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January 5, 2017 Vol. 376 No. 1

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Perspective

1-3

The End of Obamacare

J. Oberlander

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Health care reform in the United States is headed backward. It is uncertain which parts of the Affordable Care Act will survive past 2017 and what will follow it. What is certain is that Obamacare as we know it will end.

4-7

Oligonucleotide Therapeutics — A New Class of Cholesterol-Lowering Drugs

A. Khvorova

Another drug class may soon be added to cholesterol-lowering strategies: a chemically modified, small interfering RNA conjugated to the trivalent N-acetylgalactosamine. The siRNAs are oligonucleotide therapeutics, which destroy RNA before a protein is synthesized.

7-9

A View from the Edge — Creating a Culture of Caring

R.L.A. Awdish

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When a pregnant physician winds up in her own hospital with a ruptured occult adenoma of the liver and barely survives, she learns that though medical professionals do so many difficult, technical things so perfectly right, they fail their patients in many ways.

Original Articles

11-20

Epidemiology of Acute Kidney Injury in Critically Ill Children and Young Adults

A. Kaddourah, R.K. Basu, S.M. Bagshaw, and S.L. Goldstein

Comments

Most children with serious acute illness do not have underlying chronic conditions. This prospective study involving patients in pediatric intensive care units showed that acute kidney injury is common and is associated with poor outcomes, including increased mortality.

21-31

Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation

J.E. Posey and Others

Of over 7000 patients referred to a diagnostic laboratory, 28% had diagnoses based on DNA sequencing, 5% of whom had two or more diagnoses. Their phenotypes could be better understood by considering whether the implicated genes affect independent biologic processes or organ systems.

32-40

Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease

W.R. Hiatt and Others

In this randomized trial involving 13,885 patients with symptomatic peripheral artery disease (PAD), ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates with ticagrelor and clopidogrel.

41-51

A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

K. Fitzgerald and Others

CME
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In a phase 1 trial, healthy volunteers were assigned to an RNAi therapeutic inhibitor of PCSK9 or placebo. Single doses of 300 mg or more reduced LDL cholesterol by up to 50%; multiple-dose regimens reduced LDL cholesterol by up to 59%. No serious adverse events were reported.

Review Articles

52-60

The Changing Face of Clinical Trials: The Large Pharmaceutical Company Perspective

M. Rosenblatt

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The former chief medical officer of a large pharmaceutical company addresses the issue of complexity and how it affects the performance of clinical trials.

61-72

Arrhythmogenic Right Ventricular Cardiomyopathy

D. Corrado, M.S. Link, and H. Calkins

Arrhythmogenic right ventricular cardiomyopathy is a heritable heart-muscle disorder that causes progressive replacement of right ventricular myocardium by fibrofatty tissue. Mutations in genes encoding desmosomal proteins play a key role in the pathogenesis of the disease.

Images in Clinical Medicine

Gastric Cancer in Chest Radiograph

J.L. Polo and J.C. Porres

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A 90-year-old man presented with progressive edema in both legs and malaise and dizziness associated with hypoglycemia. On examination, a nontender epigastric mass was palpated. A chest radiograph showed a round, irregular opacity inside the gastric chamber.

Acromioclavicular Joint Separation

M.E. Kayaalp and A. Seker

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A 30-year-old man presented after a recent fall that had resulted from a loss of balance while he was walking. On examination, his vital signs were normal, but a palpable posterior fullness with swelling was seen over his left shoulder.

Clinical Problem-Solving

74-80

After the Party’s Over

J.N. George, J.M. Morton, N.W. Liles, and C.M. Nester

While driving home from a party, a 35-year-old previously healthy woman had a sudden onset of chills, myalgias, nausea, and abdominal cramping. That night fever, explosive nonbloody diarrhea, frequent vomiting, and abdominal and low back pain developed.

Editorials

82-83

Acute Kidney Injury in Critically Ill Children — An Ominous Legacy

J.R. Ingelfinger

Children are generally healthy. As we age, however, the chance of having ailments that affect our overall health increases. Recent data from the Centers for Disease Control and Prevention indicate that only 1.3% of children younger than 6 years of age and ...

83-85

When One Diagnosis Is Not Enough

K.M. Boycott and A.M. Innes

An accurate diagnosis is essential for effective medical management; in the case of rare genetic disease, it also guides genetic counseling. Nevertheless, clinical assessments and conventional genetic testing lead to a diagnosis in less than half of ...

Clinical Implications of Basic Research

86-88

Targeting Therapeutic Oligonucleotides

A.A. Levin

Two recent studies test whether oligonucleotide drugs that are tailored to target different cell types — the hepatocyte and the myocyte and cardiomyocyte — actually target those cell types.

Correspondence

89-92

ICD Implantation in Patients with Nonischemic Heart Failure

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To the Editor: The findings of the Danish Study to Assess the Efficacy of ICDs [Implantable Cardioverter–Defibrillators] in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) (Sept. 29 issue)¹ are important and raise doubts about the ...

93-95

Breast-Cancer Tumor Size and Screening Effectiveness

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To the Editor: Welch et al. (Oct. 13 issue)¹ report that after the introduction of screening mammography in the United States in the early 1980s, the ratio of small breast tumors to large tumors increased dramatically primarily because of overdiagnosis. ...

95-97

Limits to Precision Cancer Medicine

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To the Editor: In their Sounding Board article on personalized medicine, Tannock and Hickman (Sept. 29 issue)¹ make constructive contributions toward a possible midcourse correction. Precision medicine is based on targeting a validated and genetically ...

97-98

Implantation of an Artificial Larynx after Total Laryngectomy

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Organ loss due to late-stage cancer is a heavy burden on both the patient and the health care system. This letter describes a patient who received an artificial larynx to replace lost laryngeal functions and who underwent 16 months of follow-up.

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