dementia but also for vascular dementia)

26. The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia: A Cohort Study [Ann Intern Med. 2013;158(3):162-168] Results: Mean follow-up: 24 years Hazard ratio: Quintile 5 compared to Quintile 1= 0.64 No significant effect of educational level (mean =15 yr.) No significant difference in those with or without a history of stroke

27. Date of download: 10/8/2013 Copyright © The American College of Physicians. All rights reserved. From: The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia: A Cohort Study Ann Intern Med. 2013;158(3):162-168. doi:10.7326/0003-4819-158-3-201302050-00005 Dementia-free survival, according to midlife fitness level. Figure Legend:

28. Chronic Opioid Use is associated with increased DNA Methylation correlating with increased clinical pain. [ Pain.2013;154.15-23] Does chronic opioid therapy have pharmacoepigenetic effects which result in decreased opioid responsiveness?  The pain response to opioids varies amongst patients  Most patients develop tolerance to opioids  Some develop hyperalgesia with opioids

29. Chronic Opioid Use is associated with increased DNA Methylation correlating with increased clinical pain. [Pain.2013;154.15-23] Methods Cohort 1:Addicts on methadone Cohort 2:Matched controls Cohort 3:Pain patients on 115.8 MEDs Cohort 4:Pain patients on no opioids Quantitative Analysis: OPRM 1 (Mu receptor gene) LINE 1 (transposone on mu receptor gene)

31. The Transposon

32. DNA Methylation

33. Comparison of global methylation and pain scores

34. Prevention

35. PCV13 Pneumococcal Conjugate Vaccine  The “classic” vaccine (PPV23) is a 23 valent vaccine  In use since 1983  No anamnestic response, ergo, immunity wanes  PCV 13 is a conjugate made of a protein + a polysaccharide capsular antigen  Large scale clinical trial data not yet available

37. Date of download: 10/1/2013 Copyright © 2012 American Medical Association. All rights reserved. From: Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine for Adults With Immunocompromising Conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP) JAMA. 2013;309(4):334-336. doi:10.1001/jama.2012.31377 Figure Legend :

38. Breast Cancer Screening JT is a 56 y/o female who presents for her yearly health exam. She has visited the Are You Dense website, wants to know her breast density “score” on her recent mammogram. She disagrees with your recommendation to have mammograms every 2 years and, furthermore, wants an MRI if her breasts are dense.  Is breast density a risk for breast cancer?  Does she need yearly mammograms if she has dense breasts?  Should she have an MRI if her breasts are dense?

39. Breast Cancer Screening  Breast “density” correlates with the degree of fat replacement of breast tissue  Women with mammographically dense breast have a higher risk of invasive breast cancer  Are You Dense, a breast advocacy group, has pushed for laws mandating that women be informed of the degree of density of their breast on mammography and have more aggressive screening if their breasts are dense on mammography [J Natl Cancer Inst;2013;105:1043–1049]

40. Outcomes of Screening Mammography by Frequency, Breast Density, and Postmenopausal Hormone Therapy [ JAMA Intern Med. 2013;173(9):807-816.] Purpose:  To compare the benefits and harms of screening mammography frequencies according to age, breast density, and postmenopausal hormone therapy (HT) use. Prospective study from data from the Breast Cancer Surveillance Consortium (BCSC) mammography registries Data collected January 1994 to December 2008 11,474 women with breast cancer and 922,624 without breast cancer

41. Outcomes of Screening Mammography by Frequency, Breast Density, and Postmenopausal Hormone Therapy [ JAMA Intern Med. 2013;173(9):807-816.]  Women aged 40 to 49 years:  biennial mammography vs. annual is associated with increased risk of advanced-stage cancer (odds ratio [OR], 1.89 and large tumors (OR, 2.39).  Women age 50 to 74 years:  biennial mammography was not associated with increased risk of less favorable tumor characteristics regardless of breast density or HT usage.  Triennial mammography WAS associated with higher grade lesions only in women with extremely dense breasts

42. New Drugs, New uses of Old Drugs, News about Old Drugs

43. Zolpidem  220% increase in ER visits due to toxicity (2005-2010) [JAMA.2013;309:2203]  Impaired driving, especially women and elderly  Women: 5mg IR/ 6.25 mg XR  Elderly: [JAMA.2013 ;309:646]  Increased risk of Hip Fracture in Elderly  OR = 1.66 for hip fracture in nursing home residents [JAMA Intern Med. 2013 May 13;173(9):754-61.] [

44. Fake and Substandard Drugs  “falsified drug” misrepresents identify, source or both  “substandard drug”: fails to meet accepted standards of manufacturing  production packaging distribution JAMA.2013.309.1693-1694

45. Fake and Substandard Drugs  Supplements  Life style drugs  sildenafil  Antimicrobials  TB medications  Malaria medications  HIV medication Bull World Health Organ 2010;88: 247–248

49. Codeine A natural derivative of Opium A weak analgesic nearly on the bottom of the WHO pain ladder Converted to morphine by cytochrome P-450 enzyme 2 D6 (CYP2DR) CYP2DR activity exists as a spectrum of activity [slow metabolizers high metabolizers] 15% of Middle Eastern and Northern African patients are high metabolizers Clin Pharm & Therap.2012; 91:323-326 N. Engl. J. Med.2009; 361, 827–828 (2009).

51. Fluoroquinolones  Severe neuropathy  Usually during treatment  Potentially irreversible  Severe fluctuations in glucose levels http://1.usa.gov/17QhZK3

52. In summary…. The H7N9 influenza The increased risk of DM with rosuvastatin and simvastatin The complex role of the human microbiome in disease and metabolism The role of exercise in dementia prevention DNA methylation with chronic opioid usage Breast cancer screening and breast density PCV-13 vaccine Updates on Zolpidem, Codeine and Fake drugs

53. Thank You!