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Wintering energy management in small passerines has focused on the adaptive regulation of the daily acquisition of energy reserves within a starvation–predation trade-off framework. However, the possibility that the energetic cost of living, i.e. basal metabolic rate (BMR), is being modulated as part of the management energy strategy has been largely neglected. Here, we addressed this possibility by experimentally exposing captive great tits (Parus major) during winter to two consecutive treatments of increased starvation and predation risk for each individual bird. Body mass and BMR were measured prior to and after each week-long treatment. We predicted that birds should be lighter but with a higher metabolic capacity (higher BMR) as a response to increased predation risk, and that birds should increase internal reserves while reducing their cost of living (lower BMR) when exposed to increased starvation risk. Wintering great tits kept a constant body mass independently of a week-long predation or starvation treatment. However, great tits reduced the cost of living (lower BMR) when exposed to the starvation treatment, while BMR remained unaffected by the predation treatment. Energy management in wintering small birds partly relies on BMR regulation, which challenges the current theoretical framework based on body mass regulation., This work was supported by the Andalucıa Talent Hub Program launched by the ́ Andalusian Knowledge Agency, co-funded by the European Union’s Seventh Framework Program, Marie Skłodowska-Curie actions (COFUND – grant agreement no. 291780), the Ministry of Economy, Innovation, Science and Employment of the Junta de Andalucıa, and by the Djurskyddsfond and Royal ́ Physiographic Society from the University of Lund to J.B. The work was further supported by grants from the Swedish Research Council (Vetenskapsrådet; nos S-AA/F0 09677-311, B 650- 19981108/2000, 629-2002-1893 and 621-2003-2912) to J.-Å.N. Open Access funding provided by Museo Nacional de Ciencias Naturales (CSIC).

Mito-nuclear insertions, or NUMTs, relate to genetic material of mitochondrial origin that have been transferred to the nuclear DNA molecule. The increasing amounts of genomic data currently being produced presents an opportunity to investigate this type of patterns in genome evolution of non-model organisms. Identifying NUMTs across a range of closely related taxa allows one to generalize patterns of insertion and maintenance in auto-somes, which is ultimately relevant to the understanding of genome biology and evolution. Here we collected existing pairwise genome-mitogenome data of the order Strigiformes, a group that includes all the nocturnal bird predators. We identified NUMTs by applying percent similarity thresholds after blasting mitochondrial genomes against nuclear genome assemblies. We identified NUMTs in all genomes with numbers ranging from 4 in Bubo bubo to 24 in Ciccaba nigrolineata. Statistical analyses revealed NUMT size to negatively correlate with NUMTs sequence similarity to with original mtDNA region. Lastly, characterizing these nuclear insertions of mito-chondrial origin in a comparative genomics framework produced variable phylogenetic patterns, suggesting in some cases that insertions might pre-date speciation events within Strigiformes. Funding Agencies|Academy of Finland [321417]

Many birds and mammals show substantial circadian variation in body temperature, which has been attributed to fluctuations in ambient temperature and energy reserves. However, to fully understand the variation in body temperature over the course of the day, we also need to consider effects of variation in work rate. We made use of a dataset on body temperature during the resting and active periods in female marsh tits (Poecile palustris) that bred in a temperate area and were subjected to experimental changes in reproductive investment through brood size manipulations. Furthermore, the amplitude increased with daytime, but were unaffected by nighttime, ambient temperature. Amplitudes in females with manipulated broods were 44% above predictions based on inter-specific allometric relationships. In extreme cases, amplitudes were > 100% above predicted values. However, no individual female realised the maximum potential amplitude (8.5 °C, i.e. the difference between the highest and lowest body temperature within the population) but seemed to prioritise either a reduction in body temperature at night or an increase in body temperature in the day. This suggests that body temperature amplitude might be constrained by costs that preclude extensive use of both low nighttime and high daytime body temperatures within the same individual. Amplitudes in the range found here (0.5–6.7 °C) have previously mostly been reported from sub-tropical and/or arid habitats. We show that comparable values can also be found amongst birds in relatively cool, temperate regions, partly due to a pronounced increase in body temperature during periods with high work rate.

Increasingly warmer springs have caused phenological shifts in both plants and animals. In birds, it is well established that mean laying date has advanced to match the earlier food peak. We know less about changes in the distribution of egg-laying dates within a population and the environmental variables that determine this variation. This could be an important component of how populations respond to climate change. We, therefore, used laying date and environmental data from 39 years (1983–2021) to determine how climate change affected laying date variation in blue tits (Cyanistes caeruleus) and marsh tits (Poecile palustris), two sympatric passerines with different life histories. Both species advanced mean laying date (0.19–0.24 days per year) and mean laying date showed a negative relationship with maximum spring temperature in both blue and marsh tits. In springs with no clear temperature increase during the critical time window (the time-window in which mean laying date was most sensitive to temperature) start of breeding in blue tits was distributed over a longer part of the season. However, there was no such pattern in marsh tits. Our findings suggest that temperature change, and not necessarily absolute temperature, can shape the variation in breeding phenology in a species-specific manner, possibly linked to variation in life-history strategies. This is an important consideration when predicting how climate change affects timing of breeding within a population.

