Shift work in nurses: contribution of phenotypes and genotypes to adaptation.

BACKGROUND: Daily cycles of sleep/wake, hormones, and physiological processes are often misaligned with behavioral patterns during shift work, leading to an increased risk of developing cardiovascular/metabolic/gastrointestinal disorders, some types of cancer, and mental disorders including depression and anxiety. It is unclear how sleep timing, chronotype, and circadian clock gene variation contribute to adaptation to shift work. METHODS: Newly defined sleep strategies, chronotype, and genotype for polymorphisms in circadian clock genes were assessed in 388 hospital day- and night-shift nurses. RESULTS: Night-shift nurses who used sleep deprivation as a means to switch to and from diurnal sleep on work days (∼25%) were the most poorly adapted to their work schedule. Chronotype also influenced efficacy of adaptation. In addition, polymorphisms in CLOCK, NPAS2, PER2, and PER3 were significantly associated with outcomes such as alcohol/caffeine consumption and sleepiness, as well as sleep phase, inertia and duration in both single- and multi-locus models. Many of these results were specific to shift type suggesting an interaction between genotype and environment (in this case, shift work). CONCLUSIONS: Sleep strategy, chronotype, and genotype contribute to the adaptation of the circadian system to an environment that switches frequently and/or irregularly between different schedules of the light-dark cycle and social/workplace time. This study of shift work nurses illustrates how an environmental "stress" to the temporal organization of physiology and metabolism can have behavioral and health-related consequences. Because nurses are a key component of health care, these findings could have important implications for health-care policy.

An unofficial legislative history of the Biologics Price Competition and Innovation Act of 2009.

In March 2010, Congress passed the Biologics Price Competition and Innovation Act of 2009 (BPCIA). This law established a statutory pathway for approval of "biosimilars," follow-on versions of innovative biological products. This article traces the history of the BPCIA, beginning with a discussion of the origins of federal regulation of drugs and biologics, including passage of the Hatch-Waxman amendments, in Section I. Section I also describes the development of the European approval framework for biosimilars in the mid-2000s and how this increased interest in creation of a pathway in the United States. The article then provides, in Section II, an overview of early stakeholder discussions in the United States regarding legal and scientific issues relating to biosimilars, spanning the years 1998-2006. The legislative debate began in earnest in late 2006, when the first biosimilars bill was introduced. Section III of the article examines introduced bills, other legislative proposals, and related stakeholder discussion in detail, leading up to enactment of the BPCIA. Section IV describes the BPCIA as enacted, and the paper ends with the authors' concluding observations about the legislative negotiations and their implications for interpretation of the Act.

Genetic differences in human circadian clock genes among worldwide populations.

The daily biological clock regulates the timing of sleep and physiological processes that are of fundamental importance to human health, performance, and well-being. Environmental parameters of relevance to biological clocks include (1) daily fluctuations in light intensity and temperature, and (2) seasonal changes in photoperiod (day length) and temperature; these parameters vary dramatically as a function of latitude and locale. In wide-ranging species other than humans, natural selection has genetically optimized adaptiveness along latitudinal clines. Is there evidence for selection of clock gene alleles along latitudinal/photoperiod clines in humans? A number of polymorphisms in the human clock genes Per2, Per3, Clock, and AANAT have been reported as alleles that could be subject to selection. In addition, this investigation discovered several novel polymorphisms in the human Arntl and Arntl2 genes that may have functional impact upon the expression of these clock transcriptional factors. The frequency distribution of these clock gene polymorphisms is reported for diverse populations of African Americans, European Americans, Ghanaians, Han Chinese, and Papua New Guineans (including 5 subpopulations within Papua New Guinea). There are significant differences in the frequency distribution of clock gene alleles among these populations. Population genetic analyses indicate that these differences are likely to arise from genetic drift rather than from natural selection.