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July 7, 2015 Issue

Clinical Practice Points

Medical Knowledge

Small Brain Lesions and Incident Stroke and Mortality. A Cohort Study

Cerebral lesions that are 3 mm or larger on imaging are associated with incident stroke, but smaller lesions are typically considered clinically insignificant. This cohort study of a biracial population found that the presence of lesions smaller than 3 mm, lesions 3 mm or larger, and white matter hyperintensities may all confer a heightened risk for incident stroke and mortality.

Use this study to:

  • Review with your learners how a cohort study works. Ask what the “exposure” was in this cohort. What were the outcomes of interest, and how were they ascertained? How might the definitions used for the exposure and outcomes affect the study's results?
  • Ask your learners what the limitations of the study are. Why might it be important that one quarter of the cohort's participants declined to have baseline magnetic resonance studies?
  • Plan a visit with your team to the neuroradiology reading room. Ask a neuroradiologist to review basic neuroanatomy with your team, as well as examples of imaging from patients with hemorrhagic and nonhemorrhagic stokes. Ask what T1- and T2-weighted images demonstrate. What is white matter hyperintensity? Can the neuroradiologist show examples of “subclinical” lesions smaller than 3 mm?
  • Ask if you should do anything differently for patients with the types of subclinical lesions studied here. What further studies are required before these research findings should alter clinical practice?

Medical Knowledge
Patient Care
Systems-based Practice

Optimal Timing of Antiretroviral Therapy Initiation for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis. A Systematic Review and Meta-analysis

Global Tuberculosis Control: Toward the 2015 Targets and Beyond

This systematic review found that early initiation of ART improves survival of patients with tuberculosis and HIV infection with CD4+ T-cell counts less than 0.050 × 109 cells/L, but evidence is insufficient when the counts are lower. Another paper reviews the successes and persistent challenges in the global fight to control tuberculosis. The authors note that despite substantial gains, tuberculosis remains a major threat to health around the world and that its control must be seen as both a public health imperative and a vital component of economic development plans.

Use these papers to:

  • Start a teaching session with a multiple-choice question. We've provided one below.
  • Ask your learners what the “immune reconstitution syndrome” is and why there has been concern regarding when to initiate ART for HIV in patients diagnosed with tuberculosis. What other problems might simultaneous ART and anti-TB therapies pose? What drug–drug interactions need to be considered? Will adherence be a problem?
  • Review how to treat TB in HIV-infected patients. Use the information in ACP Smart Medicine's HIV Disease and Tuberculosis.
  • Review why the “risk of bias” assessment in a systematic review is important. How does it shape how we should consider the results? Look at Figure 2 in the systematic review of ART in patients with TB. Ask your learners to define each of the potential biases listed (allocation concealment, selective reporting, etc.) and how their presence could affect the results.
  • Discuss the challenges to controlling drug-resistant TB.

Medical Knowledge
Systems-based Practice

Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia. A Systematic Review and Meta-analysis

PCSK9 is an enzyme involved in the degradation of low-density lipoprotein (LDL) receptors, and drugs inhibiting its function are being reviewed by the FDA for the treatment of hypercholesterolemia. This meta-analysis of phase 2 and phase 3 trials in adults with hypercholesterolemia found that PCSK9 inhibitors produced profound reductions in LDL cholesterol and lipoprotein(a); caused few serious adverse events; and, although data were sparse, seemingly reduced myocardial infarction rates and all-cause mortality.

Use this paper to:

  • Review current therapies for hypercholesterolemia.
  • Review lipid metabolism, noting where PCSK9 functions and how its inhibition might be expected to affect LDL levels.
  • Invite a colleague who has expertise in clinical trials to review with your learners the process of testing and obtaining approval for a new drug. Review what each of the phases of drug trials assesses (e.g., phase 2, 3).

Medicine and Public Issues

Patient Care
Interpersonal / Communication Skills
Systems-based Practice

Electronic Cigarettes: Aggregate Harm

Electronic Cigarettes: Perhaps the Devil Unknown Is Better Than the Devil Known

Electronic cigarettes (e-cigarettes) have been promoted as a means to reduce the use of combustible cigarettes. Whether e-cigarettes should be viewed as potentially beneficial or only as a new form of cigarette-related harm is controversial. These pro/con commentaries argue whether the potential to reduce the risk posed by combustible cigarettes is outweighed by the uncertainties regarding e-cigarettes and their potential to be a “gateway” drug for youth to become addicted.

Use these commentaries to:

  • Assign the members of your team to present one or the other arguments put forth in these papers. Make a list of the pros and cons of e-cigarettes.
  • Ask your learners if they would recommend e-cigarettes to their patients who smoke. Why or why not?
  • Review available pharmacologic and behavioral options to assist in smoking cessation. Use the information in ACP Smart Medicine: Smoking Cessation or In the Clinic: Smoking Cessation.