Many hypotheses attempt to explain parasite–host associations, but rarely are they examined together in a single community. For hosts, key traits are the proportion of infected individuals (prevalence) and the diversity of parasites infecting them. A key parasite trait is host specificity, ranging from specialists infecting one or a few closely related species to generalists infecting many species. We tested 10 hypotheses to explain host-parasite associations; five ‘host-centric’ (e.g. prevalence is related to host abundance) and five ‘parasite-centric’ (e.g. parasite abundance is related to host specificity). We analyzed a community of 67 locally transmitted avian haemosporidian parasite lineages (genera Plasmodium, Haemoproteus or Leucocytozoon), sampled from 2726 birds (64 species) in southern Sweden. Among host-centric hypotheses, Haemoproteus and Leucocytozoon prevalence and Haemoproteus diversity were related to host habitat preferences, whereas there were no relationships with host abundance or body mass. Haemoproteus and Leucocytozoon prevalences were more similar among closely related than among distantly related host species. Haemoproteus prevalence and diversity were lower in host species with few close relatives (‘evolutionarily distinct’ hosts). Among parasite-centric hypotheses, most lineages, even relative generalists, infected closely related host species more often than expected by chance. However, the host species of Haemoproteus and Leucocytozoon lineages overlapped less among lineages than expected by chance. Specialists did not reach higher prevalences than generalists on single host species. However, the abundance of Haemoproteus lineages was related to host specificity with generalists more common than specialists; this was driven by three closely related generalists. Host specificity of parasites was unrelated to the abundance or evolutionarily distinctiveness of their hosts. Parasite communities are likely structured by many factors and cannot be explained by hypotheses focusing solely on hosts or parasites. However, we found consistent effects of host phylogenetic relationships, plausibly a result of evolutionarily conserved host immune systems limiting parasite distributions. (Less)

In polygynous species with biparental care, mates are often acquired in succession. Most research has focussed on the cost of polygyny in secondary females, but primary females may also suffer from reduced paternal care. The likelihood of sharing a male may be higher for early laying females, which could counteract the fitness benefits of breeding early. In this study, we use 12 years of data on pied flycatchers Ficedula hypoleuca, to show that the likelihood of becoming a primary female of a polygynous male declines over the season. Moreover, we provide experimental evidence that early breeding elevates polygyny risk, through an experimental manipulation that introduced early breeding females to a population with later breeding phenology. We found that, independently of breeding date, primary females slightly more often experienced complete brood failures than monogamous females, but did not differ in number of fledged offspring among successful broods or number of locally returning recruits. However, apparent survival in subsequent years was substantially lower in primary females, indicating that they may compensate for reduced male care at the expense of future reproduction. Our study reveals that polygyny risk indeed increases with early breeding and entails a local survival cost for primary females. However, this cost is likely largely outweighed by fitness benefits of early breeding in most years. Hence it is unlikely that the increased polygyny risk of early breeding counteracts the fitness benefits, but it may reduce selection for breeding extremely early.

Bird winter-feeding has become a popular backyard activity around the world, particu-larly in northern regions of Europe and America with cold winters. However, the short- and long-term ecological consequences of such artificial feeding remain inconclusive. In seasonal environments, timing of breeding is a crucial aspect that can strongly influ-ence reproductive output and ultimately fitness. Individual condition at the start of the breeding season is especially important in determining breeding success, by influ-encing the onset of and investment in breeding. However, empirical evidence on the effects of winter feeding on avian breeding performance remain equivocal.We studied onset of reproduction (laying date) and breeding investment (clutch size) over seven consecutive seasons in a population of wild great tits Parus major in southern Sweden. During the first three years of study, no experimental manipulation was undertaken, while over the last four years the study area was exposed to either supplemented or unmanipulated winter feeding conditions. Breeding was positively affected by supplementary feeding during winter, as birds breeding in the supplemented area increased their clutch size compared to birds from the control area, although lay-ing date remained unaffected by winter feeding. Since differences in clutch size were absent during the three years prior to the experimental manipulation, the results sug-gest that winter supplementary feeding, and not inherent differences between the two areas, was the reason for the observed effect. Both breeding parameters varied over the years of study, although the effects of the experimental manipulation on clutch size remained consistent, which suggests a carry-over effect of winter feeding on subse-quent breeding performance., JB has been funded by the Andalucía Talent Hub Program launched by the Andalusian Knowledge Agency, co-funded by the European Union’s Seventh Framework Program, Marie Skłodowska-Curie actions (COFUND – Grant Agreement no. 291780) and the Ministry of Economy, Innovation, Science and Employment of the Junta de Andalucía. Supported by the Stiftelsen Lunds Djurskyddsfond and the Jan Löfqvist Endowment from the Royal Physiographic society of Lund (JB). The supported by grants from the Swedish Research Council no. S-AA/F0 09677-311, B 650-19981108/2000, 629-2002-1893 and 621-2003-2912 (JÅN).

Basal metabolic rate (BMR) constitutes the lowest metabolic rate in a resting animal and is, therefore, considered to reflect the energetic cost of maintenance in endotherms. BMR is a reversible plastic trait that changes with environmental and ecological circumstances, albeit being heritable and susceptible to selection. Inter-individual variation within populations of small birds is substantial, and while many of the drivers of such variation have been identified, many remain unexplained. We studied winter BMR variation of juveniles over a 15-year period in a wild population of great tits Parus major at the northern border of their distribution. BMR during winter consistently changed between years, even after controlling for environmental factors, suggestive of a non-reversible developmental plasticity shaping the adult metabolic phenotype. BMR in cohorts of wintering great tits varied among winters as a response to minimum ambient temperatures experienced early in life, during the prehatching period. This developmental plasticity might be adaptive if temperatures experienced by growing embryos would metabolically prime them to an environment that they will likely encounter in future life. However, in line with a more unpredictable future climate, the risk of phenotype-environment mismatch is likely to lead to certain cohorts being poorly adapted to prevailing winter conditions, resulting in wider annual fluctuations in population size., Open access funding provided by Lund University. JB has been funded by the Andalucía Talent Hub Program launched by the Andalusian Knowledge Agency, co-funded by the European Union’s Seventh Framework Program, Marie Skłodowska-Curie actions (COFUND—Grant Agreement no 291780) and the Ministry of Economy, Innovation, Science and Employment of the Junta de Andalucía. Supported by the Academy of Finland projects no. 102286 and 47195, and the Thule Institute of the University of Oulu (JB and EH) and by grants from the Swedish Research Council no. S-AA/F0 09677-311, B 650-19981108/2000, 629-2002-1893 and 621-2003-2912 (JÅN).

