Eirik Reierth

Seasonal and Daily Variations in Plasma Melatonin in the High-Arctic Svalbard Ptarmigan (Lagopus mutus hyperboreus)

This study presents the daily rhythm of melatonin secretion throughout one year in a bird from the northern hemisphere, the Svalbard ptarmigan (Lagopus mutus hyperboreus), which lives naturally at 76-80°N. Eight Svalbard ptarmigan were caged outdoors at 70°N and blood sampled throughout one day each month for 13 months. At this latitude, daylight is continuous between May and August, but there is a short period of civil twilight around noon from late November to mid January. There was no daily rhythm in plasma melatonin in May-July. Plasma melatonin levels varied significantly throughout the day in all other months of the year, with the nighttime increase reflecting the duration of darkness. The highest mean plasma concentration occurred at midnight in March (110.1 ± 16.5 pg/ml) and represented the annual peak in estimated daily production. Around the winter solstice, melatonin levels were significantly reduced at noon and elevated during the nearly 18 h of consecutive darkness, and the estimated mean daily production of melatonin was significantly reduced. Thus, at the times of the year characterized by light-dark cycles, melatonin may convey information concerning the length of the day and, therefore, progression of season. The nearly undetectable low melatonin secretion in summer and the reduced amplitude and production in midwinter indicate a flexible circadian system that may reflect an important adaptation to life in the Arctic.

ST waveform analysis vs. cardiotocography alone for intrapartum fetal monitoring: A systematic review and meta-analysis of randomized trials

ST waveform analysis was introduced to reduce metabolic acidosis at birth and avoid unnecessary operative deliveries relative to conventional cardiotocography. Our objective was to quantify the efficacy of ST waveform analysis vs. cardiotocography and assess the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation tool.

DUAL ENTRAINMENT BY LIGHT AND FOOD IN THE SVALBARD PTARMIGAN (LAGOPUS MUTUS HYPERBOREUS)

The possibility that feeding may act as a zeitgeber has been investigated in captive Svalbard ptarmigan by recording feeding or food-searching activity (FA) in birds given periodic access to food (PAF) under light-dark (LD) cycles or in continuous bright (LL) or dim light (DD) conditions. Except during LL, anticipatory attempts to feed always occurred prior to the food access interval with a relatively stable phase relationship to the interval. There was always a second bout of feeding toward the end of the food access interval, which apparently corresponds to the afternoon bout of feeding, seen under LD and ad libitum access to food. During PAF, this afternoon peak of activity disappeared. When the LD cycle was phase delayed while restricted access to food remained unchanged, the afternoon peak of feeding was temporarily reestablished but was transiently shifted forward to reattain its position within the food access interval. After termination of PAF, the afternoon bout of feeding was reestablished through phase-delaying transients, with an initial phase corresponding to the previous food access interval. The results suggest that FA of Svalbard ptarmigan is controlled by 2 separate circadian oscillators, both of which can be entrained by light and food: a putative morning oscillator, which controls the activity associated with the beginning of the photoperiod or the food access interval, and a putative evening oscillator, which induces increased activity toward the end of these intervals. In their natural environment at very high latitudes, Svalbard ptarmigan deposit fat when the day length declines rapidly in autumn. Entrained by feeding, they appear to enjoy a longer daily period of food-searching activity than if day length was the only zeitgeber.

Systematic literature review of templates for reporting prehospital major incident medical management

