Thermoregulatory costs of the innate immune response are modulated by winter food availability in a small passerine.

In winter, a challenge to the immune system could pose a major energetic trade-off for small endotherms, whereby increasing body temperature (Tb ; i.e. eliciting fever) may be beneficial to fight off invading pathogens yet incur a cost for vital energy-saving mechanisms. Having previously shown that the availability and acquisition of energy, through manipulation of food predictability, influences the depth of rest-phase hypothermia in a wild bird in winter, we expected that the nocturnal thermoregulatory component of the acute-phase immune response would also be modulated by food availability. By manipulating winter food availability in the wild for great tits Parus major, we created an area offering a "predictable" and constant supply of food at feeding stations, while an unmanipulated area was subject to naturally "unpredictable" food. Birds were subject to an immune challenge shortly after dusk, and the thermoregulatory response was quantified via continuous recording of nocturnal Tb , using subcutaneous thermo-sensitive transponders. In response to immune challenge, all birds increased Tb above the level maintained prior to immune challenge (i.e. baseline). However, birds experiencing a naturally unpredictable food supply elevated Tb more than birds subject to predictable food resources, during the period of expected peak response and for the duration of the night. Furthermore, "unpredictable-food" females took longer to return to their baseline Tb . Assuming baseline nocturnal Tb reflects an individual's optimum, based on their available energy budget, the metabolic cost of eliciting an acute-phase response for "unpredictable-food" birds was more than double that of "predictable-food" birds. The absence of differences in absolute Tb during the peak response could support the idea of an optimal Tb for immune system activation. Alternatively, "predictable-food" birds could have acquired tolerance to endotoxin as a result of using feeding stations, thus affording them reduced costs associated with a smaller Tb increase. These findings shed new light on the trade-offs associated with food acquisition, thermoregulation and immune function in small-bodied endotherms. This knowledge is of increasing importance, given the predicted elevated pathogen risks associated with changes in climate and anthropogenic activities.

How does a physical activity programme in elementary school affect fracture risk? A prospective controlled intervention study in Malmo, Sweden.

OBJECTIVES: Recent evidence from the 7-year follow-up of the Pediatric Osteoporosis Prevention (POP) study indicates an inverse correlation between years of participation in a physical activity (PA) intervention and fracture risk in children. However, we could not see a statistically significant reduction in fracture risk, which urged for an extension of the intervention. SETTING: The study was conducted in 4 neighbouring elementary schools, where 1 school functioned as intervention school. PARTICIPANTS: We included all children who began first grade in these 4 schools between 1998 and 2012. This resulted in 1339 children in the intervention group and 2195 children in the control group, all aged 6-8 years at the state of the study. INTERVENTION: We launched an 8-year intervention programme with 40 min of moderate PA per school day, while the controls continued with the Swedish national standard of 60 min of PA per week. PRIMARY OUTCOME MEASURE: We used the regional radiographic archive to register objectively verified fractures and we estimated annual fracture incidences and incidence rate ratios (IRRs). RESULTS: During the first year after initiation of the intervention, the fracture IRR was 1.65 (1.05 to 2.08) (mean 95% CI). For each year of the study, the fracture incidence rate in the control group compared with the intervention group increased by 15.7% (5.6% to 26.8%) (mean 95% CI). After 8 years, the IRR of fractures was 52% lower in the intervention group than in the control group (IRR 0.48 (0.25 to 0.91) (mean 95% CI))]. CONCLUSIONS: Introduction of the school-based intervention programme is associated with a higher fracture risk in the intervention group during the first year followed by a gradual reduction, so that during the eighth year, the fracture risk was lower in the intervention group. TRIAL REGISTRATION NUMBER: NCT00633828.

Costs in Relation to Disability, Disease Activity, and Health-related Quality of Life in Rheumatoid Arthritis: Observational Data from Southern Sweden.

OBJECTIVE: To compare how costs relate to disability, disease activity, and health-related quality of life (HRQOL) in rheumatoid arthritis (RA). METHODS: Antitumor necrosis factor (anti-TNF)-treated patients with RA in southern Sweden (n = 2341) were monitored 2005-2010. Health Assessment Questionnaire (HAQ), 28-joint Disease Activity Score (DAS28), and EQ-5D scores were linked to register-derived costs of antirheumatic drugs (excluding anti-TNF agents), patient care, and work loss from 30 days before to 30 days after each visit (n = 13,289). Associations of HAQ/DAS28/EQ-5D to healthcare (patient care and drugs) and work loss costs (patients < 65 yrs) were studied in separate regression models, comparing standardized ß coefficients by nonparametric bootstrapping to assess which measure best reflects costs. Analyses were conducted based on both individual means (linear regression, comparing between-patient associations) and by generalized estimating equations (GEE), using all observations to also account for within-patient associations of HAQ/DAS28/EQ-5D to costs. RESULTS: Regardless of the methodology (linear or GEE regression), HAQ was most closely related to both cost types, while work loss costs were also more closely associated with EQ-5D than DAS28. The results of the linear models for healthcare costs were standardized ß = 0.21 (95% CI 0.15-0.27), 0.16 (0.11-0.21), and -0.15 (-0.21 to -0.10) for HAQ/DAS28/EQ-5D, respectively (p < 0.05 for HAQ vs DAS28/EQ-5D). For work loss costs, the results were standardized ß = 0.43 (95% CI 0.39-0.48), 0.27 (0.23-0.32), and -0.34 (-0.38 to -0.29) for HAQ/DAS28/EQ-5D, respectively (p < 0.05 for HAQ vs DAS28/EQ-5D and for EQ-5D vs DAS28). CONCLUSION: Overall, HAQ disability is a better marker of RA costs than DAS28 or EQ-5D HRQOL.

The assessment of serum-mediated phagocytosis of necrotic material by polymorphonuclear leukocytes to diagnose and predict the clinical features of systemic lupus erythematosus: an observational longitudinal study.

BACKGROUND: Serum-mediated phagocytosis of antibody- and complement-opsonized necrotic cell material (NCM) by polymorphonuclear leukocytes can be quantified by using a flow cytometry-based assay. The phagocytosis of necrotic cell material (PNC) assay parallels the well-known lupus erythematosus cell test. In this study, we aimed to investigate the diagnostic accuracy of the assay and the relationship with clinical manifestations and disease activity in systemic lupus erythematosus (SLE). METHODS: The diagnostic accuracy for SLE diagnosis of the PNC assay was studied by cross-sectional assessment of blood samples from 148 healthy control subjects and a multicenter rheumatic group (MRG) of 529 patients with different rheumatic symptoms. A cohort of 69 patients with an established SLE diagnosis (SLE cohort) underwent longitudinal clinical and laboratory follow-up for analysis of the temporal relationships between PNC positivity and specific clinical manifestations. RESULTS: In 35 of 529 MRG patients, 13 of whom had SLE, the PNC assay result was positive. Combined positivity of the PNC assay and anti-double-stranded DNA antibodies increased specificity and positive predictive value for SLE diagnosis to 0.99 and 0.67, respectively. In the longitudinal study, 42 of 69 SLE cohort patients had positive results in the PNC assay at least once. PNC assay positivity was associated with current hematological manifestations and could predict mucocutaneous manifestations. When combined with hypocomplementemia, PNC positivity preceded increased Systemic Lupus Erythematosus Disease Activity Index 2000 score, glomerulonephritis, and alopecia. CONCLUSIONS: Serum-mediated PNC by polymorphonuclear leukocytes is commonly but not exclusively seen in patients with SLE. The PNC assay may be used in follow-up of patients with SLE and, especially in combination with other routinely assessed laboratory tests, may help to predict flares and different clinical manifestations, including glomerulonephritis. Our results encourage further development of the PNC assay as a complementary laboratory tool in management of patients with SLE.

Archiving Primary Data: Solutions for Long-Term Studies.

The recent trend for journals to require open access to primary data included in publications has been embraced by many biologists, but has caused apprehension amongst researchers engaged in long-term ecological and evolutionary studies. A worldwide survey of 73 principal investigators (Pls) with long-term studies revealed positive attitudes towards sharing data with the agreement or involvement of the PI, and 93% of PIs have historically shared data. Only 8% were in favor of uncontrolled, open access to primary data while 63% expressed serious concern. We present here their viewpoint on an issue that can have non-trivial scientific consequences. We discuss potential costs of public data archiving and provide possible solutions to meet the needs of journals and researchers.

National EQ-5D tariffs and quality-adjusted life-year estimation: comparison of UK, US and Danish utilities in south Swedish rheumatoid arthritis patients.

OBJECTIVE: To study how the choice of national EQ-5D tariff may affect utility and incremental quality-adjusted life-year (QALY) estimates. METHODS: South Swedish rheumatoid arthritis patients in an observational study, starting and continuing anti-tumour necrosis factor (TNF) monotherapy (n=54) or anti-TNF plus methotrexate (n=215) for 1 year during May 2002 to April 2009, were included. EQ-5D questionnaires were completed at baseline, 3, 6 and 12 months. Utilities and accumulated QALY were compared using the UK, US and Danish EQ-5D tariffs. Utilities for all 243 possible EQ-5D health states were also compared. RESULTS: US utilities were generally higher than UK, with Danish falling in between. A substantial 1-year mean utility improvement was seen in both study groups using all tariffs (UK 0.28 vs 0.29; US 0.18 vs 0.19; Danish 0.20 vs 0.22). Adjusting for baseline differences between groups, the incremental QALY gain of combined treatment was 0.09 using the UK tariff, while 0.06 according to both US and Danish tariffs. Inter-tariff disagreement in utility and accumulated QALY varied irregularly across the range of utilities. CONCLUSIONS: Applying different national EQ-5D tariffs to the same data may result in substantially different incremental QALY estimates, crucial knowledge when interpreting cost-utility analyses. Studies using different tariffs cannot be directly compared.

Pulmonary dysfunction, smoking, socioeconomic status and the risk of developing rheumatoid arthritis.

OBJECTIVES: Environmental risk factors are of potential interest for both prevention and treatment of RA. The purpose of this study was to examine the effect of pulmonary function, smoking and socio-economic status on the future risk of RA. METHODS: Between 1974 and 1992, 22 444 men and 10 902 women were included in the Malmö Preventive Medicine Program (MPMP). Pulmonary function was assessed by a standard screening spirometry. Chronic obstructive pulmonary disease (COPD) and restrictive pulmonary dysfunction were defined based on pulmonary function tests. Individuals who developed RA were identified by linking the MPMP database to national and local RA registers. The patients were classified according to the 1987 ACR criteria for RA. Four matched controls for every case were selected. RESULTS: We identified 290 cases of incident RA (151 men/139 women; mean age at diagnosis 60 years). The median time from inclusion to diagnosis was 12 years. Forced vital capacity and forced expiratory volume within 1 s values were similar in cases and controls, overall and also in separate analysis of those screened ≤8 years before diagnosis. There was no association between COPD or restrictive pulmonary dysfunction and subsequent development of RA. Current smoking was a strong predictor for RA [odds ratio (OR) 1.79; 95% CI 1.32, 2.42]. Blue-collar workers had an increased risk of RA (OR 1.54; 95% CI 1.12, 2.10), independent of smoking. CONCLUSION: Pulmonary dysfunction did not predict RA, but smoking and low socio-economic status were independent risk factors for RA. Other effects of smoking may be important for RA susceptibility.

High disease activity disability burden and smoking predict severe extra-articular manifestations in early rheumatoid arthritis.

OBJECTIVES: To identify patients with severe extra-articular RA (ExRA) in an early RA cohort and to investigate potential risk factors. METHODS: From a cohort (n = 2900) in a structured programme for newly diagnosed RA, 40 patients with severe ExRA after RA diagnosis were identified. Disease activity score (DAS28), functional disability (HAQ) and treatment with glucocorticosteroids (GCs) and DMARDs were assessed regularly. Cases with ExRA were compared with RA controls from the same cohort matched for age, sex and duration of symptoms at inclusion. RESULTS: Patients who developed severe ExRA were more often current smokers and had higher mean DAS28, HAQ and CRP at baseline. Among the ExRA cases, 93% had a positive RF vs 59% of the controls. The area under the curve (AUC) of DAS28 odds ratio (OR) 7.79/S.D.; 95% CI 3.04, 19.95, HAQ (OR 2.30/S.D.; 95% CI 1.37, 3.88) and CRP (OR 3.05/S.D.; 95% CI 1.77, 5.26) during the first 2 years of follow-up were strong predictors of subsequent development of ExRA. The most frequently used DMARDs were MTX and SSZ, with similar frequency and duration of treatment among cases and controls. The cases were treated with GC before onset of ExRA more frequently (73 vs 47%; P = 0.005) and with higher mean cumulative dose (3667 vs 2037 mg, P = 0.015). CONCLUSIONS: High levels of disease activity and disability during the first 2 years after RA diagnosis, smoking and RF predict the development of severe extra-articular RA.

Socio-economic status and lung cancer risk including histologic subtyping--a longitudinal study.

We investigated prospectively the risk of lung cancer in relation to socio-economic status (SES) in 22,387 middle-aged individuals who attended a screening program in the city of Malmö, Sweden between 1974 and 1992. We also examined the relationship between SES and histologic subtype in smokers. By 2003, a total of 550 lung cancer cases had been identified. Relative risks (RR) were calculated with adjustment for age, current smoking, inhalation habits and marital status at baseline in the low SES group compared to high SES group. Among smokers, the RR (95% confidence interval (CI)) for lung cancer in the low SES group of men was 1.39 (1.11-1.73), and women 1.56 (1.04-2.34). Also among smokers, low SES was associated with an increased risk of squamous cell carcinoma in men; RR 1.89 (1.16-2.81) and women; RR 7.10 (1.63-30.86), and with an increased risk of mesothelioma in men RR 9.97 (1.29-76.96). We conclude that low SES groups run an increased risk of lung cancer despite accounting for smoking habits. Furthermore, low SES was positively associated with squamous cell carcinoma and mesothelioma. Our results suggest that the association between low SES and lung cancer could be mediated by unaccounted for smoking exposure, lifestyle or occupational hazards.

Social mobility, marital status, and mortality risk in an adult life course perspective: the Malmö Preventive Project.

AIMS: Adverse social factors predict increased mortality. This study aimed to assess the influence of social class and marital status on mortality, adding an adult life course perspective. METHODS: In total, 32,907 males and 20,204 females were evaluated based on census data in Malmö, Sweden. Of these subjects, 22,444 males and 10,902 females also took part in health screening. The main outcomes were all-cause and cause-specific mortality rates in subgroups based on social class and marital status, either measured once or repeatedly in adult life. Results were based on a total of 522,807 years of follow-up in men (5,761 deaths) and 239,815 in women (1,354 deaths). RESULTS: Total and cardiovascular mortality were significantly higher in manual male employees with age-adjusted risk ratios (RR) of 1.7 (95% CI 1.5-1.9) and 1.6 (1.3-2.0) in skilled manual workers, and 2.0 (1.7-2.2) and 1.9 (1.6-2.3) in unskilled manual workers, compared with high-level non-manual employees. The differences remained after adjustment for baseline risk factors and prevalent cardiovascular disease, and were similar for women. Increased mortality risk was also documented for subjects who were divorced or unmarried (adjusted for social class), as well as being downward socially mobile or in a permanent low social class (manual) position. CONCLUSIONS: Social class based on occupation, either measured once or repeatedly in adult life, is associated with marked differences in mortality risk in middle-aged subjects. People who remain married/cohabiting or remarry are at lower risk of early death than people who remain unmarried or divorced.

Obesity, survival, and hospital costs-findings from a screening project in Sweden.

OBJECTIVE: Our aims were to estimate 1) the costs of hospital treatment and 2) the value of lost production due to early death associated with overweight and obese patients, and then to extrapolate the findings to national costs. METHODS: We use regression models to analyze survival, expected number of days in hospital treatment for patients with different body mass index (BMI), and costs with data obtained from screening of 33,196 middle-aged subjects living in Malmö, Sweden, and collected during a 15-year follow-up period. We subsequently scale up costs to national aggregate level using the BMI prevalence data from the screening project to the national population. RESULTS: The total excess hospital (somatic, psychiatric) care cost (Swedish krona or SEK) for the national health-care budget, excess as compared to normal weight patients for obese (BMI > 30) and overweight (25 < or = BMI < 30) was estimated to SEK2155 million per annum (269 million dollars, assuming 1 dollar = SEK8), or about 2.3% of total hospital care costs in Sweden. The corresponding indirect costs due to early death were estimated to SEK2935 million (367 million dollars). For males at age 55, the potential hospital costs saving, excluding costs of the intervention that could be gained by an intervention that successfully and safely could alter the weight of an obese individual to become normal weight, was estimated on average to SEK4434 (554 dollars) per annum. CONCLUSION: Hospital treatment costs are found to be higher for obese and overweight patients than for normal weight patients indicating potential cost savings especially on indirect costs by effective, safe and low cost weight-loss intervention.

Self-rated health in relation to age and gender: influence on mortality risk in the Malmö Preventive Project.

AIMS: A study was undertaken to examine whether poor self-rated health (SRH) can independently predict all-cause mortality during 22-year follow-up in middle-aged men and women. SUBJECTS AND METHODS: Data are derived from a population-based study in Malmö, Sweden. This included baseline laboratory testing and a self-administered questionnaire. The question on global SRH was answered by 15,590 men (mean age 46.4 years) and 10,089 women (49.4 years). Social background characteristics (occupation, marital status) were based on data from national censuses. Mortality was retrieved from national registers. RESULTS: At screening 4,261 (27.3%) men and 3,085 (30.6%) women reported poor SRH. Among subjects rating their SRH as low, 1,022 (24.0%) men and 228 (7.4%) women died during follow-up. Corresponding figures for subjects rating their SRH as high were 1801 (15.9%) men and 376 (5.4%) women. An analysis of survival in subjects reporting poor SRH revealed an age-adjusted hazard risk ratio (HR, 95%CI) for men HR 1.5 (1.4-1.7), and for women HR 1.4 (1.2-1.6). The corresponding HR after adjusting for possible social confounders was for men HR 1.3 (1.1-1.4), and women HR 1.1 (0.9-1.4). When additional adjustment was made for biological risk factors the association for men was still significant, HR 1.2 (1.1-1.3). CONCLUSION: Poor SRH predicts increased long-term mortality in healthy, middle-aged subjects. For men the association is independent of both social background and selected biological variables. The adjustment for biological variables can be questioned as they might represent mediating mechanisms in a possible causal chain of events.

Survival costs of reproduction in the blue tit (Parus caeruleus): a role for blood parasites?

One of the central tenets in life-history theory is that there is a trade-off between current and future reproduction (i.e. a cost of reproduction). The mechanism for this cost of reproduction is, however, largely unknown. One hypothesis is that the high workload during reproduction compromises resistance to parasites and that the resulting increase in parasitaemia has negative effects on the prospects of future survival. Although empirical evidence for a negative relationship between reproductive effort and parasite resistance exists, the causal relationships between reproductive effort, parasite resistance and future reproduction are still unclear. We use a path analytical approach to investigate whether a change in parasite resistance (as measured by intensities of infections by the blood parasite Haemoproteus) after manipulation of reproductive effort, translates into altered survival in female blue tits. Our results show a negative relationship between reproductive effort and parasite resistance, although evident only in first-year breeders. Moreover, we found survival costs of reproduction in first-year breeders. These costs were, however, not mediated by the blood parasite studied.

Adverse social factors predict early ageing in middle-aged men and women: the Ebeltoft Health Study, Denmark.

AIMS: This study examined whether adverse social factors are associated with an increased rate of biological ageing in middle-aged subjects. METHODS: The authors investigated five markers of biological ageing in 690 subjects followed for five years in Ebeltoft, Denmark. Mean age at baseline was 40 years (range 30-50 years). These markers included repeated measures of pulse pressure, lung function, hearing, physical work capacity and a cardiovascular risk score. A zeta-score was calculated based on a factor analysis of the five markers used. The relative biological age was finally calculated in relation to chronological age in subgroups of different social class (occupation, educational level) and marital status, at baseline and after follow-up. RESULTS: Men and women from a higher social class appeared to be biologically younger than corresponding subjects from a lower social class (p < 0.001). This difference was still evident after 5 years of follow-up (p < 0.01) for men and women of different occupations and for women of different educational levels (p < 0.01). Married/cohabiting men were biologically younger than single men and this difference increased during the follow-up period in that the difference between groups at five-year follow-up was significant (p < 0.05). CONCLUSIONS: Middle-aged men and women from a higher social class showed signs of being biologically younger than their corresponding chronological age, while the opposite was found for men and women of lower social class. This discrepancy was still evident after five years of follow-up, and even tended to increase for single men. Differential ageing may thus be an important biological aspect of differences in health according to social class.

The resting metabolic cost of egg laying and nestling feeding in great tits.

To estimate the metabolic costs of regrowth of reproductive organs and formation of eggs, we compared the resting metabolic rate (RMR) of female great tits (Parus major) during the periods of ovarian recrudescence, egg laying, nestling feeding and during winter. We found RMR of individual females, as measured in an open circuit respirometer during night, to be significantly higher during all the breeding phases when compared to measurements during the winter. Females had a 12% increase in RMR during the nest-building phase, an increase of 27% during egg production and an increase of 20% during the chick feeding phase compared to RMR during winter. However, we found no significant difference in energy expenditure during the night between females producing eggs and females feeding chicks. A causal link between RMR and egg production was further confirmed by females producing large eggs having a higher RMR than females producing small eggs. Mass-specific RMR increased steadily from the winter throughout the breeding season, being highest when females were feeding their nestlings. Thus, even though females did not produce ovary-oviduct tissue or eggs during chick feeding, they had a very high RMR. We conclude that the biosynthetic cost of egg formation will probably not limit clutch size but may well, together with the cost of ovary-oviduct recrudescence, influence the timing of reproduction. We suggest that the high RMR of females feeding nestlings, probably is due to an increase in size and efficiency of the alimentary tract, needed to sustain a high rate of energy turnover during this period.