Includes phenological and climate data used for analysis of article titled 'Bird populations most exposed to climate change are less sensitive to climatic variation' (Nature Communications). Each data file is described below, with a description of all columns. - baileyetal_phenology_data.csv: Primary data used as the basis for all analysis. Column name Description Pop_ID Unique population ID. Species Species ID. Can be either GT (great tit/Parus major) or BT (blue tit/Cyanistes caeruleus). Sample_year Calendar year in which laying date was recorded. Mean Mean laying date (April days). SE Standard error of mean laying date (April days). Min Minimum observed laying date (April days). Count Total number of first nests laying date records for this population/species/year combination. Date Starting date used sliding window analysis (dd/mm/yyyy). SE_calc Inverse of standard error (1/SE), used to weight statistical models. Temp Mean temperature (oC) within population specific temperaturewindow - Pop_info.csv:Information about each study location where data were collected. Column name Description Site_Name Full name of study site Pop_ID Unique population ID Habitat_Type Either deciduous dominant (DEC), evergreen dominant (EVE), or mixed (MIX). Latitude Latitudinal coordinates of study site Longitude Longitudinal coordinates of study site Latitude_new_temp Latitudinal coordinates used to extract data from ECA&D gridded dataset. In most cases this will be identical to column Latitude; however, in 4 cases (Sagunto, Cardiff, Barcelona, Askainen) latitude is shifted slightly to overlap with the gridded dataset. Longitude_new_temp Longitudinal coordinates used to extract data from ECA&D gridded dataset. In most cases this will be identical to column Longitude; however, in 4 cases (Sagunto, Cardiff, Barcelona, Askainen) longitude is shifted slightly to overlap with the gridded dataset. -Sicily_temp_data.csv:Temperature data from study population in Sicily used to fit temperature window. Column name Description Year Year of temperature data collection Month Month of temperature data collection Day Day of temperature data collection Temperature Mean daily temperature (oC) -Vlieland_temp_data_old.csv: Temperature data used to determine temperature windows for Vlieland, Netherlands (1954 - 2016). Column name Description STN KNMI station number Date Date of weather data (dd/mm/yyyy) Mean Daily mean temperature (oC) Min Daily minimum temperature (oC) Max Daily maximum temperature (oC) -Vlieland_temp_data_new.csv: Temperature data used to determine temperature windows for Vlieland, Netherlands (1996 - 2017). Column name Description Station_no KNMI station number Date Date of weather data (yyyymmdd) Mean Daily mean temperature (oC) Min Daily minimum temperature (oC) Max Daily maximum temperature (oC) -slidingwin_results.rar:Compressed file containing results of sliding time window analysis for all population/species combinations. Each population/species combination has three corresponding files: - PopID_Sp.RDS: Results of sliding time window analysis. - PopID_Sp_rand.RDS: Results of randomization procedure to deal with issues of multiple testing. - PopID_Sp_SEM.RDS: Results of structural equation model used to apply detrending to analysis.

Milk polar lipids provide choline, ethanolamine, and polyunsaturated fatty acids, which are needed for the growth and plasticity of the tissues in a suckling child. They may also inhibit cholesterol absorption by interacting with cholesterol during micelle formation. They may also have beneficial luminal, mucosal, and metabolic effects in both the neonate and the adult. The milk fat globule membrane contains large proportions of sphingomyelin (SM), phosphatidylcholine (PC), and phosphatidylethanolamine (PE), and some phosphatidylserine (PS), phosphatidylinositol (PI), and glycosphingolipids. Large-scale technical procedures are available for the enrichment of milk fat globule membrane (MFGM) in milk replacement formulations and food additives. Pancreatic phospholipase A2 (PLA2) and mucosal phospholipase B digest glycero-phospholipids in the adult. In the neonate, where these enzymes may be poorly expressed, pancreatic lipase-related protein 2 probably has a more important role. Mucosal alkaline SM-ase and ceramidase catalyze the digestion of SM in both the neonate and the adult. In the mucosa, the sphingosine is converted into sphingosine-1-phosphate, which is both an intermediate in the conversion to palmitic acid and a signaling molecule. This reaction sequence also generates ethanolamine. Here, we summarize the pathways by which digestion and absorption may be linked to the biological effects of milk polar lipids. In addition to the inhibition of cholesterol absorption and the generation of lipid signals in the gut, the utilization of absorbed choline and ethanolamine for mucosal and hepatic phospholipid synthesis and the acylation of absorbed lyso-PC with polyunsaturated fatty acids to chylomicron and mucosal phospholipids are important.

Human view on nature has fluctuated over time, depending on contemporary knowledge and beliefs. In recent centuries, the view has shifted from an instrumental to an existential apprehension of natu ...

