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  • 151.
    Andreo, Pedro
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Dose to 'water-like' media or dose to tissue in MV photons radiotherapy treatment planning: still a matter of debate2015In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 60, no 1, p. 309-337Article in journal (Refereed)
    Abstract [en]

    The difference between Monte Carlo Treatment Planning (MCTP) based on the assumption of 'water-like' tissues with densities obtained from CT procedures, or on tissue compositions derived from CT-determined densities, have been investigated. Stopping powers and electron fluences have been calculated for a range of media and body tissues for 6 MV photon beams, including changes in their physical data (density and stopping powers). These quantities have been used to determine absorbed doses using cavity theory. It is emphasized that tissue compositions given in ICRU or ICRP reports should not be given the standing of physical constants as they correspond to average values obtained for a limited number of human-body samples. It has been shown that mass stopping-power ratios to water are more dependent on patient-to-patient composition differences, and therefore on their mean excitation energies (I-values), than on mass density. Electron fluence in different media are also more dependent on media composition (and their I-values) than on density. However, as a consequence of the balance between fluence and stopping powers, doses calculated from their product are more constant than what the independent stopping powers and fluence variations suggest. Additionally, cancelations in dose ratios minimize the differences between the 'water-like' and 'tissue' approaches, yielding practically identical results except for bone, and to a lesser extent for adipose tissue. A priori, changing from one approach to another does not seem to be justified considering the large number of approximations and uncertainties involved throughout the treatment planning tissue segmentation and dose calculation procedures. The key issue continues to be the composition of tissues and their I-values, and as these cannot be obtained for individual patients, whatever approach is selected does not lead to significant differences from a water reference dose, the maximum of these being of the order of 5% for bone tissues. Considering, however, current developments in advanced dose calculation methods, planning in terms of dose-to-tissue should be the preferred choice, under the expectancy that progress in the field will gradually improve some of the crude approximations included in MCTP and numerical transport methods. The small differences obtained also show that a retrospective conversion from dose-to-tissue to dose-to-water, based on a widely used approach, would mostly increase the final uncertainty of the treatment planning process. It is demonstrated that, due to the difference between electron fluence distributions in water and in body tissues, the conversion requires an additional fluence correction that has so far been neglected. An improved expression for the conversion and data for the fluence correction factor are provided. These will be necessary even in a dose-to-tissue environment, for the normalization of the treatment plan to the reference dosimetry of the treatment unit, always calibrated in terms of absorbed dose to water.

  • 152.
    Andreo, Pedro
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Wulff, Joerg
    Burns, David T.
    Palmans, Hugo
    Consistency in reference radiotherapy dosimetry: resolution of an apparent conundrum when Co-60 is the reference quality for charged-particle and photon beams2013In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 58, no 19, p. 6593-6621Article in journal (Refereed)
    Abstract [en]

    Substantial changes in ion chamber perturbation correction factors in Co-60 gamma-rays, suggested by recent Monte Carlo (MC) calculations, would cause a decrease of about 1.5% in the reference dosimetry of all types of charged particles (electrons, protons and heavier ions) based on calculated k(Q) values. It has gone largely unnoticed that the ratio of calibration coefficients N-D,N-w,N-Co60 and N-K,N-air,N-Co60 yields an experimental value of F-ch,F-Co60 = (s(w-air) pch)(Co60) through N-D,N-air,N-Co60. Coefficients provided by the IAEA and traceable to the BIPM for 91 NE-2571 chambers result in an average F-ch,F-Co60 which is compared with published (and new) MC simulations and with the value in IAEA TRS-398. It is shown that TRS-398 agrees within 0.12% with the experimental F-ch,F-Co60. The 1.5% difference resulting from MC calculations (1.1% for the new simulations) cannot be justified using current fundamental data and BIPM standards if consistency in the entire dosimetry chain is sought. For photons, MC k(Q) factors are compared with TRS-398. Using the same uncertainty for W-air, the two sets of data overlap considerably. Experimental k(Q) values from standards laboratories lie between the two sets of calculated values, showing no preference for one set over the other. Observed chamber-to-chamber differences, that include the effect of waterproof sleeves (also seen for Co-60), justify the recommendation in TRS-398 for k(Q) values specifically measured for the user chamber. Current developments on I-values for the stopping powers of water and graphite are presented. A weighted average I-water = 78 +/- 2 eV is obtained from published experimental and DRF-based values; this would decrease sw-air for all types of radiotherapy beams between 0.3% and 0.6%, and would consequently decrease the MC derived F-ch,F-Co60. The implications of a recent proposal for I-graphite = 81 eV are analysed, resulting in a potential decrease of 0.7% in N-K,N-air,N-Co60 which would raise the experimental F-ch,F-Co60; this would result in an increase of about 0.8% in the current TRS-398 value when referred to the BIPM standards. MC derived F-ch,F-Co60 using new stopping powers would then agree at a level of 0.1% with the experimental value, confirming the need for consistency in the dosimetry chain data. Should world average standards be used as reference, the figures would become +0.4% for TRS-398 and -0.3% for the MC calculation. F-ch,F-Q calculated for megavoltage photons using new stopping powers would decrease by between 0.2% and 0.5%. When they enter as a ratios in k(Q), differences with MC values based on current key data would be within 0.2% but their discrepancy with k(Q) experimental photon values remains unresolved. For protons the new data would require an increase in W-air,W-Q of about 0.6%, as this is inferred from a combination of calorimetry and ionometry. This consistent scenario would leave unchanged the current TRS-398 k(Q) (NE-2571) data for protons, as well as for ions heavier than protons unless new independent W-air,W-Q values become available. Also in these advanced radiotherapy modalities, the need for maintaining data consistency in an analysis that unavoidably must include the complete dosimetry chain is demonstrated.

