Hypothesis: A perfect day conveys internal time.

In 2007 the International Agency for Research on Cancer [IARC] concluded "shift work that involves circadian disruption is probably carcinogenic to humans" (Group 2A). To investigate the "probable" causal link, information on individual chronobiology is needed to specify exposures to circadian disruption associated with shift work. In epidemiological studies this information is usually assessed by questionnaire. The most widely used Morningness-Eveningness-Questionnaire (MEQ) and MunichChronoTypeQuestionnaire (MCTQ) reveal information on circadian type (MEQ) and actual sleep behaviour (MCTQ). As a further option we suggest to obtain preferred sleep times by using what we call the perfect day (PD) approach. We hypothesize that a PD - as a day of completely preferred sleep behaviour - captures pristine internal time. We argue that the PD approach may measure internal time more accurately than the MEQ and MCTQ which convey influences by work and social time pressures. The PD approach may therefore reduce misclassifications of internal time and reveal circadian disruption caused by different shift systems.

Sleep and cancer: Synthesis of experimental data and meta-analyses of cancer incidence among some 1,500,000 study individuals in 13 countries.

Sleep and its impact on physiology and pathophysiology are researched at an accelerating pace and from many different angles. Experiments provide evidence for chronobiologically plausible links between chronodisruption and sleep and circadian rhythm disruption (SCRD), on the one hand, and the development of cancer, on the other. Epidemiological evidence from cancer incidence among some 1 500 000 study individuals in 13 countries regarding associations with sleep duration, napping or "poor sleep" is variable and inconclusive. Combined adjusted relative risks (meta-RRs) for female breast cancer, based on heterogeneous data, were 1.01 (95% CI: 0.97-1.06). Meta-RRs for cancers of the colorectum and of the lung in women and men and for prostate cancer were 1.08 (95% CI: 1.03-1.13), 1.11 (95% CI: 1.00-1.22) and 1.05 (95% CI: 0.83-1.33), respectively. The significantly increased meta-RRs for colorectal cancer, based on homogeneous data, warrant targeted study. However, the paramount epidemiological problem inhibiting valid conclusions about the associations between sleep and cancer is the probable misclassification of the exposures to facets of sleep over time. Regarding the inevitable conclusion that more research is needed to answer How are sleep and cancer linked in humans? we offer eight sets of recommendations for future studies which must take note of the complexity of multidirectional relationships.

Analyzing the Publish-or-Perish Paradigm with Game Theory: The Prisoner's Dilemma and a Possible Escape.

The publish-or-perish paradigm is a prevailing facet of science. We apply game theory to show that, under rather weak assumptions, this publication scenario takes the form of a prisoner's dilemma, which constitutes a substantial obstacle to beneficial delayed publication of more complete results. One way of avoiding this obstacle while allowing researchers to establish priority of discoveries would be an updated "pli cacheté", a sealed envelope concept from the 1700s. We describe institutional rules that could additionally favour high-quality work and publications and provide examples of such policies that are already in place. Our analysis should be extended to other publication scenarios and the role of other stakeholders such as scientific journals or sponsors.

The association between different night shiftwork factors and breast cancer: a case-control study.

BACKGROUND: Research on the possible association between shiftwork and breast cancer is complicated because there are many different shiftwork factors, which might be involved including: light at night, phase shift, sleep disruption and changes in lifestyle factors while on shiftwork (diet, physical activity, alcohol intake and low sun exposure). METHODS: We conducted a population-based case-control study in Western Australia from 2009 to 2011 with 1205 incident breast cancer cases and 1789 frequency age-matched controls. A self-administered questionnaire was used to collect demographic, reproductive, and lifestyle factors and lifetime occupational history and a telephone interview was used to obtain further details about the shiftwork factors listed above. RESULTS: A small increase in risk was suggested for those ever doing the graveyard shift (work between midnight and 0500 hours) and breast cancer (odds ratio (OR)=1.16, 95% confidence interval (CI)=0.97-1.39). For phase shift, we found a 22% increase in breast cancer risk (OR=1.22, 95% CI=1.01-1.47) with a statistically significant dose-response relationship (P=0.04). For the other shiftwork factors, risks were marginally elevated and not statistically significant. CONCLUSION: We found some evidence that some of the factors involved in shiftwork may be associated with breast cancer but the ORs were low and there were inconsistencies in duration and dose-response relationships.

Meta-analyses of published epidemiological studies, 1979-2006, point to open causal questions in silica-silicosis-lung cancer research.