Animals typically respond to stressful stimuli such as handling by increasing core body temperature. However, small birds in cold environments have been found to decrease body temperature (Tb) when handled over longer periods, although there are no data extending beyond the actual handling event in such birds. We therefore measured both the initial Tb decrease during ringing and standardized Tb sampling, and subsequent recovery of Tb after this handling protocol in wild Great Tits Parus major roosting in nestboxes in winter. Birds reduced their Tb by 2.3 °C during c. 4 min of handling. When birds were returned to their nestboxes after handling, Tb decreased by a further 1.9 °C over c. 2 min, reaching a Tb of 34.6 °C before taking 20 min to rewarm to 2.5 °C above their initial Tb. The Tb reduction during handling could be a consequence of increased heat loss rate from disrupted plumage insulation, whereas Tb reduction after handling might reflect reduced heat production. These are important factors to consider when handling small birds in the cold.

ObjectiveTo investigate the risk of cancer in patients with biopsy-proven giant cell arteritis (GCA) from a defined population in southern Sweden.Methods.The study cohort consisted of 830 patients (mean age at GCA diagnosis was 75.3 yrs, 74% women) diagnosed with biopsy-proven GCA between 1997 and 2010. Temporal artery biopsy results were retrieved from a regional database and reviewed to ascertain GCA diagnosis. The cohort was linked to the Swedish Cancer Registry. The patients were followed from GCA diagnosis until death or December 31, 2013. Incident malignancies registered after GCA diagnosis were studied. Based on data on the first malignancy in each organ system, age- and sex-standardized incidence ratios (SIR) with 95% CI were calculated compared to the background population.Results.One hundred seven patients (13%) were diagnosed with a total of 118 new malignancies after the onset of GCA. The overall risk for cancer after the GCA diagnosis was not increased (SIR 0.98, 95% CI 0.81–1.17). However, there was an increased risk for myeloid leukemia (2.31, 95% CI 1.06–4.39) and a reduced risk for breast cancer (0.33, 95% CI 0.12–0.72) and upper gastrointestinal tract cancer (0.16, 95% 0.004–0.91). Rates of other site-specific cancers were not different from expected.Conclusion.In this Swedish population-based cohort of GCA, the overall risk for cancer was not increased compared to the background population. However, there was an increased risk for leukemia and a decreased risk for breast and upper gastrointestinal tract cancer.

Billions of animals migrate between breeding and non-breeding areas worldwide. Partial migration, where both migrants and residents coexist within a population, occurs in most animal taxa, including fish, insects, birds and mammals. Partial migration has been hypothesised to be the most common form of migration and to be an evolutionary precursor to full migration. Despite extensive theoretical models about partial migration and its potential to provide insight into the ecology and evolution of migration, the physiological mechanisms that shape partial migration remain poorly understood. Here, we review current knowledge on how physiological processes mediate the causes and consequences of avian partial migration, and how they may help us understand why some individuals migrate and others remain resident. When information from birds is missing, we highlight examples from other taxa. In particular, we focus on temperature regulation, metabolic rate, immune function, oxidative stress, telomeres, and neuroendocrine and endocrine systems. We argue that these traits provide physiological pathways that regulate the ecological and behavioural causes and/or consequences of partial migration, and may provide insight into the mechanistic basis of wintering decisions. They may, thus, also help us to explain why individuals switch strategies among winters. We also highlight current gaps in our knowledge and suggest promising future research opportunities. A deeper understanding of the physiological mechanisms mediating the causes and consequences of partial migration will not only provide novel insights into the ecology and evolution of migration in general, but will also be vital to precisely modelling population trends and predicting range shifts under global change.

Small animals that winter at northern latitudes need to maximize energy intake and minimize energy loss. Many passerine birds use night-time hypothermia to conserve energy. A potential cost of night-time hypothermia with much theoretical (but little empirical) support is increased risk of night-time predation, due to reduced vigilance and lower escape speed in hypothermic birds. This idea has never been tested in the wild. We, therefore, increased perceived predation risk in great tits (Parus major) and blue tits (Cyanistes caeruleus) roosting in nest boxes during cold winter nights to measure any resultant effect on their use of night-time hypothermia. Roosting birds of both species that experienced their first winter were less prone to use hypothermia as an energy-saving strategy at low ambient temperatures when exposed to increased perceived predation risk either via handling (great tits) or via predator scent manipulation (blue tits). However, we did not record such effects in birds that were in their second winter or beyond. Our results suggest that effects of increased predation risk are age- and temperature specific. This could be caused by age-related differences in experience and subsequent risk assessment, or by dominance-related variation in habitat quality between young and old birds. Predation risk could, through its effect on use and depth of night-time hypothermia, be important for total energy management and winter survival for resident birds at northern latitudes.