In the Clinic

Medical Knowledge
Patient Care
High Value Care

Gastroesophageal Reflux Disease

This eminently practical review is structured to answer key questions in the care of patients with GERD, including diagnosis and treatment.

Use this review to:

  • Ask your learners to generate a differential diagnosis for patients with symptoms consistent with GERD.
  • Ask which patients require endoscopy. Ask what the long-term effects are of acid suppression therapy.
  • Use the multiple-choice questions at the end to break up and introduce new discussion topics during a teaching session. Log on afterward and enter your answers to earn CME for yourself!
  • Download the prepared teaching slides to use in your teaching.

Humanism and Professionalism

Interpersonal / Communication Skills

Annals Graphic Medicine: One in a Million

Annals Graphic Medicine

On Being a Doctor: Letters

This graphic narrative is written by a young physician who watches as his childhood friend is affected by amyotrophic lateral sclerosis. The essay is written by a clinician who, having practiced over 35 years, has taken to writing letters to the families of his patients who have died.

Use these stories to:

  • Ask if friends or family have had serious illnesses before and since your learners became physicians. Is the experience different once one becomes a physician?
  • Do we feel “guilty” when we cannot stop disease from affecting a loved one? How is the experience different from taking care of our patients?
  • Play an audio recording of the On Being a Doctor essay, read by Dr. Michael Lacombe.
  • Ask your learners what they do in “follow-up” to a patient's death. Have they attended the funeral? Have they stayed in touch with the family? Have they written letters? Has it helped them or the patients' families? What do they think they should do?


A 33-year-old man is evaluated after learning that a person living in his home was recently found to have active tuberculosis. The patient has no acute symptoms. He was recently diagnosed with HIV infection, and his CD4 cell count is 250/µL. He is a U.S. citizen and has no history of incarceration, homelessness, or travel to areas with an increased prevalence of tuberculosis. He takes no medications but had been planning to begin antiretroviral therapy at his next office visit.

On physical examination, vital signs are normal. The remainder of the examination, including cardiopulmonary findings, is normal.

A tuberculin skin test induces 0 mm of induration. A chest radiograph is normal.

Which of the following is the most appropriate next step in the management of this patient?

A. Begin isoniazid and pyridoxine
B. Begin isoniazid, rifampin, pyrazinamide, pyridoxine, and ethambutol
C. Begin rifampin and pyrazinamide
D. No additional evaluation or therapy is needed

Correct Answer
A. Begin isoniazid and pyridoxine

Key Point
Regardless of their response to a tuberculin skin test or interferon-γ release assay, patients with HIV infection who have had a known recent exposure to a close contact with active tuberculosis should receive treatment for latent tuberculosis infection after active disease has been excluded.

Educational Objective
Manage an immunocompromised patient who has been exposed to a close contact with active tuberculosis.

Isoniazid and pyridoxine should be started for treatment of latent tuberculosis infection (LTBI). This patient has HIV infection and was recently exposed to a close contact with active tuberculosis. Patients with HIV infection or other serious immunocompromising conditions who are close contacts of persons with active tuberculosis should be treated for LTBI regardless of the results of a tuberculin skin test or interferon-γ release assay (IGRA) once active disease has been excluded. This patient is asymptomatic and has a normal chest radiograph, which exclude active disease. Patients with LTBI are typically treated with a 9-month regimen of isoniazid. Pyridoxine may also be given to certain patients at risk for developing peripheral neuropathy secondary to isoniazid. These include patients with HIV infection, diabetes mellitus, uremia, alcoholism, malnutrition, and seizure disorders, as well as pregnant women. In this patient, the tuberculin skin test or IGRA should be repeated 8 to 10 weeks after the most recent exposure. If results are still negative, isoniazid and pyridoxine can be discontinued. However, some experts recommend a complete course of treatment for LTBI in patients with HIV infection, who may not be able to mount a positive tuberculin skin test or IGRA response because of anergy.

Isoniazid, rifampin, pyrazinamide, pyridoxine, and ethambutol are used to treat active tuberculosis. This patient is asymptomatic and has a normal chest radiograph, making active disease highly unlikely.

The use of rifampin and pyrazinamide for treatment of LTBI is not recommended by the Centers for Disease Control and Prevention and the American Thoracic Society because of associated hepatic toxicity, which results in increased rates of hospitalization and death.

This patient with HIV infection and a recent exposure to a close contact with active tuberculosis requires treatment for latent tuberculosis infection, regardless of the results of a tuberculin skin test or IGRA; providing no further evaluation or treatment would not be appropriate.

National Tuberculosis Controllers Association; Centers for Disease Control and Prevention (CDC). Guidelines for the investigation of contacts of persons with infectious tuberculosis: Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep. 2005;54(RR-15):1-47. PMID: 16357823

This question was derived from MKSAP® 16, the latest edition of the Medical Knowledge Self-Assessment Program.

From the Editors of Annals of Internal Medicine and Education Guest Editor, Gretchen Diemer, MD, FACP, Program Director in Internal Medicine, Thomas Jefferson University.


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