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The study of shift schedule design, and its impact on the health, safety and the performance of shiftworkers, has seen considerable advances in methodology in the last decade. Much of the early research that helped identify shift schedule design principals was based on observational studies. Quite many featured cross-sectional designs that were subject to residual confounding from unadjusted potential confounders. Moreover, the early studies were almost universally based on self-reported exposure and many relied upon self-reported outcomes, making them subject to information bias. Researchers have since built on the findings of earlier research with more sophisticated and robust designs and metrics, many of which are exemplified in studies that have been published in this journal. These provide a firmer evidence base on which to develop recommendations for the design of shift schedules. Here, several methodological approaches in the study of shift schedule design are discussed.

OBJECTIVE: This paper discusses the past and present highlights of working hours and health research and identifies key research needs for the future. METHOD: We analyzed over 220 original articles and reviews on working hours and health in the Scandinavian Journal of Work, Environment & Health published during the last 50 years. Key publications from other journals were also included. RESULTS: The majority of identified articles focussed on the effects of shift and night work, with fewer studying long and reduced working hours and work time control. We observed a transition from small-scale experimental and intensive field studies to large-scale epidemiological studies utilizing precise exposure assessment, reflecting the recent emergence of register-based datasets and the development of analytic methods and alternative study designs for randomized controlled designs. The cumulative findings provide convincing evidence that shift work and long working hours, which are often associated with night work and insufficient recovery, increase the risk of poor sleep and fatigue, sickness absence, occupational injuries, and several chronic health conditions such as cardiovascular diseases and cancer. The observed risks are strongly modified by individual and work-related factors. CONCLUSIONS: Although the observed health risks of shift work and long working hours are mostly low or moderate, the widespread prevalence of exposure and the hazardousness of the many associated potential outcomes makes such working time arrangements major occupational health risks. Further research is needed to identify exposure–response associations, especially in relation to the chronic health effects, and to elucidate underlying pathways and effective personalized intervention strategies.

Objectives Shift work, like chronic jet lag, is known to disrupt workers’ normal circadian rhythms and social life, and to be associated with increased health problems (eg, ulcers, cardiovascular disease, metabolic syndrome, breast cancer, reproductive difficulties) and with acute effects on safety and productivity. However, very little is known about the long-term consequences of shift work on cognitive abilities. The aim of this study was to assess the chronicity and reversibility of the effects of shift work on cognition. Methods We conducted a prospective cohort study of 3232 employed and retired workers (participation rate: 76%) who were 32, 42, 52 and 62 years old at the time of the first measurement (t1, 1996), and who were seen again 5 (t2) and 10 (t3) years later. 1484 of them had shift work experience at baseline (current or past) and 1635 had not. The main outcome measures were tests of speed and memory, assessed at all three measurement times. Results Shift work was associated with impaired cognition. The association was stronger for exposure durations exceeding 10 years (dose effect; cognitive loss equivalent to 6.5 years of age-related decline in the current cohort). The recovery of cognitive functioning after having left shift work took at least 5 years (reversibility). Conclusions Shift work chronically impairs cognition, with potentially important safety consequences not only for the individuals concerned, but also for society.

Compared to individuals who work during the day, shift workers are at higher risk of a range of metabolic disorders and diseases (eg, obesity, cardiovascular disease, peptic ulcers, gastrointestinal problems, failure to control blood sugar levels, and metabolic syndrome). At least some of these complaints may be linked to the quality of the diet and irregular timing of eating, however other factors that affect metabolism are likely to play a part, including psychosocial stress, disrupted circadian rhythms, sleep debt, physical inactivity, and insufficient time for rest and revitalization. In this overview, we examine studies on food and nutrition among shift workers [ie, dietary assessment (designs, methods, variables) and the factors that might influence eating habits and metabolic parameters]. The discussion focuses on the quality of existing dietary assessment data, nutritional status parameters (particularly in obesity), the effect of circadian disruptions, and the possible implications for performance at work. We conclude with some dietary guidelines as a basis for managing the nutrition of shift workers.

OBJECTIVES: Quick returns (<11 hours of rest between shifts) have been associated with shortened sleep length and increased sleepiness, but previous efforts have failed to find effects on sleep quality or stress. A shortcoming of most previous research has been the reliance on subjective measures of sleep. The aim of this study was to combine diary and actigraphy data to investigate intra-individual differences in sleep length, sleep quality, sleepiness, and stress during quick returns compared to day-day transitions. METHODS: Of 225 nurses and assistant nurses who wore actigraphy wristbands and kept a diary of work and sleep for seven days, a subsample of 90 individuals with one observation of both a quick return and a control condition (day-day transition) was extracted. Sleep quality was assessed with actigraphy data on sleep fragmentation and subjective ratings of perceived sleep quality. Stress and sleepiness levels were rated every third hour throughout the day. Shifts were identified from self-reported working hours. Data was analyzed in multilevel models. RESULTS: Quick returns were associated with 1 hour shorter sleep length [95% confidence interval (CI) -1.23– -0.81], reduced subjective sleep quality (-0.49, 95% CI -0.69– -0.31), increased anxiety at bedtime (-0.38, 95% CI -0.69– -0.08) and increased worktime sleepiness (0.45, 95%CI 0.22– 0.71), compared to day-day transitions. Sleep fragmentation and stress ratings did not differ between conditions. CONCLUSIONS: The findings of impaired sleep and increased sleepiness highlight the need for caution when scheduling shift combinations with quick returns.