  • 153. Andres Gimeno-Feliu, Luis
    et al.
    Calderón-Larrañaga, Amaia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Miguel Servet University Hospital, Spain; Carlos III Health Institute, Spain.
    Diaz, Esperanza
    Laguna-Berna, Clara
    Poblador-Plou, Beatriz
    Coscollar, Carlos
    Prados-Torres, Alexandra
    Multimorbidity and immigrant status: associations with area of origin and length of residence in host country2017In: Family Practice, ISSN 0263-2136, E-ISSN 1460-2229, Vol. 34, no 6, p. 662-666Article in journal (Refereed)
    Abstract [en]

    Aim. Multimorbidity is a growing phenomenon in primary care, and knowledge of the influence of social determinants on its evolution is vital. The aim of this study was to understand the relationship between multimorbidity and immigration, taking into account length of residence in the host country and area of origin of the immigrant population. Methods. Cross-sectional retrospective study of all adult patients registered within the public health service of Aragon, Spain (N = 1 092 279; 144 238 were foreign-born), based on data from the EpiChron Cohort. Age-standardized prevalence rates of multimorbidity were calculated. Different models of binary logistic regressions were conducted to study the association between multimorbidity, immigrant status and length of residence in the host country. Results. The risk of multimorbidity in foreign-borns was lower than that of native-borns [odds ratio (OR): 0.54, 95% confidence interval (CI): 0.53-0.55]. The probability of experiencing multimorbidity was lowest for Asians (OR: 0.34, 95% CI: 0.31-0.37) and Eastern Europeans (OR: 0.42, 95% CI: 0.40-0.43), and highest for Latin Americans (OR: 0.70, 95% CI: 0.68-0.72). Foreign-born immigrants residing in Aragon for >= 5 years had a higher multimorbidity risk than those residing for < 5 years (OR: 2.3, 95% CI: 2.2-2.4). Conclusion. Prevalence of multimorbidity is lower among foreign-borns as compared with native-borns, but increases rapidly with length of residence in the host country. However, the progressive development of multimorbidity among immigrants varies widely depending on area of origin. These findings provide important insight into the health care needs of specific population groups and may help minimize the negative impact of multimorbidity among the most vulnerable groups.

  • 154. Andrieu, S.
    et al.
    Aboderin, I.
    Baeyens, J.-P.
    Beard, J.
    Benetos, A.
    Berrut, G.
    Brainin, M.
    Cha, H.-B.
    Chen, L.-K.
    Du, P.
    Forette, B.
    Franco, A.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Gillette-Guyonnet, S.
    Gold, G.
    Gomez, F.
    Guimaraes, R.
    Gustafson, D.
    Khachaturian, A.
    Luchsinger, J.
    Mangialasche, Francesca
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Mathiex-Fortunet, H.
    Michel, J.-P.
    Richard, E.
    Schneider, L.S.
    Solomon, Alina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). 1Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland.
    Vellas, B.
    IAGG workshop: health promotion program on prevention of late onset dementia2011In: The Journal of Nutrition, Health & Aging, ISSN 1279-7707, E-ISSN 1760-4788, Vol. 15, no 7, p. 562-575Article, review/survey (Refereed)
  • 155.
    Andræ, Nils
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    Commissioning and validation of small subfields in Step-and-shoot IMRT2008Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    One of the most used irradiation techniques in modern radiation therapy is step-and-shoot IMRT. The accuracy of this technique when delivering complex dose distributions strongly depends on the size of the subfields. The aims of this study is to determine the minimum size of subfields that can be used efficiently in Step-and-Shoot IMRT, to investigate the validation process for beam delivery and treatment planning dose calculations, and to find recommendations for practical clinical implementations.

    Two different detectors, a CC04 ion chamber and a SFD stereotactic diode, have been used for measuring head scatter factors in air (Sc), total output factors (Scp) and dose profiles in water for a wide range of field sizes. The measurements were compared to calculations done with a pre-release version of the Nucletron MasterPlanTM v 3.1 treatment planning system that employs a novel, high resolution fluence modelling for both its pencil beam and collapsed cone dose calculation algorithms. Collimator settings were explicitly checked using FWHM film measurements with a build-up sheet of tungsten placed close to the treatment head to reduce the influence from lateral electron transport and geometrical penumbra. An analysis of the influence and sensitivity of Scp for small fields with respect to the linear accelerator source size and shape was also made.

