The origins and functional effects of postzygotic mutations throughout the human life span.

Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remain unclear. To study the origins and functional consequences of PZMs, we generated a multitissue atlas of PZMs spanning 54 tissue and cell types from 948 donors. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, and 9% can be attributed to donor-specific effects.

Cancer-associated POT1 mutations lead to telomere elongation without induction of a DNA damage response.

Mutations in the shelterin protein POT1 are associated with chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, angiosarcoma, melanoma, and other cancers. These cancer-associated POT1 (caPOT1) mutations are generally heterozygous, missense, or nonsense mutations occurring throughout the POT1 reading frame. Cancers with caPOT1 mutations have elongated telomeres and show increased genomic instability, but which of the two phenotypes promotes tumorigenesis is unclear.

When Doctors Disagree: A Case-Based Discussion of Pro-Active Ethics.

This article addresses a common yet rarely discussed aspect of hospital care-a pro-active approach to ethical dilemmas. Potential ethical conflicts often present warning signs to clinicians, analogous to the warning lights on a car's dashboard. Using a recent case study, a commonly encountered clinical decision-a conflict about whether to terminally extubate a critically ill patient versus whether to offer a tracheostomy-we describe a pro-active approach to ethical conflicts and outline three learning objectives: (1) the need for a robust understanding of the term "futility," (2) the need for an appreciation the various and often conflicting interpretations of "improved/improving," and (3) the need to understand the challenges of surrogate decision making.