Objective To identify and describe the content of templates for reporting prehospital major incident medical management. Design Systematic literature review according to PRISMA guidelines. Data sources PubMed/MEDLINE, EMBASE, CINAHL, Scopus and Web of Knowledge. Grey literature was also searched. Eligibility criteria for selected studies Templates published after 1 January 1990 and up to 19 March 2012. Non-English language literature, except Scandinavian; literature without an available abstract; and literature reporting only psychological aspects were excluded. Results The main database search identified 8497 articles, among which 8389 were excluded based on title and abstract. An additional 96 were excluded based on the full-text. The remaining 12 articles were included in the analysis. A total of 107 articles were identified in the grey literature and excluded. The reference lists for the included articles identified five additional articles. A relevant article published after completing the search was also included. In the 18 articles included in the study, 10 different templates or sets of data are described: 2 methodologies for assessing major incident responses, 3 templates intended for reporting from exercises, 2 guidelines for reporting in medical journals, 2 analyses of previous disasters and 1 Utstein-style template. Conclusions More than one template exists for generating reports. The limitations of the existing templates involve internal and external validity, and none of them have been tested for feasibility in real-life incidents. Trial registration The review is registered in PROSPERO (registration number: CRD42012002051).

PHOTOPERIODIC AND AMBIENT TEMPERATURE CONTROL OF THE ANNUAL BODY MASS CYCLE IN SVALBARD PTARMIGAN

The present study describes the photoperiodic control of annual body mass changes in captive. Svalbard ptarmigan, in particular the onset of autumnal increase and midwinter decrease in fat content under natural and simulated daylight-conditions in Tromsø (69° 46′ N). Autumnal fattening commences when the birds become photorefractory and presumably depends on this condition. At present it is not known if any causal relationship is involved. Under outdoor ambient temperature, body mass begins to decline in November. However, when Svalbard ptarmigan are caged indoors at higher ambient temperatures and exposed to natural or simulated annual changes in daylength, body mass remains high until February. In these birds the depletion of fat stores appears to be triggered by the increasing daylength, since body mass remained high under permanent exposure to short days throughout spring but decreased promptly following photostimulation in May. When ptarmigan caged indoors were starved in midwinter body mass fell but increased briefly upon refeeding and thereafter declined as in the control birds throughout spring. This indicates that the winter body mass profile in Svalbard ptarmigan is not merely the passive outcome of shifts in the energy expenditure associated with thermoregulation, and that a sliding set point for body mass exists and is temporally fixed at the seasonal maximum in mid winter in birds caged under indoor ambient temperatures. The possibility is discussed that the decline in body mass seen outdoors may be associated with the increased hypothalamus-pituitary-gonadal activity which follows the breaking of photorefractoriness, and that this activity is sufficiently suppressed in Svalbard ptarmigan caged indoors under exposure to short days, to delay the reduction until they are photostimulated.

When should acute exacerbations of COPD be treated with systemic corticosteroids and antibiotics in primary care: a systematic review of current COPD guidelines

Not all patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) benefit from treatment with systemic corticosteroids and antibiotics. The aim of the study was to identify criteria recommended in current COPD guidelines for treating acute exacerbations with systemic corticosteroids and antibiotics and to assess the underlying evidence. Current COPD guidelines were identified by a systematic literature search. The most recent guidelines as per country/organisation containing recommendations about treating acute exacerbations of COPD were included. Guideline development and criteria for treating acute exacerbations with systemic corticosteroids and antibiotics were appraised. Randomised controlled trials directly referred to in context with the recommendations were evaluated in terms of study design, setting, and study population. A total of 19 COPD guidelines were included. Systemic corticosteroids were often universally recommended to all patients with acute exacerbations. Criteria for treatment with antibiotics were mainly an increase in respiratory symptoms. Objective diagnostic tests or clinical examination were only rarely recommended. Only few criteria were directly linked to underlying evidence, and the trial patients represented a highly specific group of COPD patients. Current COPD guidelines are of little help in primary care to identify patients with acute exacerbations probably benefitting from treatment with systemic corticosteroids and antibiotics in primary care, and might contribute to overuse or inappropriate use of either treatment.