BACKGROUND AND OBJECTIVES: Following up on a previous meta-analysis of lung cancer risk in individuals without silicosis, we provide more detailed results of silica associated lung cancer risk in both silicotics and non-silicotics. The objective was to examine in depth whether current data allows to answer the pressing question "does silica cause lung cancer in the absence of silicosis"? METHODS: We updated earlier meta-analyses of silicosis and lung cancer and compared the results with our 2009 meta-analysis of risks in individuals without silicosis. We performed fixed (FE) and random (RE) effects meta-analyses, calculated heterogeneity statistics, stratified the study material, performed sensitivity analyses with modified study results and meta-regressions to detect effect modification. RESULTS: In silicotics, lung cancer risks were found to be doubled in 38 studies (FE: RR = 2.1; 95% CI = 2.0-2.3). In non-silicotics, eight studies without smoking adjustment suggested marginally elevated risks (FE: RR = 1.2; 95% CI = 1.1-1.3; RE: RR = 1.2; 95% CI =1.0-1.4) but three studies which were controlled for smoking showed null results (FE and RE: RR = 1.0; 95% CI = 0.8-1.3). Heterogeneity was substantial but could be linked to study characteristics, like sector of industry, and other second-level data in meta-regression. As no excess was observe dfor other smoking-related effects in studies ofllung cancer among non-silicotics, smoking was not considered to be an important confounder or modifier. CONCLUSIONn: Our meta-analyses further substantiate evidence of a strong association between silicosis and lung cancer. However, questions remain regarding lung cancer caused by silica in non-silicotics. Ideally, future investigations should consider the entire exposure-response range between silica exposure, silicosis development and lung cancer occurrence, and analyze data in terms of processes taking intermediate confounding into account.

Hypotheses for mechanisms linking shiftwork and cancer.

Shift work has been associated with various adverse health outcomes. In particular, there has been a recent flourish in investigating potential cancer risk associated with working night shifts and other shift schedules. Epidemiologic studies have revealed generally weak associations due to several methodological challenges such as lack of standard classifications of shift or night work. The field also has been hindered by a lack of clarity about the possible mechanisms by which shiftwork could have an effect on cancer risk. One possible mechanism is reduced production of melatonin caused by exposure to light at night. Although there is a growing body of evidence that provides some support for this mechanism, several other mechanisms also make sense from a biological point of view. Further, the relatively weak magnitude of the associations between light at night and melatonin level suggests that multiple factors may be operating along the pathway between shift work and adverse health consequences (including cancer risk). Here we propose four additional mechanisms that should be considered for a comprehensive investigation of these potential pathways. These are: phase shift; sleep disruption; lifestyle factors (such as poor quality diets, less physical activity and higher BMI); and lower vitamin D. Consideration of all these mechanisms is necessary in order to design effective preventative workplace strategies. In developed countries, approximately 20% of the population undertake shiftwork and, while we are unlikely to be able to eliminate shiftwork from current work practices, there are aspects of shiftwork that can be modified and there may be facets of individual susceptibility that we may be able to identify and target for prevention.

Clockwork blue: on the evolution of non-image-forming retinal photoreceptors in marine and terrestrial vertebrates.

This paper presents a hypothesis that could explain why blue light appears to dominate non-image-forming (NIF) ocular photoreception in marine as well as terrestrial vertebrates. Indeed, there is more and more evidence suggesting that 'novel' retinal photoreceptors, which are sensitive to blue light and were only discovered in the 1990s, could be a feature shared by all vertebrates. In our view, blue light photoreception evolved and persisted as NIF photoreception because it has been useful in the colonisation of extensive photo-dependent oceanic habitats and facilitated the move of vertebrates from an aquatic to a terrestrial environment. Because the available scattered evidence is compatible with the validity of our hypothesis, we hope that our rationale will be followed up. Indeed, it (1) involves testable predictions, (2) provides plausible explanations for previous observations, (3) unites phenomena not previously considered related to one another and (4) suggests tests that have not been carried out before. Overall, our approach not only embraces cross-disciplinary links; it, moreover, serves as a reminder of an all-embracing evolutionary history, especially with regard to a ubiquitous photoreceptive 'clockwork-blue' in marine and terrestrial vertebrates.

Maximal manual stretcher carriage: performance and recovery of male and female ambulance workers.

The effects of a maximal duration stretcher carriage on heart rate (HR), lactate concentration, hand steadiness and hand-grip strength were studied up to 72 h post-exercise in 17 male and 15 female military ambulance personnel. Using both hands for transport, the participants walked on a treadmill ergometer at a speed of 4.5 km/h. Force measurements at the handlebars yielded mean loads of 245 N (25 kg) on each side. Each step on the treadmill induced additional force oscillations with peak forces up to 470 N corresponding to 130% (women) and 98% (men) of maximal voluntary contraction (MVC). In the males the maximal transport time was about twice the time in women (mean +/- SD: 184 +/- 51 s vs. 98 +/- 34 s). These differences had no significant effect on HR and lactate values. The same applies to hand steadiness, which showed only a transient deterioration immediately after exercise. In contrast to these parameters, substantial differences were seen in hand-grip strength recovery. Immediately after exercise, maximal hand-grip strength decreased by 150 N (25% MVC) in the males vs. 50 N (14%) in the females. Irrespective of gender, individuals with larger hand-grip strength and longer carriage durations (range 120 s-280 s) showed the slowest strength recoveries (up to 72 h) as compared to 1 h of recovery in participants with short transport durations (range 27 s-120 s). These findings suggest that the increasing number of eccentric strains during uninterrupted stretcher carriage induces cumulative muscle damages that may require some days for complete recovery.

Can fat explain the human brain's big bang evolution?-Horrobin's leads for comparative and functional genomics.

When David Horrobin suggested that phospholipid and fatty acid metabolism played a major role in human evolution, his 'fat utilization hypothesis' unified intriguing work from paleoanthropology, evolutionary biology, genetic and nervous system research in a novel and coherent lipid-related context. Interestingly, unlike most other evolutionary concepts, the hypothesis allows specific predictions which can be empirically tested in the near future. This paper summarizes some of Horrobin's intriguing propositions and suggests as to how approaches of comparative genomics published in Cell, Nature, Science and elsewhere since 1997 may be used to examine his evolutionary hypothesis. Indeed, systematic investigations of the genomic clock in the species' mitochondrial DNA, the Y and autosomal chromosomes as evidence of evolutionary relationships and distinctions can help to scrutinize associated predictions for their validity, namely that key mutations which differentiate us from Neanderthals and from great apes are in the genes coding for proteins which regulate fat metabolism, and particularly the phospholipid metabolism of the synapses of the brain. It is concluded that beyond clues to humans' relationships with living primates and to the Neanderthals' cognitive performance and their disappearance, the suggested molecular clock analyses may provide crucial insights into the biochemical evolution-and means of possible manipulation-of our brain.

ELF-EMF, endocrine disruptors, light: what if we apply triage to research?

Triage in medicine is an effective means to maximize health benefits of limited resources. This paper suggests to use triage principles as a means to identify biomedical and epidemiological research priorities. The author applies the following questions to three putative problems which receive different research and funding attention: (a) Does a suspected exposure render many humans at risk? (b) Is a disease frequent, difficult to treat and expensive? and (c) Is a causal link between (a) and (b) biologically plausible? On the basis of answers to (a), (b), and (c) it is concluded that ELF-EMF and childhood leukaemia would not qualify for further urgent investigations and that endocrine disruptors and to-be-identified end-points would not qualify for urgent investigations. Provided that answers to the outlined triage questions can be considered as a practical guide to urgent research investigations, the suggestive link between light, endocrine systems and hormone-dependent cancers should become a higher priority research focus.

Preventive research and interventive research: in favour of to act rather than to react.

Conventional wisdom knows that "prevention is better than cure". However, in the many cases where we do not understand how to cure or intervent, prevention is not only better but may be the only way to promote public health. As the principal basis for preventive action, this paper advocates to focus more on preventive rather than on interventive research. Preventive research, as defined here, aims to identify a determinant A in the environment which causes an undesirable health effect B in the human body. Preventive research ends when the critical nature of A is convincingly established and ways to avoid A are identified. Interventive research, as defined here, aims to understand and manipulate the chain from A to B within the human body. Examples of real (poliomyelitis, lung cancer, AIDS) and possible scourges (BSE) from the last and this century indicate that preventive research has delivered culprits but that interventive research could not-and likely will not-unravel the whole chain from A to B. Based also on conceptual considerations it is concluded that, while both research approaches are needed, a strategy with more emphasis on preventive research and taking action at an earlier stage may lead to more community success.

[Light, melatonin and internal cancers - recent facts and research perspectives]. / Licht, Melatonin und innere Krebserkrankungen - Aktuelle Fakten und Forschungsperspektiven.

Visible light of sufficient intensity inhibits melatonin biosynthesis and numerous experimental studies suggest that melatonin may protect against cancer. From a public health point of view it is important to verify or falsify the hypothesis that artificial light - or even sunlight itself - suppresses melatonin production sufficiently to increase the risk of developing cancers of internal organs. Since humans are exposed universally, even small risk elevations could lead to numerous cases. Recent epidemiological studies of people exposed to anthropogenic light-at-night in the course of shift work and first evaluations of natural light experiments in blind people and in residents of the Arctic are compatible with the possibility that light can influence - at least hormone- dependent - cancer developments via melatonin. To systematically investigate the effect of geographically different light intensities on melatonin production in man, a pan-European study is suggested. Further epidemiological investigations can contribute to the understanding of the patho-physiological relationships between light, melatonin and human biology.