Isolation of antigen-specific antibodies or antibody fragments, whether through B-cell immortalization or recombinant libraries, generally requires laborious screening. Reddy et al . circumvent this step using high-throughput sequencing of plasma cells and bioinformatic analysis of the variable-gene repertoire. Isolation of antigen-specific monoclonal antibodies (mAbs) and antibody fragments relies on high-throughput screening of immortalized B cells 1 , 2 or recombinant antibody libraries 3 , 4 , 5 , 6 . We bypassed the screening step by using high-throughput DNA sequencing and bioinformatic analysis to mine antibody variable region (V)-gene repertoires from bone marrow plasma cells (BMPC) of immunized mice. BMPCs, which cannot be immortalized, produce the vast majority of circulating antibodies. We found that the V-gene repertoire of BMPCs becomes highly polarized after immunization, with the most abundant sequences represented at frequencies between ∼1% and >10% of the total repertoire. We paired the most abundant variable heavy (V H ) and variable light (V L ) genes based on their relative frequencies, reconstructed them using automated gene synthesis, and expressed recombinant antibodies in bacteria or mammalian cells. Antibodies generated in this manner from six mice, each immunized with one of three antigens were overwhelmingly antigen specific (21/27 or 78%). Those generated from a mouse with high serum titers had nanomolar binding affinities.

Persistence of human fetal hemoglobin (HbF, α₂γ₂ ) in adults lessens the severity of sickle cell disease (SCD) and the β-thalassemias. Here, we show that the repressor BCL11A is required in vivo for silencing of γ-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, we demonstrate that inactivation of BCL11A in SCD transgenic mice corrects the hematologic and pathologic defects associated with SCD through high-level pancellular HbF induction. Thus, interference with HbF silencing by manipulation of a single target protein is sufficient to reverse SCD.

Forkhead transcription factors are key participants in development and immune regulation. Here we demonstrate that absence of the gene encoding the forkhead transcription factor Foxp1 resulted in a profound defect in early B cell development. Foxp1 deficiency was associated with decreased expression of all B lineage genes in B220 + fetal liver cells as well as with a block in the transition from pro–B cell to pre–B cell involving diminished expression of recombination-activating genes 1 and 2. Foxp1 bound to the Erag enhancer and was involved in controlling variable-(diversity)-joining recombination of the gene encoding immunoglobulin heavy chain in a B cell lineage–specific way. Our results identify Foxp1 as an essential participant in the transcriptional regulatory network of B lymphopoiesis.

The N-linked glycan of immunoglobulin G (IgG) is indispensable for the interaction of the Fc domain with Fcγ receptors on effector cells and the clearance of target cells via antibody dependent cell-mediated cytotoxicity (ADCC). Escherichia coli expressed, aglycosylated Fc domains bind effector FcγRs poorly and cannot elicit ADCC. Using a novel bacterial display/flow cytometric library screening system we isolated Fc variants that bind to FcγRI (CD64) with nanomolar affinity. Binding was critically dependent on amino acid substitutions (E382V, and to a lesser extent, M428I) distal to the putative FcγRI binding epitope within the CH3 domain. These mutations did not adversely affect its pH-dependent interaction with FcRn in vitro nor its serum persistence in vivo. Remarkably, the anti-Her2 IgG trastuzumab containing the E382V, M428I substitutions and expressed in E. coli exhibited highly selective binding to FcγRI but not to the other activating receptors (FcγRIIa, FcγRIIIa) nor to the inhibitory receptor, FcγRIIb. In contrast, the glycosylated version of trastuzumab (E382V, M428I) purified from HEK293T cells bound to all Fcγ receptors in a manner similar to that of clinical grade trastuzumab. E. coli-purified trastuzumab (E382V, M428I), but not glycosylated trastuzumab (E382V, M428I) or clinical grade trastuzumab, was capable of potentiating the killing of Her2 overexpressing tumor cells with dendritic cells (DCs) as effectors. These results indicate that aglycosylated IgGs can be engineered to display unique FcγR selectivity profiles that, in turn, mediate ADCC via mechanisms that are not normally displayed by glycosylated monoclonal antibodies.

Chromatin modifying enzymes play a critical role in cardiac differentiation. Previously, it has been shown that the targeted deletion of the histone methyltransferase, Smyd1, the founding member of the SET and MYND domain containing (Smyd) family, interferes with cardiomyocyte maturation and proper formation of the right heart ventricle. The highly related paralogue, Smyd2 is a histone 3 lysine 4- and lysine 36-specific methyltransferase expressed in heart and brain. Here, we report that Smyd2 is differentially expressed during cardiac development with highest expression in the neonatal heart. To elucidate the functional role of Smyd2 in the heart, we generated conditional knockout (cKO) mice harboring a cardiomyocyte-specific deletion of Smyd2 and performed histological, functional and molecular analyses. Unexpectedly, cardiac deletion of Smyd2 was dispensable for proper morphological and functional development of the murine heart and had no effect on global histone 3 lysine 4 or 36 methylation. However, we provide evidence for a potential role of Smyd2 in the transcriptional regulation of genes associated with translation and reveal that Smyd2, similar to Smyd3, interacts with RNA Polymerase II as well as to the RNA helicase, HELZ.