    The measurements with the ionization chamber and the stereotactic diode showed good agreements with each other and with the treatment planning system calculations for field sizes larger than 2×2 cm2. For small field sizes, measurements with different detectors yielded different results. Calculations showed agreements with measurements with the smallest detector, provided careful field size calibration and commissioning of calculation parameters. Uncertainties in collimator settings and source characteristics were shown to yield large uncertainties in Scp for fields smaller than 2×2 cm2.

    The treatment planning system was found to properly handle small subfields but results were very sensitive to uncertainties in source size, as well as calibration and reproducibility of the collimator settings. Therefore if subfields smaller than 2×2 cm2 are to be used in IMRT extra care should be taken to determine the source characteristics and to calibrate the collimators. The volume of the detectors used for validation of such small fields and the loss of charged particle equilibrium conditions also have to be taken into consideration.

  • 156.
    Anghammar, Fredrik
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Psykologiska bedömningar inför arbete med föräldrar inom BUP2010Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Psykologiska bedömningar av föräldrar beskrivs sällan som en mer uttalad och tydlig del av arbetet inom barn- och ungdomspsykiatri, utan det är i hög grad ett underförstått arbetsområde. Syftet med den här undersökningen var att beskriva hur arbetet med psykologiska bedömningar av föräldrar konceptualiseras och praktiseras under det inledande skedet av behandlingskontakter inom BUP. Nio psykologer vid sju öppenvårdsmottagningar intervjuades och intervjuerna analyserades tematiskt. En viktig aspekt som framkommer i resultatet är hur det gemensamma arbetet mellan psykolog och förälder för att etablera en arbetsallians erbjuder goda möjligheter till psykologiska bedömningar av föräldern. Under arbetet med alliansen, och med alliansen som bas, kan olika former av systematik och modeller för psykologiska bedömningar tillämpas. Resultatet indikerar också att arbetsalliansens centrala betydelse för bedömningsarbetet är tydligt relaterad till organisationens påverkan på det arbetet, liksom till betydelsen av psykologisk kompetens vid arbete med psykologiska bedömningar av föräldrar.

  • 157.
    Angleman, Sara B.
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Santoni, Giola
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Pilotto, Alberto
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Karolinska Institutet.
    Welmer, Anna-Karin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Multidimensional Prognostic Index in Association with Future Mortality and Number of Hospital Days in a Population-Based Sample of Older Adults: Results of the EU Funded MPI_AGE Project2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133789Article in journal (Refereed)
    Abstract [en]

    Background The Multidimensional Prognostic Index (MPI) has been found to predict mortality in patients with a variety of clinical conditions. We aimed to assess the association of the MPI with future mortality and number of in-hospital days for the first time in a population-based cohort. Methods The study population consisted of 2472 persons, aged 66-99 years, from the Swedish National Study on Aging and Care in Kungsholmen, Sweden, who underwent the baseline visit 2001-4, and were followed up >10 years for in-hospital days and >12 years for mortality. The MPI was a modified version of the original and aggregated seven domains (personal and instrumental activities of daily living, cognitive function, illness severity and comorbidity, number of medications, co-habitation status, and nutritional status). The MPI score was divided into risk groups: low, medium and high. Number of in-hospital days (within 1, 3 and 10 years) and mortality data were derived from official registries. All analyses were age-stratified (sexagenarians, septuagenarians, octogenarians, nonagenarians). Results During the follow-up 1331 persons (53.8%) died. Laplace regression models, suggested that median survival in medium risk groups varied by age from 2.2-3.6 years earlier than for those in the corresponding low risk groups (p = 0.002-p<0.001), and median survival in high risk groups varied by age from 3.8-9.0 years earlier than for corresponding low risk groups (p<0.001). For nonagenarians, the median age at death was 3.8 years earlier in the high risk group than for the low risk group (p<0.001). The mean number of in-hospital days increased significantly with higher MPI risk score within 1 and 3 years for people of each age group. Conclusion For the first time, the effectiveness of MPI has been verified in a population-based cohort. Higher MPI risk scores associated with more days in hospital and with fewer years of survival, across a broad and stratified age range.