Templates for reporting pre-hospital major incident medical management: systematic literature review

Introduction In 2010, a total of 385 natural disasters killed more than 297 000 people worldwide and affected over 217 million others. More standardised reporting of major incident management have been advocated in the previous years. Prevention, mitigation, preparedness and major incident response may be improved through collection and analysis of high-quality standardised data on medical management of major incidents. Standardised data may elevate the level of scientific evidence within disaster medicine research. Methods and analysis A systematic literature review will be conducted to identify templates for reporting pre-hospital major incident medical management. The first set of entry terms aims to describe major incidents published during the last 20 years. The second set aims to focus the number of search results from the first set to those publications that describe templates based on data collections from these major incidents. Predefined free search phases will be combined with the first two sets. Ethics and dissemination The results will be submitted for publication in an open access, peer-reviewed scientific journal. The PRISMA checklist will be applied. No ethics approval is considered indicated, as this is a literature review only. Registration details This review is registered in PROSPERO (registration number: CRD42012002051).

Biological Rhythms in Arctic Animals

With increasing latitude the daily light-dark cycle becomes progressively distorted during substantial parts of the year. At high-Arctic latitudes (77–81°N) there is continuous darkness (polar night) between November and February and continuous light (polar day) from April to September. Circadian mechanisms generally rely heavily on the synchronizing or entraining effect of the daily light/dark cycle, and it is therefore important to study animals living under conditions where this zeitgeber is absent. Migratory birds visiting the Arctic in summer to breed apparently perceive sufficient environmental rhythmic information to remain entrained. Humans and resident animals such as ptarmigan and reindeer do not, but whereas humans show persistent circadian freerunning sleep/ wake rhythms, reindeer and ptarmigan become continuously active. This is also revealed by their secretion of melatonin, which is markedly reduced at those times of the year when the light/dark cycle is absent. Presumably, their endogenous biological clocks or circadian machinery is flexible and becomes dampened to such an extent as to allow these animals to exploit their environment maximally at those times of the year when there is no marked differences between day and night.

STAN technology, surrogate outcomes and possible sources of bias

Sir, We appreciate the comments from Olofsson (1) and Kessler et al. (2). We investigated several outcomes in our review, and two (risk of metabolic acidosis and operative vaginal delivery) showed statistically significant differences in favor of STAN. (3). Two other high quality meta-analyses were published almost simultaneously (4,5), and neither reported significant differences in rates of metabolic acidosis. Saccone et al. (4) and Neilson (5) used risk ratio (RR) and random effect models, whereas we used peto odds ratio (OR) and fixed effect model for outcomes with an incidence <1%. Both approaches have pros and cons and we hesitate to define either one as superior. Olofsson argues that we did the most correct metaanalysis (3). Positive feedback is always welcome, but it is tempting to ask whether this judgment is related to the fact that our metaanalysis shows positive results for metabolic acidosis, whereas the others do not. We once again emphasize the need to view all results in context, particularly when the only interesting effect manifests itself in a surrogate outcome with uncertain clinical validity. Surrogate outcomes are used to predict the risk of future serious events, thus shortening the size, duration and cost of trials. Unfortunately, this is associated with pitfalls and bias (6,7). The uncertain validity of metabolic acidosis is demonstrated in an individual patient data review (4) investigating a composite endpoint (at least one of the following: intrapartum fetal death, neonatal death, Apgar score ≤3 at five minutes, neonatal seizures, metabolic acidosis, intubation for ventilation at delivery or neonatal encephalopathy) without finding a difference between STAN and CTG. Hence, we disagree with Kessler et al. and Olofsson, who seem to take the validity of metabolic acidosis for granted. Kessler et al. assume that 10.3% of all babies born with metabolic acidosis have severe adverse outcomes due to an intrapartum hypoxic event. Their calculation presupposes that the risk reductions for metabolic acidosis and for serious adverse events are linearly related. We find this inference speculative, and wonder why one should trust estimates based on assumption rather than direct data. Direct data suggest that that STAN might be associated with reduced survival (3–5). Kessler et al. estimated that STAN will prevent 493 operative vaginal deliveries in Norway each year. This estimate is based on the questionable assumption that all delivery units use STAN on all laboring women, and they ask whether we regard this reduction as unimportant. We welcome efforts to reduce operative deliveries without compromising neonatal outcomes, but this should involve other approaches rather than STAN. Olofsson further argues that our GRADE assessments are influenced by culture, norms and other preferences. This is of course true. The use of GRADE does not guarantee consensus, but we note that the Cochrane meta-analysis (5) arrived at very similar conclusions. Olofsson states that relying more on negative than positive evidence is a part of being human, suggesting that our conclusions are prone to bias. We believe that confirmation bias, conflicts of interest and uncritical embracement of new technology (8) are the most potent sources of bias in this field. We do not see any reasons why we could be more exposed to this type of bias than others. As an extension of the latter argument, it is tempting to refer to the criticism of the recently published US study (9). This study was funded with 3 million USD and supported by Neoventa AB (10). The STAN algorithm was different from that used in Europe, but the algorithm was the same as used by Neoventa for their FDA approval (10). In 2014, Olofsson, Kessler, Yli and others published a review (11) and concluded: “The results of the ongoing multicenter RCT in the United States are some months away. Certainly the contribution of the USA data will help to determine whether the addition of ST analysis to conventional CTG results in improved perinatal outcomes.” After the US study showed negative results, Kessler, Yli and others published a statement with severe objections to this study on the Neoventa homepage (12). It is tempting to speculate whether this criticism would have been raised if the US study had published positive results.