The “heat dissipation limit” theory (HDL) posits that animals with higher capacity to dissipate metabolic heat can increase reproductive investment. This theory remains untested in the wild. We recently showed that increased workload in a small bird causally relates to maximum body temperature. Here, we have expanded this approach by experimentally facilitating sensible heat transfer rate in nestling-feeding blue tits—a small bird with high resting- and work-induced body temperatures—through removal of ventral plumage. Feather-clipped parents did not increase work rate but sired larger, and sometimes heavier, nestlings while maintaining lower body temperature and losing less body mass than controls. Thus, when relieved of the demands to dissipate metabolic heat, parents could invest more into both current (nestling condition) and future (self-maintenance) reproduction. In accordance with the HDL theory, we conclude that constraints on heat dissipation rate could be a potent mediator of life-history trade-offs in wild animals. A plain language summary is available for this article. (Less)

Parasites exert a strong selection pressure on their hosts as manifested in behavioural antiparasite traits to reduce negative impacts on fitness. The numerous nest-dwelling ecto-parasites residing in avian nests make altricial birds excellent model-systems for investigating the relationship between parasites and their hosts. Here, we experimentally increased natural levels of hen fleas Ceratophyllus gallinae in blue tit Cyanistes caeruleus nests during incubation, and tested their effects on parental incubation behaviours and reproductive performance. Our experimental addition of fleas resulted in an increase in feeding effort of males to incubating females. Frequency of male feedings was also positively related to clutch size. These results suggest that males increase their reproductive effort in flea manipulated and large broods. This will, at least partly, compensate female costs in nests with high ecto-parasite density and many nestlings. Furthermore, nestling mass at day six in experimental nests decreased with brood size, which was not the case in nests with a natural level of fleas. In line with male incubation feeding, parents may try to compensate for the costs inflicted by the fleas but can only partly compensate when brood size is large. (Less)

Background Radiographic damage in rheumatoid arthritis (RA) includes erosions and joint space narrowing (JSN). Different mechanisms may underlie their development. The objective of this study was to evaluate predictors of these entities separately. Methods Consecutive early RA patients (symptom duration ≤12 months) from a defined area (Malmö, Sweden) recruited during 1995–2005 were investigated. Radiographs of hands and feet were scored by a trained reader according to the modified Sharp-van der Heijde score. Fat mass and lean mass distribution were measured at baseline using dual energy x-ray absorptiometry. Potential predictors of erosion and JSN progression from inclusion to the 5-year follow-up were evaluated. Results Two hundred and thirty-three patients were included. Radiographs at baseline and 5 years were available for 162 patients. The median (interquartile) progression of erosion and JSN scores were 4 (0–8) and 8 (1–16), respectively. Rheumatoid factor (RF) was a robust significant predictor of both erosion and JSN score progression. In adjusted analyses, anti-CCP antibodies predicted erosions while the erythrocyte sedimentation rate was predictive of both outcomes. Smoking and high baseline disease activity (DAS28 > 5.1) predicted progression of erosions. Baseline erosion score was associated with progression of both erosion and JSN progression, while baseline JSN score was predictive only of the progression of JSN. Overweight/obesity (BMI ≥ 25 kg/m2) was a significant negative predictor of JSN score progression (β = − 0.14, p = 0.018, adjusted for RF, age, baseline JSN score) also when additionally adjusting for ever smoking (p = 0.041). Among female patients, this effect was observed in those of estimated post-menopausal age (> 51 years), but not in younger women. The truncal to peripheral fat ratio was associated with less JSN score progression in women, but not in men. Conclusions Overweight RA patients had less JSN progression, independent of smoking status. This effect was seen in particular among older women (mainly post-menopausal), but not younger. Truncal fat was associated with less JSN progression in female patients. Smoking predicted erosion progression, and erosions may precede JSN. BMI and fat distribution may influence cartilage damage in early RA and might be related to hormonal factors.

Background: Rupture of atherosclerotic plaques is the major cause of acute cardiovascular events. The biomarker PRO-C6 measuring Endotrophin, a matrikine of collagen type VI, may provide valuable information detecting subjects in need of intensified strategies for secondary prevention.Objective: In this study, we evaluate endotrophin in human atherosclerotic plaques and circulating levels of PRO-C6 in patients with atherosclerosis, to determine the predictive potential of the biomarker. Methods: Sections from the stenotic human carotid plaques were stained with the PRO-C6 antibody. PRO-C6 was measured in serum of patients enrolled in the Carotid Plaque Imagining Project (CPIP) (discovery cohort, n = 577) and the innovative medicines initiative surrogate markers for micro- and macrovascular hard end-points for innovative diabetes tools (IMI-SUMMIT, validation cohort, n = 1,378). Median follow-up was 43 months. Kaplan–Meier curves and log-rank tests were performed in the discovery cohort. Cox proportional hazard regression analysis (HR with 95% CI) was used in the discovery cohort and binary logistic regression (OR with 95% CI) in the validation cohort. Results: PRO-C6 was localized in the core and shoulder of the atherosclerotic plaque. In the discovery cohort, PRO-C6 independently predicted future cardiovascular events (HR 1.089 [95% CI 1.019 −1.164], p = 0.01), cardiovascular death (HR 1.118 [95% CI 1.008 −1.241], p = 0.04) and all-cause death (HR 1.087 [95% CI 1.008 −1.172], p = 0.03). In the validation cohort, PRO-C6 predicted future cardiovascular events (OR 1.063 [95% CI 1.011 −1.117], p = 0.017). Conclusion: PRO-C6 is present in the atherosclerotic plaque and associated with future cardiovascular events, cardiovascular death and all-cause mortality in two large prospective cohorts.

Background: Giant cell arteritis (GCA) is a systemic disease with extensive vascular involvement. There is limited and conflicting information on the relation between patient characteristics at diagnosis and future disease phenotypes. We aimed to investigate predictors of time dependent large vessel involvement (LVI) in a population-based cohort of patients with GCA. Methods: GCA patients with positive temporal artery biopsies (TAB) between 1997and 2010 were identified through a regional pathology register. A structured review of histopathology reports and relevant imaging studies was performed. Cases with LVI through July 2016 were identified. Patients were followed to first LVI, death, migration from the area or July 29, 2016. Event free survival by clinical and histopathologic features was estimated using the Kaplan-Meier method. Potential predictors of LVI were examined using Cox regression models.Results: A total of 274 patients were included. The mean age at GCA diagnosis was 75.7 years. Fifty-one patients (19 %) had documented LVI during the follow-up, corresponding to an incidence rate of 2.4/100 person-years. The median time from GCA diagnosis to the diagnosis of LVI was 4.5 years (interquartile range 0.6-7.4). Thirty-four patients had aortic involvement (67% of those with LVI; 12% of all GCA cases). Survival free of LVI was longer in patients with giant cells in the TAB (75th percentile 14.0 vs 6.7 years; p=0.014). In age-adjusted analysis, the presence of giant cells in the TAB was associated with reduced risk of LVI (hazard ratio 0.48; 95 % confidence interval 0.27-0.86). Conclusions: The negative association with giant cells in the TAB suggests that patients with LVI constitute a subset of GCA with particular disease mechanisms. This underlines the heterogeneity of GCA, which should be further explored in prospective studies.

Background and purpose CD40 and CD40 ligand (CD40L) are costimulatory molecules and members of the TNF receptor superfamily well known for their involvement in inflammatory and autoimmune diseases. This study uses two large human cohorts – the SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) and the Carotid Plaque Imaging Project (CPIP) – to explore the potential of plasma or intra-plaque expression of CD40 and CD40L as biomarkers and to locally affect plaque stability. Methods Proximity Extension Assay (PEA) technique was used to measure soluble CD40 and CD40L (sCD40 and sCD40L) in plasma from 1437 subjects from the SUMMIT cohort, the majority of which (80%) with pre-existing cardiovascular disease, and in atherosclerotic plaque homogenates from 199 subjects of the CPIP cohort undergoing carotid endarterectomy. The Mann-Whitney U test was used to compare groups and Spearman's rank correlation/the Chi-square test was used to assess correlations. Multiple comparisons were corrected for using the Holm-Šídák test. A logistic regression model was used to test for associations with future cardiovascular events and mortality. Results In the SUMMIT cohort both plasma CD40 and CD40L levels were elevated in individuals with a history of stroke (p=0.000030 and p=0.020, respectively), while sCD40 levels also were higher in individuals with a prior acute myocardial infarction (p=0.016). Plasma levels of sCD40 correlated with carotid plaque burden (as measured by ultrasound imaging, r=0.355, p sCD40 and sCD40L were associated with a plaque phenotype characterized by the strong presence of features both of vulnerability such as high content oxidized low-density lipoprotein (LDL; r=0.236, p=0.004 and r=0.259, p=0.0037, respectively) and pro-inflammatory cytokines (e.g. tumour necrosis factor-α: p=3.1x10–7 and p=0.0006, respectively) and low calcium content (r=−0.208, p=0.012 and r=0.268, p=0.00034, respectively). Conclusion High plasma CD40 and CD40L levels are associated with symptomatic cardiovascular disease. Plasma CD40 levels correlate with the severity of carotid atherosclerosis and are associated with an increased risk for future cardiovascular events. Additionally, intra-plaque levels are associated with a vulnerable plaque phenotype. Our findings thus support the value of sCD40 and sCD40L both as biomarkers and therapeutic targets for cardiovascular disease. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Swedish Heart and Lung Foundation (1) and the Swedish Research Council (2)

Background Following acute myocardial infarction (MI), the left ventricle undergoes molecular and extracellular matrix (ECM) changes. The ECM is a dynamic structure with a potential role in cardiac remodeling post-MI. Collagens are the major components of both cardiac and arterial ECM. Purpose We evaluated circulating levels of type I, IV and VI collagen fragments in two cohorts of patients with acute MI to investigate collagen turnover post-MI. The cohorts were Malmö AMI in elderly (MAMI-Y) and Assessing Platelet Activity in Coronary Heart Disease (APACHE). Methods Serum was collected from 190 patients from the discovery cohort (MAMI-Y: mean age 74, SD 10.8) at four timepoints: admission when MI, after 3–6 days, 6 weeks, 12 months; citrate plasma was collected from 142 patients from the validation cohort (APACHE: mean age 65, SD 11.6) at four timepoints: hospitalization, 3 days, 7–9 days, 6 months. The biomarkers of matrix metalloproteinase (MMP)-mediated degradation of type I collagen (C1M), MMP-mediated degradation of type IV collagen (C4M) and formation of type VI collagen (PRO-C6) were measured at all timepoints (immunosorbent assays). Differences in the markers at the different timepoints were calculated using repeated measures ANOVA. Results Circulating levels of the formation biomarker PRO-C6 significantly increased from baseline and remained high at all three following timepoints in both MAMI-Y and APACHE studies (all p Conclusions We observed changes in circulating fragments reflecting collagen turnover in the acute phase post-MI, more pronounced in STEMI patients. This may indicate that STEMI patients have more active collagen remodeling than NSTEMI patients and may have more altered left ventricle function and remodeling. Funding Acknowledgement Type of funding source: Other. Main funding source(s): This work was supported by the Danish Research Foundation “den danske forskningsfond”, the Innovation foundation (Innovationsfonden), Swedish Research Council, Swedish Heart and Lung Foundation, Swedish Society for Medical Research, Swedish Society of Medicine, the Crafoord Foundation, the Åke Wiberg foundation and the Stroke foundation.

Background/Introduction Activation of the receptor for advanced glycation end products (RAGE) by AGEs and various immune mediators has pro-inflammatory and pro-atherogenic effects. RAGE also exists in a soluble form, sRAGE, that acts as a decoy receptor for RAGE ligands. Low plasma sRAGE has previously been found to be associated with a higher risk for major adverse coronary events (MACE) in the population. Purpose The purpose of our study was to examine the causality of the association, by exploring whether genetic variants that influence sRAGE are associated with atherosclerosis progression and incident MACE and mortality in the population. Methods We performed a genome-wide association study (GWAS) in 4192 individuals from a randomly selected subgroup of a population-based cohort. Subsequently, we explored the associations between the identified single nucleotide polymorphims (SNPs) associated with plasma sRAGE levels, baseline intima media thickness (IMT) and IMT progression in the common carotid artery during a median follow-up of 16.5 years. Further, we analyzed the prospective relationships between the sRAGE-associated SNPs, incident MACE and mortality in the entire population-based cohort of 29245 individuals. The median follow-up time from baseline was 21.2 years for MACE and 21.6 years for total mortality (time to event or end of follow-up). Results We found the minor alleles of two single nucleotide polymorphisms (SNPs), rs2070600 and rs204993, to be independently associated with lower plasma sRAGE. While rs204993 is a silent intronic mutation, rs2070600 is known to cause a Gly82Ser polymorphism in the ligand binding domain, enhancing RAGE propensity for activation. In Cox regression analyses, we found an association between the minor T (vs. C) allele of rs2070600 and increased risk for first-time MACE [HR 1.12 (1.02–1.23); P=0.023]. The association was independent of traditional cardiovascular risk factors, blood pressure-lowering medication and lipid-lowering medication at baseline. rs204993 was not associated with MACE. Neither SNP was associated with carotid IMT at baseline or with IMT progression. We did not identify any relationships with total mortality. Conclusions We demonstrate for the first time an independent link between a genetic RAGE determinant and the risk for MACE in the population. Despite both identified SNPs being associated with lower sRAGE levels, only the functional rs2070600 mutation was associated with MACE, suggesting that the link is probably due to the enhancement of RAGE function rather than to the sRAGE lowering effect. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This study was supported by grants from the Swedish Research Council and the Swedish Heart and Lung foundation.

Weather influences both the distribution and life-history strategies of birds. Temperature ranks amongst the more important weather parameters in this regard since warming springs in temperate and high latitudes and more frequent heat-waves globally have caused major changes in breeding phenology and negatively affected adult and juvenile survival, respectively. Both long-term and stochastic changes in temperature can have fundamental consequences for avian reproduction even when the effects are not lethal, such as via thermal constraints on parental provisioning and chick growth. To date, most of what we know about temperature effects on nestling development and parental effort during reproduction is based on correlative data. In addition, an increasing amount of evidence indicates that temperature change also significantly affects birds that breed in cooler temperate areas, which so far has been somewhat overlooked. Therefore, in this perspective piece, we outline the existing literature on temperature effects on nestling development and parental behavior, with an emphasis on what needs to be done to address the causal effects of temperature change on avian reproduction under climate change. We finish by providing an outlook over future avenues of research, and give suggestions of some specific areas that might be especially promising in developing this field of research.

The phenology of many species shows strong sensitivity to climate change; however, with few large scale intra-specific studies it is unclear how such sensitivity varies over a species’ range. We document large intra-specific variation in phenological sensitivity to temperature using laying date information from 67 populations of two European songbirds covering a large part of their breeding range. Populations inhabiting deciduous habitats showed stronger phenological sensitivity compared with those in evergreen and mixed habitats. Strikingly, however, the lowest sensitivity was seen in populations that had experienced the greatest change in climate. Therefore, we predict that the strongest phenological advancement will not occur in those populations with the highest sensitivity. Our results show that to effectively assess the impact of climate change on phenology across a species range it will be necessary to account for intra-specific variation in phenological sensitivity, climate change exposure, and the ecological characteristics of a population.

Objective Autoantibodies, such as anti-citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral density (BMD). We therefore examined the association between osteoporosis and autoantibodies in two independent RA cohorts.Methods Dual x-ray absorptiometry (DXA) of the lumbar spine and left hip was performed in 408 Dutch patients with early RA during 5 years of follow-up and in 198 Swedish patients with early RA during 10 years of follow-up. The longitudinal effect of ACPAs and other autoantibodies on several BMD measures was assessed using generalized estimating equations.Results In the Dutch cohort, significantly lower BMD at baseline was observed in ACPA-positive patients compared to ACPA-negative patients, with an estimated marginal mean BMD in the left hip of 0.92 g/cm(2) (95% confidence interval [95% CI] 0.91-0.93) versus 0.95 g/cm(2) (95% CI 0.93-0.97) (P = 0.01). In line with this, significantly lower Z scores at baseline were noted in the ACPA-positive group compared to the ACPA-negative group (estimated marginal mean Z score in the left hip of 0.18 [95% CI 0.08-0.29] versus 0.48 [95% CI 0.33-0.63]) (P < 0.01). However, despite clear differences at baseline, ACPA positivity was not associated with greater decrease in absolute BMD or Z scores over time. Furthermore, there was no association between BMD and higher levels of ACPAs or other autoantibodies (rheumatoid factor and anti-carbamylated protein antibodies). In the Swedish cohort, ACPA-positive patients tended to have a higher prevalence of osteopenia at baseline (P = 0.04), but again, ACPA positivity was not associated with an increased prevalence of osteopenia or osteoporosis over time.Conclusion The presence of ACPAs is associated with significantly lower BMD at baseline, but not with greater BMD loss over time in treated RA patients. These results suggest that ACPAs alone do not appear to contribute to bone loss after disease onset when disease activity is well-managed.