  • 158.
    Angleman, Sara B.
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Santoni, Giola
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Von Strauss, Eva
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). The Swedish Red Cross University College, Sweden.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). The Swedish Red Cross University College, Sweden.
    Temporal Trends of Functional Dependence and Survival Among Older Adults From 1991 to 2010 in Sweden: Toward a Healthier Aging2015In: The journals of gerontology. Series A, Biological sciences and medical sciences, ISSN 1079-5006, E-ISSN 1758-535X, Vol. 70, no 6, p. 746-752Article in journal (Refereed)
    Abstract [en]

    Background. Declines in functional dependence among older adults were observed before the 1990s, but there is uncertainty about subsequent trends. Our study aimed to verify the temporal trends in disability during 1991-2010 in an older Swedish population and to estimate the associated changes in survival. Methods. Functional status in octogenarians and nonagenarians was assessed at seven occasions with intervals of 2-3 years. Sample size varied at each assessment with an average of 646 (range 212-1096). Disability was defined as difficulty in one or more of personal activities of daily living. We compared prevalence and incidence, as well as mortality, and survival associated with disability over the 20-year period. Results. Sex-standardized prevalence of disability remained steady over time with a tendency toward a gradual decline, and a statistically significant decrease was present among nonagenarians. Sex-standardized cumulative incidence also remained steady. The proportion of people with prevalent disability who died <3 years remained stable, as did the survival time of people with incident disability. In contrast, among nondisabled persons, 3-year mortality decreased significantly, and for octogenarians median survival time was 1.3 years longer at the more recent assessment than a decade earlier. Conclusions. Both prevalence and incidence of disability remained stable over the last two decades in this urban Swedish population, with a trend toward a slow decline. Mortality remained steady among disabled persons but decreased among persons without disability, suggesting that increased life expectancy during the last two decades may be essentially driven by longer lives of functionally independent people.

  • 159. Anh, Nhi
    et al.
    Taylan, Fulya
    Zachariadis, Vasilios
    Ivanov Öfverholm, Ingegerd
    Lindstrand, Anna
    Vezzi, Francesco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lötstedt, Britta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nordenskjöld, Magnus
    Nordgren, Ann
    Nilsson, Daniel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Barbany, Gisela
    High-resolution detection of chromosomal rearrangements in leukemias through mate pair whole genome sequencing2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 3, article id e0193928Article in journal (Refereed)
    Abstract [en]

    The detection of recurrent somatic chromosomal rearrangements is standard of care for most leukemia types. Even though karyotype analysis-a low-resolution genome-wide chromosome analysis-is still the gold standard, it often needs to be complemented with other methods to increase resolution. To evaluate the feasibility and applicability of mate pair whole genome sequencing (MP-WGS) to detect structural chromosomal rearrangements in the diagnostic setting, we sequenced ten bone marrow samples from leukemia patients with recurrent rearrangements. Samples were selected based on cytogenetic and FISH results at leukemia diagnosis to include common rearrangements of prognostic relevance. Using MP-WGS and in-house bioinformatic analysis all sought rearrangements were successfully detected. In addition, unexpected complexity or additional, previously undetected rearrangements was unraveled in three samples. Finally, the MP-WGS analysis pinpointed the location of chromosome junctions at high resolution and we were able to identify the exact exons involved in the resulting fusion genes in all samples and the specific junction at the nucleotide level in half of the samples. The results show that our approach combines the screening character from karyotype analysis with the specificity and resolution of cytogenetic and molecular methods. As a result of the straightforward analysis and high-resolution detection of clinically relevant rearrangements, we conclude that MP-WGS is a feasible method for routine leukemia diagnostics of structural chromosomal rearrangements.

  • 160. Anisimov, Vladimir N.
    et al.
    Egorov, Maxim V.
    Krasilshchikova, Marina S.
    Lyamzaev, Konstantin G.
    Manskikh, Vasily N.
    Moshkin, Mikhail P.
    Novikov, Evgeny A.
    Popovich, Irina G.
    Rogovin, Konstantin A.
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Shekarova, Olga N.
    Skulachev, Maxim V.
    Titova, Tatiana V.
    Vygodin, Vladimir A.
    Vyssokikh, Mikhail Yu.
    Yurova, Maria N.
    Zabezhinsky, Mark A.
    Skulachev, Vladimir P.
    Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents2011In: Aging, ISSN 1945-4589, E-ISSN 1945-4589, Vol. 3, no 11, p. 1110-1119Article in journal (Refereed)
    Abstract [en]

    The effect of the mitochondria-targeted, plastoquinone-containing antioxidant SkQ1 on the lifespan of outbred mice and of three strains of inbred mice was studied. To this end, low pathogen (LP) or specific pathogen free (SPF) vivaria in St. Petersburg, Moscow, and Stockholm were used. For comparison, we also studied mole-voles and dwarf hamsters, two wild species of small rodents kept under simulated natural conditions. It was found that substitution of a LP vivarium for a conventional (non-LP) one doubled the lifespan of female outbred mice, just as SkQ1 did in a non-LP vivarium. SkQ1 prevented age-dependent disappearance of estrous cycles of outbred mice in both LP and non-LP vivaria. In the SPF vivarium in Moscow, male BALB/c mice had shorter lifespan than females, and SkQ1 increased their lifespan to the values of the females. In the females, SkQ1 retarded development of such trait of aging as heart mass increase. Male C57Bl/6 mice housed individually in the SPF vivarium in Stockholm lived as long as females. SkQ1 increased the male lifespan, the longevity of the females being unchanged. SkQ1 did not change food intake by these mice. Dwarf hamsters and mole-voles kept in outdoor cages or under simulated natural conditions lived longer if treated with SkQ1. The effect of SkQ1 on longevity of females is assumed to mainly be due to retardation of the age-linked decline of the immune system. For males under LP or SPF conditions, SkQ1 increased the lifespan, affecting also some other system(s) responsible for aging.

  • 161.
    Ankarklev, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lebbad, Marianne
    Einarsson, Elin
    Franzen, Oscar
    Ahola, Harri
    Troell, Karin
    Svard, Staffan G.
    A novel high-resolution multilocus sequence typing of Giardia intestinalis Assemblage A isolates reveals zoonotic transmission, clonal outbreaks and recombination2018In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 60, p. 7-16Article in journal (Refereed)
    Abstract [en]

    Molecular epidemiology and genotyping studies of the parasitic protozoan Giardia intestinalis have proven difficult due to multiple factors, such as low discriminatory power in the commonly used genotyping loci, which has hampered molecular analyses of outbreak sources, zoonotic transmission and virulence types. Here we have focused on assemblage A Giardia and developed a high-resolution assemblage-specific multilocus sequence typing (MLST) method. Analyses of sequenced G. intestinalis assemblage A genomes from different sub-assemblages identified a set of six genetic loci with high genetic variability. DNA samples from both humans (n = 44) and animals (n = 18) that harbored Giardia assemblage A infections, were PCR amplified (557-700 bp products) and sequenced at the six novel genetic loci. Bioinformatic analyses showed five to ten-fold higher levels of polymorphic sites than what was previously found among assemblage A samples using the classic genotyping loci. Phylogenetically, a division of two major clusters in assemblage A became apparent, separating samples of human and animal origin. A subset of human samples (n = 9) from a documented Giardia outbreak in a Swedish day-care center, showed full complementarity at nine genetic loci (the six new and the standard BG, TPI and GDH loci), strongly suggesting one source of infection. Furthermore, three samples of human origin displayed MLST profiles that were phylogenetically more closely related to MLST profiles from animal derived samples, suggesting zoonotic transmission. These new genotyping loci enabled us to detect events of recombination between different assemblage A isolates but also between assemblage A and E isolates. In summary, we present a novel and expanded MLST strategy with significantly improved sensitivity for molecular analyses of virulence types, zoonotic potential and source tracking for assemblage A Giardia.

  • 162. Anstey, Kaarin J.
    et al.
    Cherbuin, Nicolas
    Herath, Pushpani M.
    Qiu, Chengxuan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kuller, Lewis H.
    Lopez, Oscar L.
    Wilson, Robert S.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    A Self-Report Risk Index to Predict Occurrence of Dementia in Three Independent Cohorts of Older Adults: The ANU-ADRI2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, p. e86141-Article in journal (Refereed)
    Abstract [en]

    Background and Aims: The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer's disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts. Methods: This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age >= 53 years), the Kungsholmen Project (KP) (n = 905, age >= 75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age >= 65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index. Results: For the ANU-ADRI using available data, the MAP study c-statistic was 0.637 (95% CI 0.596-0.678), for the KP study it was 0.740 (0.712-0.768) and for the CVHS it was 0.733 (0.691-0.776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650-0.727), 0.666 (0.628-0.704) and 0.734 (0.707-0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427-0.554) to 0.595 (0.565-0.625). Conclusion: A composite risk score derived from the ANU-ADRI weights including 8-10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up.

  • 163.
    Antonovic, Laura
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    Evaluation of the lithium formate EPR dosimetry system for dose measurements around 192Ir brachytherapy sources2008Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The dose distribution around brachytherapy (BT) sources is characterized by steep dose gradients and an energy spectrum varying rapidly with depth in water around the source. These two properties make experimental verification of the dose distribution difficult, and put high demands on the dosimetry system in use regarding precision, size and energy dependence. The American Association of Physicists in Medicine (AAPM) recommends lithium fluoride (LiF) thermo-luminescence dosimetry (TLD) to be used for verification measurements, as it is the only dosimetry system meeting the requirements, but still the total combined uncertainty in dose-rate determination is as high as 7-9 % (1 σ). Lithium formate is a new dosimetry material that is less energy dependent than LiF, but more sensitive than the most common EPR (electron paramagnetic resonance) dosimetry material, alanine. In order to evaluate lithium formate EPR for BT dosimetry, dosimeters were produced for experimental dose determination around BT source 192Ir. The dosimeters were calibrated against an ionization chamber in a high energy photon beam. Dose to water was determined at 1, 3 and 5 cm radial distance from the source, which was stepped along a straight line in a PMMA phantom. The experiments were performed twice using 4 dosimeters per distance and experiment. Methods to correct for energy dependence were developed and evaluated. The uncertainty in measured dose was estimated. The experimental dose values agreed with the values from the treatment planning system with a maximum deviation of 3.3 %, and an average 1 σ uncertainty of 3 % at 3 and 5 cm and 5 % at 1cm. Uncertainty in radial distance from the source as well as source calibration were the dominating contributions to the total combined uncertainty. Lithium formate EPR has been shown to be a promising alternative to LiF TLD for BT dosimetry.

  • 164.
    Antonovic, Laura
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Brahme, Anders
    Furusawa, Yoshiya
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions2013In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 54, no 1, p. 18-26Article in journal (Refereed)
    Abstract [en]

    Light-ion radiation therapy against hypoxic tumors is highly curative due to reduced dependence on the presence of oxygen in the tumor at elevated linear energy transfer (LET) towards the Bragg peak. Clinical ion beams using spread-out Bragg peak (SOBP) are characterized by a wide spectrum of LET values. Accurate treatment optimization requires a method that can account for influence of the variation in response for a broad range of tumor hypoxia, absorbed doses and LETs. This paper presents a parameterization of the Repairable Conditionally-Repairable (RCR) cell survival model that can describe the survival of oxic and hypoxic cells over a wide range of LET values, and investigates the relationship between hypoxic radiation resistance and LET. The biological response model was tested by fitting cell survival data under oxic and anoxic conditions for V79 cells irradiated with LETs within the range of 30 – 500 keV/μm. The model provides good agreement with experimental cell survival data for the range of LET investigated, confirming the robustness of the parameterization method. This new version of the RCR model is suitable for describing the biological response of mixed populations of oxic and hypoxic cells and at the same time taking into account the distribution of doses and LETs in the incident beam and its variation with depth in tissue. The model offers a versatile tool for the selection of LET and dose required in the optimization of the therapeutic effect, without severely affecting normal tissue in realistic tumors presenting highly heterogeneous oxic and hypoxic regions.

  • 165.
    Antonovic, Laura
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Lindblom, Emely
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    Bassler, Niels
    Furusawa, Yoshiya
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes2014In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 55, no 5, p. 902-911Article in journal (Refereed)
    Abstract [en]

    The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of low linear energy transfer (LET) values in the spread-out Bragg peak (SOBP). The aim of this study was to investigate the role of hypoxia and local oxygenation changes (LOCs) in fractionated carbon ion radiotherapy. Three-dimensional tumors with hypoxic subvolumes were simulated assuming interfraction LOCs. Different fractionations were applied using a clinically relevant treatment plan with a known LET distribution. The surviving fraction was calculated, taking oxygen tension, dose and LET into account, using the repairable–conditionally repairable (RCR) damage model with parameters for human salivary gland tumor cells. The clinical oxygen enhancement ratio (OER) was defined as the ratio of doses required for a tumor control probability of 50% for hypoxic and well-oxygenated tumors. The resulting OER was well above unity for all fractionations. For the hypoxic tumor, the tumor control probability was considerably higher if LOCs were assumed, rather than static oxygenation. The beneficial effect of LOCs increased with the number of fractions. However, for very low fraction doses, the improvement related to LOCs did not compensate for the increase in total dose required  for tumor control. In conclusion, our results suggest that hypoxia can influence the outcome of carbon ion radiotherapy because of the non-negligible oxygen effect at the low LETs in the SOBP. However, if LOCs occur, a relatively high level of tumor control probability is achievable with a large range of fractionation schedules for tumors with hypoxic subvolumes, but both hyperfractionation and hypofractionation should be pursued with caution.

  • 166. Anund, A.
    et al.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Fors, C.
    Ihlström, J.
    Ingre, Michael
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Radun, Igor
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Söderström, B.
    Bussförares arbetstider kopplat till trötthet [Bus drivers' working hours and the relationship to fatigue]2014Report (Other (popular science, discussion, etc.))
  • 167. Anund, Anna
    et al.
    Ahlström, Christer
    Fors, Carina
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Are professional drivers less sleepy than non-professional drivers?2018In: Scandinavian Journal of Work, Environment and Health, ISSN 0355-3140, E-ISSN 1795-990X, Vol. 44, no 1, p. 88-95Article in journal (Refereed)
    Abstract [en]

    Objective It is generally believed that professional drivers can manage quite severe fatigue before routine driving performance is affected. In addition, there are results indicating that professional drivers can adapt to prolonged night shifts and may be able to learn to drive without decreased performance under high levels of sleepiness. However, very little research has been conducted to compare professionals and non-professionals when controlling for time driven and time of day.

    Method The aim of this study was to use a driving simulator to investigate whether professional drivers are more resistant to sleep deprivation than non-professional drivers. Differences in the development of sleepiness (self-reported, physiological and behavioral) during driving was investigated in 11 young professional and 15 non-professional drivers.

    Results Professional drivers self-reported significantly lower sleepiness while driving a simulator than nonprofessional drivers. In contradiction, they showed longer blink durations and more line crossings, both of which are indicators of sleepiness. They also drove faster. The reason for the discrepancy in the relation between the different sleepiness indicators for the two groups could be due to more experience to sleepiness among the professional drivers or possibly to the faster speed, which might unconsciously have been used by the professionals to try to counteract sleepiness.