Statistical significance is not necessarily equal to clinical significance.

Sir, We thank Vayssiere et al. for their comment (1). Vayssiere et al. state that there were contradictory findings regarding neonatal metabolic acidosis between the three recently published meta-analyses on STAN vs. CTG alone (2–4). We disagree, as all three meta-analyses reported a decrease but only one reached statistical significance. Further, Vayssiere et al. state that only we used revised data from previous trials appropriately, and they have performed new analyses using different methods based on the numbers used in our study (2). All their new analyses reached statistical significance, and Vayssiere et al. conclude that that the STAN method reduces metabolic acidosis by one-third and conclude that it is beneficial. We reported a statistically significant difference (relative risk reduction 36%, absolute risk reduction 0.25%). The significance was lost when we used peto OR in combination with a randomeffect model rather than a fixed-effect model. We argued that the result should be interpreted with caution because metabolic acidosis is a surrogate endpoint with a questionable relation to harder outcomes and because we did not observe similar effects in other clinical outcomes. In addition, the statistically significant result disappeared when using another method, which underpins the need for caution. We have previously argued carefully for our view (2,5) and will not repeat the arguments here. Vayssiere et al. (1) state that metabolic acidosis is one of the best indicators available at birth for the immediate assessment – without providing any arguments as to why it makes metabolic acidosis a predictive indicator for adverse fetal outcomes in this setting. If they could provide studies showing good correlations between metabolic acidosis and adverse outcomes, it would be useful. No long-term outcomes, as cerebral palsy, are published from the randomized controlled trials using the STAN technology. After publishing our meta-analysis, we have experienced that supporters of STAN conclude that we used the most appropriate methods and the right data – but criticized us for our conclusions. They are unwilling to discuss the problem about use of surrogate outcomes and risk of bias (6,7), or the low absolute risk reduction of 0.25%. Based on data from six trials of good quality, with more than 26 000 women included, there is currently no evidence to conclude that STAN improves neonatal outcomes compared with CTG alone. We are now discussing whether small changes in numbers extracted from the primary studies or slightly different methods can change results and conclusions in the three recent meta-analyses. It is unlikely that future trials comparing STAN with CTG alone will be funded, and it is unlikely that evidence from observational studies can change the conclusions from the meta-analyses based on RCTs. It is time to consider whether the resources (human and economic) available can be used better to improve perinatal outcomes than just focusing on the STAN technology. Ellen Blix, Kjetil Gundro Brurberg, Eirik Reierth, Liv Merete Reinar and P al Øian Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, The Norwegian Knowledge Centre for the Health Services, Oslo, Centre for Evidence Based Practice, Bergen University College, Bergen, Science and Health Library, University Library, UiT The Arctic University of Norway, Tromsø, Department of Obstetrics and Gynecology, University Hospital of North Norway, Tromsø, and Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway