Targeting S100A9 protein affects mTOR-ER stress signaling and increases venetoclax sensitivity in Acute Myeloid Leukemia.

Acute Myeloid Leukemia (AML) is a heterogeneous disease with limited treatment options and a high demand for novel targeted therapies. Since myeloid-related protein S100A9 is abundantly expressed in AML, we aimed to unravel the therapeutic impact and underlying mechanisms of targeting both intracellular and extracellular S100A9 protein in AML cell lines and primary patient samples. S100A9 silencing in AML cell lines resulted in increased apoptosis and reduced AML cell viability and proliferation. These therapeutic effects were associated with a decrease in mTOR and endoplasmic reticulum stress signaling. Comparable results on AML cell proliferation and mTOR signaling could be observed using the clinically available S100A9 inhibitor tasquinimod. Interestingly, while siRNA-mediated targeting of S100A9 affected both extracellular acidification and mitochondrial metabolism, tasquinimod only affected the mitochondrial function of AML cells. Finally, we found that S100A9-targeting approaches could significantly increase venetoclax sensitivity in AML cells, which was associated with a downregulation of BCL-2 and c-MYC in the combination group compared to single agent therapy. This study identifies S100A9 as a novel molecular target to treat AML and supports the therapeutic evaluation of tasquinimod in venetoclax-based regimens for AML patients.

Questionnaire study suggests grave consequences of infectious laryngotracheitis, infectious coryza and mycoplasmosis in small chicken flocks.

BACKGROUND: A growing number of people in western countries keep small chicken flocks. In Sweden, respiratory disease is a common necropsy finding in chickens from such flocks. A respiratory real-time polymerase chain reaction (PCR) panel was applied to detect infectious laryngotracheitis virus (ILTV), Avibacterium paragallinarum (A. paragallinarum) and Mycoplasma gallisepticum (M. gallisepticum) in chickens from small flocks which underwent necropsy in 2017-2019 and had respiratory lesions. Owners (N = 100) of PCR-positive flocks were invited to reply to a web-based questionnaire about husbandry, outbreak characteristics and management. RESULTS: Response rate was 61.0%. The flocks were from 18 out of Sweden's 21 counties indicating that respiratory infections in small chicken flocks are geographically widespread in Sweden. Among participating flocks, 77.0% were coinfected by 2-3 pathogens; 91.8% tested positive for A. paragallinarum, 57.4% for M. gallisepticum and 50.8% for ILTV. Larger flock size and mixed-species flock structure were associated with PCR detection of M. gallisepticum (P = 0.00 and P = 0.02, respectively). Up to 50% mortality was reported by 63.9% of respondents. Euthanasia of some chickens was carried out in 86.9% of the flocks as a result of the outbreaks. Full clinical recovery was reported by 39.3% of owners suggesting chronic infection is a major challenge in infected flocks. Live birds had been introduced in many flocks prior to outbreaks, which suggested these as an important source of infection. Following the outbreaks, 36.1% replaced their flocks with new birds and 9.8% ceased keeping chickens. CONCLUSIONS: This study highlights the severity of respiratory outbreaks in small non-commercial chicken flocks and points to the need for more research and veterinary assistance to prevent and manage respiratory infections in small chicken flocks.

Occupational exposure to noise and dust in Swedish soft paper mills and mortality from ischemic heart disease and ischemic stroke: a cohort study.

OBJECTIVE: To elucidate whether occupational noise exposure increases the mortality from ischemic heart disease (IHD) and stroke, and if exposure to paper dust modified the risks. METHODS: We studied 6686 workers from soft paper mills, with occupational noise exposure, < 85 dBA, 85-90 dBA and > 90 dBA, and high (> 5 mg/m3) exposure to paper dust. Person-years 1960-2019 were stratified according to gender, age, and calendar-year. Expected numbers of deaths were calculated using the Swedish population as the reference and standardized mortality ratios (SMR) with 95% confidence intervals (95% CI) were assessed. RESULTS: SMR for IHD was 1.12 (95% CI 0.88-1.41) for noise < 85 dBA, 1.18 (95% CI 0.90-1.55) for 85-90 dBA, and 1.27 (95% CI 1.10-1.47) among workers exposed > 90 dBA. Joint exposure to high noise exposure and high exposure to paper dust resulted in slightly higher IHD mortality (SMR 1.39, 95% CI 1.15-1.67). SMR for ischemic stroke was 0.90 (95% CI 0.37-2.15) for noise < 85 dBA, 1.08 (95% CI 0.45-2.59) for 85-90 dBA, and 1.48 (95% CI 0.99-2.00) among workers exposed > 90 dBA. High noise exposure and high exposure to paper dust resulted in higher ischemic stroke mortality (SMR 1.83, 95% CI 1.12-2.98). CONCLUSION: Noise levels > 90 dBA was associated with increased IHD mortality. Combined exposures of noise and paper dust may further increase the risks. Our results do not provide support for a causal relationship for ischemic stroke. Residual confounding from smoking has to be considered. Workers need to be protected from occupational noise levels exceeding 90 dBA.

Cancer incidence among workers in soft paper mills: A cohort study.

OBJECTIVES: To elucidate whether occupational exposure to soft paper dust increases the incidence of cancer. METHODS: We studied 7988 workers in Swedish soft paper mills from 1960 to 2008, of whom 3233 (2 187 men and 1046 women) had more than 10 years of employment. They were divided into high exposure (>5 mg/m3 for >1 year) or lower exposure to soft paper dust based on a validated job-exposure matrix. They were followed from 1960 to 2019, and person-years at risk were stratified according to gender, age, and calendar-year. The expected numbers of incident tumors were calculated using the Swedish population as the reference, and standardized incidence ratios (SIR) with 95% confidence intervals (95% CI) were assessed. RESULTS: Among high-exposure workers with more than 10 years of employment, there was an increased incidence of colon cancer (SIR 1.66, 95% CI 1.20-2.31), small intestine cancer (SIR 3.27, 95% CI 1.36-7.86), and thyroid gland cancer (SIR 2.68, 95% CI 1.11-6.43), as well as lung cancer (SIR 1.56, 95% CI 1.12-2.19). Among the lower-exposed workers there was an increased incidence of connective tissue tumors (sarcomas) (SIR 2.26, 95% CI 1.13-4.51) and pleural mesothelioma (SIR 3.29, 95% CI 1.37-7.91). CONCLUSION: Workers in soft paper mills with high exposure to soft paper dust have an increased incidence of large and small intestine tumors. Whether the increased risk is caused by paper dust exposure or some unknown associated factors is unclear. The increased incidence of pleural mesothelioma is probably linked to asbestos exposure. The reason for increased incidence of sarcomas is unknown.

S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes.

Multiple myeloma is characterized by clonal proliferation of plasma cells that accumulate preferentially in the bone marrow (BM). The tumor microenvironment is one of the leading factors that promote tumor progression. Neutrophils and monocytes are a major part of the BM tumor microenvironment, but the mechanism of their contribution to multiple myeloma progression remains unclear. Here, we describe a novel mechanism by which S100A8/S100A9 proteins produced by BM neutrophils and monocytes promote the expansion of megakaryocytes supporting multiple myeloma progression. S100A8/S100A9 alone was not sufficient to drive megakaryopoiesis but markedly enhanced the effect of thrombopoietin, an effect that was mediated by Toll-like receptor 4 and activation of the STAT5 transcription factor. Targeting S100A9 with tasquinimod as a single agent and in combination with lenalidomide and with proteasome inhibitors has potent antimyeloma effect that is at least partly independent of the adaptive immune system. This newly identified axis of signaling involving myeloid cells and megakaryocytes may provide a new avenue for therapeutic targeting in multiple myeloma. Significance: We identified a novel mechanism by which myeloid cells promote myeloma progression independently of the adaptive immune system. Specifically, we discovered a novel role of S100A8/S100A9, the most abundant proteins produced by neutrophils and monocytes, in regulation of myeloma progression via promotion of the megakaryocyte expansion and angiogenesis. Tasquinimod, an inhibitor of S100A9, has potent antimyeloma effects as a single agent and in combination with lenalidomide and with proteasome inhibitors.

Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma.

BACKGROUND: Immunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myeloid cell accumulation and suppressive activity. Tasquinimod, a small molecule inhibitor of S100A9, is currently in a phase Ib/IIa clinical trial in MM patients (NCT04405167). We aimed to gain more insights into its mechanisms of action both on the myeloma cells and the immune microenvironment. METHODS: We analyzed the effects of tasquinimod on MM cell viability, cell proliferation and downstream signaling pathways in vitro using RNA sequencing, real-time PCR, western blot analysis and multiparameter flow cytometry. Myeloid cells and T cells were cocultured at different ratios to assess tasquinimod-mediated immunomodulatory effects. The in vivo impact on immune cells (myeloid cell subsets, macrophages, dendritic cells), tumor load, survival and bone disease were elucidated using immunocompetent 5TMM models. RESULTS: Tasquinimod treatment significantly decreased myeloma cell proliferation and colony formation in vitro, associated with an inhibition of c-MYC and increased p27 expression. Tasquinimod-mediated targeting of the myeloid cell population resulted in increased T cell proliferation and functionality in vitro. Notably, short-term tasquinimod therapy of 5TMM mice significantly increased the total CD11b+ cells and shifted this population toward a more immunostimulatory state, which resulted in less myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly reduced the tumor load and increased the trabecular bone volume, which resulted in prolonged overall survival of MM-bearing mice in vivo. CONCLUSION: Our study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients.

Psychosocial job conditions and biomarkers of cardiovascular disease: A cross-sectional study in the Swedish CArdioPulmonary bioImage Study (SCAPIS).

AIMS: The aim of this study was to investigate associations between psychosocial work exposure and the presence of biological and imaging biomarkers of cardiovascular disease. METHODS: This cross-sectional study was conducted in a sub-cohort of the Swedish CArdioPulmonary bioImage Study (SCAPIS). Psychosocial exposure was evaluated with the job demand-control model, and analysed according to the standard categorization: high strain, active, passive and low strain (reference). Biomarkers (blood pressure, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, coronary artery calcification (CAC) and metabolic syndrome) were measured, or derived through measurements, from clinical examinations. Gender-specific prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated with regression models and adjusted for age, education, smoking, physical activity, general life stress and body mass index (BMI). RESULTS: The analyses included 3882 participants (52.5% women). High strain (high demands-low control) was linked to increased PR for low HDL cholesterol in women, adjusted for all covariates (PR 1.76; 95% CI 1.25-2.48). High strain was also related to moderately increased PR for metabolic syndrome in men, after adjustments for all covariates except BMI (PR 1.25; 95% CI 1.02-1.52). In addition, passive work (low demands-low control) was associated with diastolic hypertension in women (fully adjusted: PR 1.29; 95% CI 1.05-1.59). All relationships between psychosocial factors and LDL cholesterol or CAC (both genders), or hypertension (men), were non-significant. CONCLUSIONS: Poor psychosocial job conditions was associated with the presence of low HDL cholesterol and diastolic hypertension in women, and metabolic syndrome in men. These findings contribute to the knowledge of potential pathways between stressful work and coronary heart disease.

Erysipelothrix rhusiopathiae-specific T-cell responses after experimental infection of chickens selectively bred for high and low serum levels of mannose-binding lectin.

Erysipelas, caused by infection with Erysipelothrix rhusiopathiae (ER) is an important emerging disease in laying hens. We have earlier observed prominent mannose-binding lectin (MBL) acute phase responses in experimentally ER infected chickens. The present study aimed to further examine immune responses to ER by using chickens selectively bred for high (L10H) and low (L10L) serum MBL levels. Chickens were infected with ER at 3 weeks of age and immune parameters and bacterial load were monitored in blood until day 18 after infection. Blood and spleen leukocytes collected on day 18 were stimulated in vitro with ER antigens and blast transformation of different T-cell populations was assessed. The ER infection gave a very varied outcome and no clear differences were observed between L10H and L10L chickens with respect to leukocyte counts, bacterial load or clinical outcome. Nonetheless, rapid innate responses, e.g., heterophilia and increased serum MBL levels were noted in bacteraemic chickens. All ER infected chickens also showed transient increased expression of mannose receptor MRC1L-B and decreased expression of major histocompatibility complex II on monocytes day 1 after infection indicating monocyte activation or relocation. In vitro ER stimulation showed antigen specific blast transformation of CD4+, TCRγ/δ-CD8αß+ and TCRγ/δ+CD8αß+ spleen cells from all infected chickens. For CD4+ and TCRγ/δ-CD8αß+ cells the proportions of blast transformed cells were significantly higher for samples from L10L chickens than those for samples from L10H chickens. This is the first observation of ER-specific T-cells in chickens and interestingly a Th1-type response comprising cytotoxic T-cells was indicated.