    Conclusion Professional drivers self-reported significantly lower sleepiness while driving a simulator than non-professional drivers. However, they showed longer blink durations and more line crossings, both of which are indicators of sleepiness, and they drove faster.

  • 168. Anund, Anna
    et al.
    Ahlström, Christer
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Rumble strips in centre of the lane and the effect on sleepy drivers2011In: Industrial Health, ISSN 0019-8366, E-ISSN 1880-8026, Vol. 49, no 5, p. 549-558Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to describe the effects of sleep loss on behavioural and subjective indicators of sleepiness on a road containing a milled rumble strip in the centre of the lane. Particular attention was paid to behavioural and subjective indicators of sleepiness when using the centre lane rumble strip, and to possible erratic driving behaviour when hitting a rumble strip. In total 9 regular shift workers drove during the morning hours after a full night shift and after a full night sleep. The order was balanced. The experiment was conducted in a moving base driving simulator on rural roads with a road width of 6.5 and 9 meters. Out of the 1,636 rumble strip hits that occurred during the study, no indications of erratic driving behaviour associated with the jolt caused by making contact with the centre lane rumble strip could be found. Comparing the alert condition with the sleep deprived condition, both the standard deviation of lateral position (SDLP) and the Karolinska Sleepiness Scale (KSS) increased for sleepy drivers. For the two road widths, the drivers drove closer to the centre line on the 6.5-meter road. The KSS and the SDLP increased with time on task. This simulator study indicates that rumble strips in the centre of the lane may be an alternative to centreline and edgeline rumble strips on narrow roads.

  • 169. Anund, Anna
    et al.
    Fors, Carina
    Hallvig, David
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Observer rated sleepiness and real road driving: an explorative study2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, article id e64782Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to explore if observer rated sleepiness (ORS) is a feasible method for quantification of driver sleepiness in field studies. Two measures of ORS were used: (1) one for behavioural signs based on facial expression, body gestures and body movements labelled B-ORS, and (2) one based on driving performance e.g. if swerving and other indicators of impaired driving occurs, labelled D-ORS. A limited number of observers sitting in the back of an experimental vehicle on a motorway about 2 hours repeatedly 3 times per day (before lunch, after lunch, at night) observed 24 participant's sleepiness level with help of the two observer scales. At the same time the participant reported subjective sleepiness (KSS), EOG was recorded (for calculation of blink duration) and several driving measure were taken and synchronized with the reporting. Based on mixed model Anova and correlation analysis the result showed that observer ratings of sleepiness based on drivers' impaired performance and behavioural signs are sensitive to extend the general pattern of time awake, circadian phase and time of driving. The detailed analysis of the subjective sleepiness and ORS showed weak correspondence on an individual level. Only 16% of the changes in KSS were predicted by the observer. The correlation between the observer ratings based on performance (D-ORS) and behavioural signs (B-ORS) are high (r = .588), and the B-ORS shows a moderately strong association (r = .360) with blink duration. Both ORS measures show an association (r>0.45) with KSS, whereas the association with driving performance is weak. The results show that the ORS-method detects the expected general variations in sleepy driving in field studies, however, sudden changes in driver sleepiness on a detailed level as 5 minutes is usually not detected; this holds true both when taking into account driving behaviour or driver behavioural signs.

  • 170. Anund, Anna
    et al.
    Fors, Carina
    Ihlstrom, Jonas
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Radboud University, The Netherlands.
    An on-road study of sleepiness in split shifts among city bus drivers2018In: Accident Analysis and Prevention, ISSN 0001-4575, E-ISSN 1879-2057, Vol. 114, p. 71-76Article in journal (Refereed)
    Abstract [en]

    Bus drivers often work irregular hours or split shifts and their work involves high levels of stress. These factors can lead to severe sleepiness and dangerous driving. This study examined how split shift working affects sleepiness and performance during afternoon driving. An experiment was conducted on a real road with a specially equipped regular bus driven by professional bus drivers. The study had a within-subject design and involved 18 professional bus drivers (9 males and 9 females) who drove on two afternoons; one on a day in which they had driven early in the morning (split shift situation) and one on a day when they had been off duty until the test (afternoon shift situation). The hypothesis tested was that split shifts contribute to sleepiness during afternoon, which can increase the safety risks. The overall results supported this hypothesis. In total, five of the 18 drivers reached levels of severe sleepiness (Karolinska Sleepiness Scale 8) with an average increase in KSS of 1.94 when driving in the afternoon after working a morning shift compared with being off duty in the morning. This increase corresponded to differences observed between shift workers starting and ending a night shift. The Psychomotor Vigilance Task showed significantly increased response time with split shift working (afternoon: 0.337 s; split shift 0.347 s), as did the EEG-based Karolinska Drowsiness Score mean/max. Blink duration also increased, although the difference was not significant. One driver fell asleep during the drive. In addition, 12 of the 18 bus drivers reported that in their daily work they have to fight to stay awake while driving at least 2-4 times per month. While there were strong individual differences, the study clearly showed that shift working bus drivers struggle to stay awake and thus countermeasures are needed in order to guarantee safe driving with split shift schedules.