The combination of short days and long cold winter nights, in temperate regions, presents a major challenge for small diurnal birds. Small birds regularly employ heterothermy and enter rest-phase hypothermia during winter nights to conserve energy. However, we know little about how environmental conditions, such as food availability, shape these strategies. We experimentally manipulated food availability in winter to free-living great tits Parus major. A ‘predictable' and constant food supply was provided to birds in one area of a forest, while birds in another area did not have access to a reliable supplementary food source. We found that predictability of food affected the extent of nocturnal hypothermia, but the response differed between the sexes. Whereas male nocturnal body temperature was similar regardless of food availability, females exposed to a naturally ‘unpredictable' food supply entered deeper hypothermia at night, compared with females that had access to predictable food and compared with males in both treatment groups. We suggest that this response is likely a consequence of dominance, and subdominant females subject to unpredictable food resources cannot maintain sufficient energy intake, resulting in a higher demand for energy conservation at night.

Objective.To investigate the association between infections and the subsequent development of giant cell arteritis (GCA) in a large population-based cohort from a defined geographic area in Sweden.Methods.Patients diagnosed with biopsy-confirmed GCA between 2000 and 2016 were identified through the database of the Department of Pathology in Skåne, the southernmost region of Sweden. For each GCA case, 10 controls matched for age, sex, and area of residence were randomly selected from the general population. Using the Skåne Healthcare Register, we identified all infection events prior to patients’ date of GCA diagnosis and controls’ index date. With infection as exposure, a conditional logistic regression model was employed to estimate the OR for developing GCA. The types of infections contracted nearest in time to the GCA diagnosis/index date were identified.Results.A total of 1005 patients with biopsy-confirmed GCA (71% female) and 10,050 controls were included in the analysis. Infections were more common among patients subsequently diagnosed with GCA compared to controls (51% vs 41%, OR 1.78, 95% CI 1.53–2.07). Acute upper respiratory tract infection (OR 1.77, 95% CI 1.47–2.14), influenza and pneumonia (OR 1.72, 95 % CI 1.35–2.19), and unspecified infections (OR 5.35, 95 % CI 3.46–8.28) were associated with GCA. Neither skin nor gastrointestinal infections showed a correlation.Conclusion.Infections, especially those of the respiratory tract, were associated with subsequent development of biopsy-confirmed GCA. Our findings support the hypothesis that a range of infections may trigger GCA.

Background There are limited data regarding efficacy of abatacept treatment for rheumatoid arthritis (RA) outside clinical trials. Quality registers have been useful for observational studies on tumor necrosis factor inhibition in clinical practice. The aim of this study was to investigate clinical efficacy and tolerability of abatacept in RA, using a national register. Methods RA patients that started abatacept between 2006 and 2017 and were included in the Swedish Rheumatology Quality register (N = 2716) were investigated. Survival on drug was estimated using Kaplan-Meier analysis. The European League Against Rheumatism (EULAR) good response and Health Assessment Questionnaire (HAQ) response (improvement of ≥ 0.3) rates (LUNDEX corrected for drug survival) at 6 and at 12 months were assessed. Predictors of discontinuation were investigated by Cox regression analyses, and predictors of clinical response by logistic regression. Significance-based backward stepwise selection of variables was used for the final multivariate models. Results There was a significant difference in drug survival by previous biologic disease-modifying antirheumatic drug (bDMARD) exposure (p Conclusions In this population-based study of RA, bDMARD naïve patients and male patients were more likely to remain on abatacept with a major clinical response.

Additional file 3. Proportions of patients achieving LUNDEX corrected DAS 28 remission by previous bDMARD exposure. *p

Background and purpose ��� As previous studies indicate time trends in pediatric fracture incidence, we followed the incidence in a Swedish city between 1950 and 2016. Patients and methods ��� Malm�� city, Sweden had 322,574 inhabitants in 2015. We used diagnosis registry, charts, and radiographs of the only city hospital to classify fractures in individuals < 16 years in 2014���2016, and compared these with data from 1950���2006. We used joinpoint regression to analyze time trends and present results as mean annual percentage changes (APC). Differences between periods are described as incident rate ratios (IRR). To describe uncertainty, 95% confidence intervals (CI) are used. Results ��� During 2014���2016 the pediatric fracture incidence was 1,786 per 105 person-years (boys 2,135 and girls 1,423). From 1950 onwards age-adjusted fracture incidence increased until 1979 in both boys (APC +1.5%, CI 1.2���1.8) and girls (APC +1.6%, CI 0.8���2.5). The incidence remained stable from 1979 to 2016 (APC in boys 0.0%, CI ���0.3 to 0.3 and in girls ���0.2%, CI ���1.1 to 0.7). Age-adjusted incidence 2014���2016 was higher than 2005���2006 in girls (IRR 1.1, CI 1.03���1.3), but not in boys (IRR 1.0, CI 0.9���1.1). Interpretation ��� Fracture incidence was in girls higher in 2014���2016 than in 2005���2006. However, only with more than 2 measuring points are meaningful trend analyses possible. When we analyzed the period 1950���2016 with 17 measuring points and joinpoint regression, we found that fracture incidence increased in both sexes until 1979 but has thereafter been stable.