Gizzard erosions in broiler chickens in Sweden caused by fowl adenovirus serotype 1 (FAdV-1): investigation of outbreaks, including whole-genome sequencing of an isolate.

The present paper describes the investigation of the first outbreaks of adenoviral gizzard erosions (AGE) in Sweden, in five broiler flocks. The investigation included whole viral genome sequencing and investigation of genomic organization and sequence relationships with other adenoviruses. All five flocks had a history of decreased growth and uneven size of birds since 9-10 days of age. Macroscopically, lesions consistent with AGE (detached koilin layers, discolouration, bleeding, erosions) were identified in gizzards in all five flocks. In four flocks histology was performed, and degeneration and inflammation of the koilin layer and gizzard mucosa were identified in all four. In one flock, intranuclear inclusion bodies typical for fowl adenovirus (FAdV) were detected in trapped epithelial cells in the koilin layer. In four flocks in situ hybridization was performed, and cells positive for FAdV serotype 1 (FAdV-1) were demonstrated in the koilin layer and gizzard mucosa. FAdV species A (FAdV-A) was detected in gizzard, liver, caecal tonsils and bursa of Fabricius by polymerase chain reaction (PCR) and sequencing. Ten out of ten examined parent flocks of the affected chickens were seropositive for FAdV, indicating former or on-going infection. However, FAdV was not detected in embryos from seropositive parent flocks and thus vertical transmission was not demonstrated. The entire nucleotide sequence of one sample was determined and found to be 43,856 base pairs (bp) in length. The genome sequence and organization were found to be similar to that of the reference apathogenic avian adenovirus "chicken embryo lethal orphan" (CELO). RESEARCH HIGHLIGHTSAGE in Swedish broilers: necropsy, histopathology, ISH, PCR, whole-genome sequencing.Whole FAdV-genome analysed: 43,856 bp, found to be most similar to CELO (U46933.1).Multiple point mutations, site insertions and deletions identified compared to CELO.Paper adds knowledge about European disease situation and pathogenic FAdV-strains.

Cancer incidence in a cohort of Swedish merchant seafarers between 1985 and 2011.

PURPOSE: Lung cancer, mesothelioma and several lifestyle-associated cancer forms have been reported more common in merchant seafarers. However, few studies reflect recent occupational settings and women seafarers are usually too scarce for meaningful analyses. We conducted a study on cancer incidence between 1985 and 2011 in a Swedish cohort consisting of male and female seafarers. METHODS: All seafarers in the Swedish Seafarers' Register with at least one sea service between 1985 and 2011 and a cumulated sea service time of ≥ 30 days (N = 75,745; 64% men, 36% women; 1,245,691 person-years) were linked to the Swedish Cancer Register and followed-up until 31 December 2011. Standardized incidence ratios (SIR) were calculated with the general population as reference. RESULTS: There were 4159 cancer cases in total, with 3221 among men and 938 among women. Male seafarers had an increased risk of total cancer (SIR 1.05; 95% CI 1.01-1.09), lung cancer (SIR 1.51; 95% CI 1.35-1.67) and urinary bladder cancer (SIR 1.17; 95% CI 1.02-1.33). Several lifestyle-associated cancer forms were more common in men. Previous work on tankers was associated with leukaemia (SIR 1.41; 95% CI 1.00-1.86). The risk of cancer decreased with a start as a male seafarer after 1985, with a significant trend for total cancer (P < 0.001), lung cancer (P = 0.001) and, for tanker seafarers, leukaemia (P = 0.045). Women seafarers had an increased risk of lung cancer (SIR 1.54; 95% CI 1.23-1.87) but the risk of total cancer was not increased (SIR 0.83; 95% CI 0.78-0.89). CONCLUSIONS: In this cohort of merchant Swedish seafarers 1985-2011, the risk of total cancer was increased in men but not in women compared to the general population. Lung cancer was increased in both genders. The risk of cancer seems to decrease over the last decades, but better exposure assessments to occupational carcinogens and longer observation times are needed.

Assessment of requests for medication-related follow-up after hospital discharge, and the relation to unplanned hospital revisits, in older patients: a multicentre retrospective chart review.

BACKGROUND: The discharge of older hospitalised patients is critical in terms of patient safety. Inadequate transfer of information about medications to the next healthcare provider is a known problem, but there is a lack of understanding of this problem in settings where shared electronic health records are used. The aims of this study were to evaluate the prevalence of patients for whom hospitals sent adequate requests for medication-related follow-up at discharge, the proportion of patients with unplanned hospital revisits because of inadequate follow-up requests, and the association between medication reviews performed during hospitalisation and adequate or inadequate follow-up requests. METHODS: We conducted a retrospective chart review. The study population was randomly selected from a cluster-randomised crossover trial which included patients 65 years or older who had been admitted to three hospitals in Sweden with shared electronic health records between hospital and primary care. Each patient was assessed with respect to the adequacy of the request for follow-up. For patients where the hospitals sent inadequate requests, data about any unplanned hospital revisits were collected, and we assessed whether the inadequate requests had contributed to the revisits. The association between medication reviews and adequate or inadequate requests was analysed with a Chi-square test. RESULTS: A total of 699 patients were included. The patients' mean age was 80 years; an average of 10 medications each were prescribed on hospital admission. The hospitals sent an adequate request for 418 (60%) patients. Thirty-eight patients (14%) had a hospital revisit within six months of discharge which was related to an inadequate request. The proportion of adequate or inadequate requests did not differ between patients who had received a medication review during hospitalisation and those who had not (p = 0.83). CONCLUSIONS: The prevalence of patients for whom the hospitals sent adequate follow-up requests on discharge was low. More than one in every ten who had an inadequate request revisited hospital within six months of discharge for reasons related to the request. Medication reviews conducted during hospitalisation did not affect the proportion of adequate or inadequate requests sent. A communication gap still exists despite the usage of a shared electronic health record between primary and secondary care levels.

Retrospective analysis of post-mortem findings in domestic ducks and geese from non-commercial flocks in Sweden, 2011-2020.

BACKGROUND: Small poultry flock ownership has become a popular hobby in Europe and North America in recent years but there is a general lack of information regarding bird health and welfare. This retrospective analysis of routine post-mortem cases of non-commercial anseriform poultry aimed at providing information on causes of mortality mostly in relation to mortality events. For this purpose, birds that were submitted for routine post-mortem diagnostics to the National Veterinary Institute (SVA) in Sweden in 2011-2020 were retrospectively reviewed to determine main causes of mortality. RESULTS: Records from 79 necropsy submissions involving 120 birds (domestic ducks n = 41, Muscovy ducks n = 45, hybrid ducks n = 2 and domestic geese n = 32) were retrieved and analysed. Most submissions (72.2%) represented flock disease events and unexpected mortality was the most common cause of submission (70.9% of submissions). Twenty-two submissions (27.8%) were referred by veterinarians. There was a wide range of diagnoses of infectious and noninfectious aetiologies. Infectious causes of mortality included parasitic (19.2%), bacterial (13.3%), fungal (10.0%) and viral infections (3.3%) (at bird level of all 120 birds). Some of these infections such as duck virus enteritis (DVE), highly pathogenic influenza (HPAI H5N8) in Muscovy ducks and leucocytozoonosis (Leucocytozoon sp.) in all three species were most likely acquired from contact with wild free-living waterfowl. Generalised yeast infection (Muscovy duck disease) was diagnosed in Muscovy ducks and in a Muscovy duck/domestic duck hybrid. Other diseases were related to generalised noninfectious causes (27.5% of all birds) including diseases such as kidney disease, amyloidosis, cardiac dilatation, reproductive diseases and idiopathic inflammatory conditions. Nutritional or management-related diseases were diagnosed in 14.2% of all birds including rickets and gastrointestinal impaction/obstruction. Congenital/developmental, neoplastic, toxic and traumatic causes of mortality were rare. CONCLUSIONS: The information obtained in this study can be used to identify and evaluate risks and help owners and veterinarians to prevent disease and provide adequate veterinary care for non-commercial anseriform poultry.

Influence of Anthropic Environmental-Related Factors on Erysipelas in Wild Boar.

Erysipelothrix rhusiopathiae (ER) is an old but still emerging zoonotic infection that is not yet completely understood. ER infects a wide range of species and wild boar is of significant interest because of their similarities to pigs, a known ER reservoir. Moreover, the increase of its densities and the limited data available about ER in this species should be considered. The need is to investigate whether wild boar could represent a risk of erysipelas at the wildlife-domestic-human interface. Here, 1067 sera and 149 tonsils of wild boar from five hunting districts in Northwest Italy were tested using ELISA and bacteriological culture, respectively. Using generalized linear models, we evaluated host and environmental factors influencing ER spread and dynamics. We found an ER seroprevalence of 69.4% among wild boar. Increased human density and pig farm density lead to an increase of ER seropositivity highlighting its association with anthropic environmental-related factors. The high ER percentage of isolation (34.2%) found in healthy wild boar suggests that this species can serve as a healthy carrier. This fact, together with the high seroprevalence, supports a role of wild boar as an ER reservoir. Potential zoonotic and economic risks should be considered in light of these data.

An open-label study to evaluate biomarkers and safety in systemic sclerosis patients treated with paquinimod.

OBJECTIVES: To evaluate the changes in disease-related biomarkers and safety of paquinimod, an oral immunomodulatory compound, in patients with systemic sclerosis (SSc). METHODS: In this open-label, single-arm, multicenter study, SSc patients with a rapidly progressive disease received paquinimod for 8 weeks. Blood and skin biopsies were collected at baseline, during treatment, and at follow-up for the analyses of type I interferon (IFN) activity, chemokine (C-C motif) ligand 2 (CCL2), and the number of myofibroblasts. The safety of paquinimod was evaluated throughout the study. RESULTS: Nine SSc patients were enrolled and completed the study treatment with paquinimod at 3 mg/day for 8 weeks. After the treatment, a reduction of type I IFN activity in the plasma from one patient with elevated baseline IFN activity was recorded. A trend towards reduced IFN activity in the skin after treatment was also observed in patients. The serum level of CCL2 was reduced in 7 of 9 patients after paquinimod treatment. There was a median reduction of 10% of the number of myofibroblasts in skin biopsies at week 8 compared to baseline. No change in modified Rodnan skin score and quality of life was detected in the study. Reported adverse events (AEs) were mild to moderate and expected with the most common being arthralgia (n = 3) and headache (n = 3), and C-reactive protein (CRP) increase. CONCLUSIONS: Analysis of biomarkers before and after treatment suggest reduced type I IFN activity and reduced number of myofibroblasts in lesional skin. Paquinimod was overall well tolerated with mild to moderate and expected AEs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01487551 . Registered on 7 September 2011.

Psychosocial job exposure and risk of coronary artery calcification.

PURPOSE: The aim was to examine potential associations between psychosocial job exposures, evaluated with the Job Demand-Control-model, and presence of coronary artery calcium. METHODS: We performed a cross-sectional study using the Swedish CArdioPulmonary bioImage Study,(SCAPIS)pilot study. Coronary artery calcium was assessed through computed tomography of the coronary arteries and with coronary artery scoring, CACS. Main outcome was CACS ≥100 compared to CACS 0. Job demand and control was analysed according to the standard categorization of the two variables into: high strain, active, passive and low strain (reference). Associations between these variables and CACS were calculated with prevalence ratios (PR) using Cox regression with robust variance, 95% confidence intervals (CI) and adjusted for age, smoking, education, socioeconomic area and metabolic syndrome. RESULTS: In total 777 participants were used in our analyses, for which 20% of the men and 5% of the women had CACS ≥100, respectively. The PR of having CACS ≥100 was non-significantly elevated for men in high strain jobs 1.54 (95% CI 0.88-2.69) and in active jobs 1.67 (95% CI 0.92-3.06), adjusted for covariates. For women there was no association between exposure to high strain and having CACS ≥100 PR 1.02 (95% CI 0.24-4.31). Among women reporting passive job, the PR was non-significantly elevated, 2.40 (95% CI 0.83-6.92), adjusted for covariates. CONCLUSION: The statistical power of the study was limited, but our results suggests the possibility that exposure to a high strain or an active job situation may increase the risk of CACS in men, while in women, it may rather be exposure to passive job.

Quantification of IgY to Erysipelothrix rhusiopathiae in serum from Swedish laying hens.

BACKGROUND: Erysipelas, caused by Erysipelothrix rhusiopathiae (ER), is an important emerging disease in free-range and organic egg-production. The aim of the present study was to assess if quantification of ER specific IgY titers may aid the understanding of erysipelas in commercial laying hens. The methodology was validated with sequentially collected sera from experimentally ER infected SPF-chickens and subsequently applied on sera from Swedish commercial laying hens collected during and after outbreaks of erysipelas or collected at slaughter from healthy hens housed in furnished cages, barn production or in organic production (with outdoor access). RESULTS: In experimentally infected SPF-chickens, titers to ER were significantly increased approximately one week after infection while IgY to ER in uninfected age-matched controls remained low. Also chickens infected with low doses of ER, not displaying clinical signs of disease and with low recovery of ER in blood samples showed high titers of IgY to ER. For laying hens during and after erysipelas outbreaks the majority of samples were considered positive for antibodies to ER with a large variation in levels of IgY titers to ER between individuals. For healthy laying hens at slaughter all samples were deemed positive for antibodies to ER. An influence of flock on levels of IgY titers to ER was observed for both healthy hens and hens during erysipelas outbreaks. For healthy laying hens at slaughter no influence of the housing systems included in the study, history of erysipelas outbreaks at the farm or vaccination on levels of IgY titers to ER was noticed. CONCLUSIONS: Taken together, these results show that high numbers of commercial laying hens showed high IgY titers to ER, comparable to those elicited by experimental ER infection, indicating that ER or bacteria that raises antibodies that cross-react with ER are common in this environment.

Cardiovascular mortality in a Swedish cohort of female industrial workers exposed to noise and shift work.

PURPOSE: The aim was to study mortality due to cardiovascular disease as well as total mortality, among female industrial workers, and the association to occupational noise and shift work. METHODS: Women from cohorts of soft tissue paper mills (N = 3013) and pulp and paper mills (N = 1483) were merged into one cohort. Job exposure matrices were developed and used for classification of shift work and noise exposure. Every year was classified as shift work excluding nights or shift work including nights. Noise was classified into seven 5 dB(A) bins from < 75 to ≥ 100 dB(A). Mortality from cardiovascular diseases and total mortality during 1956-2013 was calculated as a standardized mortality ratio (SMR) with 95% confidence interval (CI) using the female general population as a reference. RESULTS: Fatal myocardial infarctions (N = 144) were increased in the total cohort, SMR 1.20 (95% CI 1.01-1.41) but not total mortality. The SMR for myocardial infarction for women exposed to noise ≥ 90 dB(A) for > 10 years was 1.41 (95% CI 1.02-1.89) and for those exposed to night shifts > 10 years, 1.33 (95% CI 0.91-1.89). Shift workers without nights ≤ 65 years, with noise exposure ≥ 90 dB(A), had SMR 2.41 (95% CI 1.20-4.31) from myocardial infarction. There was no increased mortality from cerebrovascular disease. CONCLUSIONS: Female paper mill workers had an increased mortality from acute myocardial infarction, especially before retirement age, when exposed to noise ≥ 90 dB(A) and with long-time employment. Exposure to shift work and noise usually occurred concurrently.

Immune responses upon experimental Erysipelothrix rhusiopathiae infection of naïve and vaccinated chickens.

Erysipelas, a disease caused by Erysipelothrix rhusiopathiae (ER), is an increasing problem in laying hens housed in cage-free systems. This study aimed to monitor immune responses during ER infection of naïve chickens and chickens vaccinated intra muscularly with a commercial inactivated ER vaccine. Chickens were infected intra muscularly with ER at 30 days of age and blood leukocyte counts, serum levels of mannose binding lectin (MBL) and ER-specific IgY were monitored until the experiment was terminated at day 15 after infection. ER was detected in blood from more chickens and at higher bacterial counts in the naïve group (day 1: 1 of 7 chickens; day 3: 6 of 6 chickens) than in the vaccinated group (day 1: 0 of 7 chickens; day 3: 1 of 6 chickens). During the acute phase of infection transient increases in circulating heterophil numbers and serum MBL levels were detected in all ER infected chickens but these responses were prolonged in chickens from the naïve group compared to vaccinated chickens. Before infection IgY titers to ER in vaccinated chickens did not differ significantly from those of naïve chickens but vaccinated chickens showed significantly increased IgY titers to ER earlier after infection compared to chickens in the naïve group. In conclusion, the ER infection elicited prompt acute innate responses in all chickens. Vaccinated chickens did not have high IgY titers to ER prior to infection but did however show lower levels of bacteraemia and their acute immune responses were of shorter duration.

Comparative genome analysis of Erysipelothrix rhusiopathiae isolated from domestic pigs and wild boars suggests host adaptation and selective pressure from the use of antibiotics.

The disease erysipelas caused by Erysipelothrix rhusiopathiae (ER) is a major concern in pig production. In the present study the genomes of ER from pigs (n=87), wild boars (n=71) and other sources (n=85) were compared in terms of whole-genome SNP variation, accessory genome content and the presence of genetic antibiotic resistance determinants. The aim was to investigate if genetic features among ER were associated with isolate origin in order to better estimate the risk of transmission of porcine-adapted strains from wild boars to free-range pigs and to increase our understanding of the evolution of ER. Pigs and wild boars carried isolates representing all ER clades, but clade one only occurred in healthy wild boars and healthy pigs. Several accessory genes or gene variants were found to be significantly associated with the pig and wild boar hosts, with genes predicted to encode cell wall-associated or extracellular proteins overrepresented. Gene variants associated with serovar determination and capsule production in serovars known to be pathogenic for pigs were found to be significantly associated with pigs as hosts. In total, 30 % of investigated pig isolates but only 6 % of wild boar isolates carried resistance genes, most commonly tetM (tetracycline) and lsa(E) together with lnu(B) (lincosamides, pleuromutilin and streptogramin A). The incidence of variably present genes including resistance determinants was weakly linked to phylogeny, indicating that host adaptation in ER has evolved multiple times in diverse lineages mediated by recombination and the acquisition of mobile genetic elements. The presented results support the occurrence of host-adapted ER strains, but they do not indicate frequent transmission between wild boars and domestic pigs. This article contains data hosted by Microreact.

Mortality from cardiovascular disease in a cohort of Swedish seafarers.

PURPOSE: The aim of this study was to investigate whether Swedish seafarers have increased mortality from cardiovascular disease compared with the general population. METHODS: Register-based longitudinal cohort study of 85,169 Swedish seafarers where all subjects with a minimum of 30 days service registered in the Seafarers' Register 1985-2013 were included. Mortality from coronary heart disease, cerebrovascular disease and total mortality for comparison were analysed by calculating standardised mortality ratios (SMRs), with 95% confidence intervals (CIs). Mortality was further analysed by gender, duty on board, type of vessel, and over time. RESULTS: There was no increase in either mortality from cardiovascular disease or total mortality for seafarers, who had worked solely on passenger ferries. Mortality from coronary heart disease and cerebrovascular disease was increased for male seafarers < 46 years old who had worked on different types of vessels, SMR 1.48 (95% CI 1.06-2.01) and SMR 1.93 (95% CI 1.16-3.02), respectively. Analysing the seafarers by duty showed significantly increased SMRs from coronary heart disease in males aged < 46 of the categories "deck crew" and "engine officer/crew (ever)". The total mortality for seafarers who had worked on different types of vessels was increased; males SMR 1.05 (95% CI 1.02-1.09) and females SMR 1.17 (95% CI 1.04-1.30), but decreased over time. CONCLUSIONS: No increased mortality on passenger ferries but younger male seafarers on different types of vessels had increased mortality from cardiovascular disease. Reduction of hazardous occupational exposures onboard is important, such as shift work, stress and noise.