  • 171. Anund, Anna
    et al.
    Fors, Carina
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    van Leeuwen, Wessel M A
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Countermeasures for fatigue in transportation: A review of existing methods for drivers on road, rail, sea and in aviation2015Report (Other academic)
  • 172. Anund, Anna
    et al.
    Ihlström, Jonas
    Fors, Carina
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Filtness, Ashleigh
    Factors associated with self-reported driver sleepiness and incidents in city bus drivers2016In: Industrial Health, ISSN 0019-8366, E-ISSN 1880-8026, Vol. 54, no 4, p. 337-346Article in journal (Refereed)
    Abstract [en]

    Driver fatigue has received increased attention during recent years and is now considered to be a major contributor to approximately 15-30% of all crashes. However, little is known about fatigue in city bus drivers. It is hypothesized that city bus drivers suffer from sleepiness, which is due to a combination of working conditions, lack of health and reduced sleep quantity and quality. The overall aim with the current study is to investigate if severe driver sleepiness, as indicated by subjective reports of having to fight sleep while driving, is a problem for city based bus drivers in Sweden and if so, to identify the determinants related to working conditions, health and sleep which contribute towards this. The results indicate that driver sleepiness is a problem for city bus drivers, with 19% having to fight to stay awake while driving the bus 2-3 times each week or more and nearly half experiencing this at least 2-4 times per month. In conclusion, severe sleepiness, as indicated by having to fight sleep during driving, was common among the city bus drivers. Severe sleepiness correlated with fatigue related safety risks, such as near crashes.

  • 173. Anund, Anna
    et al.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Peters, Björn
    Akerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Driver sleepiness and individual differences in preferences for countermeasures.2008In: J Sleep Res, ISSN 1365-2869, Vol. 17, no 1, p. 16-22Article in journal (Other academic)
    Abstract [en]

    1: J Sleep Res. 2008 Mar;17(1):16-22. Links

    Driver sleepiness and individual differences in preferences for countermeasures.

    Anund A, Kecklund G, Peters B, Akerstedt T.

    Swedish National Road and Transport Research Institute (VTI), Linköping, Sweden. anna.anund@vti.se

    The aim of the present national questionnaire study was to relate the use of sleepiness countermeasures among drivers to possible explanatory factors such as age, sex, education, professional driving, being a shift worker, having experience of sleepy driving, sleep-related crashes, problems with sleep and sleepiness in general and sleep length during working days. Also the attitude to countermeasures related to information or driver support system was studied. A random sample of 3041 persons was drawn from the national register of vehicle owners. The response rate was 62%. The most common countermeasures were to stop to take a walk (54%), turn on the radio/stereo (52%), open a window (47%), drink coffee (45%) and to ask passengers to engage in conversation (35%). Logistic regression analysis showed that counteracting sleepiness with a nap (a presumably efficient method) was practiced by those with experience of sleep-related crashes or of driving during severe sleepiness, as well as by professional drivers, males and drivers aged 46-64 years. The most endorsed means of information to the driver about sleepiness was in-car monitoring of driving performance providing drivers with information on bad or unsafe driving. This preference was related to experience of sleepy driving, not being a professional driver and male gender. Four clusters of behaviours were identified: alertness-enhancing activity while driving (A), stopping the car (S), taking a nap (N) and ingesting coffee or other sources of caffeine (C) (energy drinks, caffeine tablets). The participants were grouped according to their use of any of the four categories of countermeasures. The most common cluster was those who used activity, as well as stopping and drinking caffeine.

    PMID: 18275551 [PubMed - in process]

  • 174. Anund, Anna
    et al.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Peters, Björn
    Forsman, Asa
    Lowden, Arne
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Driver impairment at night and its relation to physiological sleepiness.2008In: Scand J Work Environ Health, ISSN 0355-3140, Vol. 34, no 2, p. 142-50Article in journal (Refereed)
    Abstract [en]

    Driver impairment at night and its relation to physiological sleepiness.

    Anund A, Kecklund G, Peters B, Forsman A, Lowden A, Akerstedt T.

    VTI, S-581 95 Linköping, Sweden. anna.anund@vti.se.

    OBJECTIVES: Studies of devices detecting sleepiness need reference points of physiological sleepiness. The present study sought to validate the Karolinska drowsiness score (KDS) as an indicator of physiological sleepiness against driving impairment and eye blink duration during a 45-minute drive in an advanced moving-base driving simulator. METHODS: Data from 19 persons were used in the analysis. Electrooculography, electroencephalography, and electromyography were administered continuously. Physiological sleepiness was quantified by scoring the percentage (0-100%) of the scoring epoch with alpha and theta activity and slow eye movements (KDS). Lateral position and speed were used as measures of driving behavior. Lane departure was defined as two wheels touching the lane markers. Blink duration was used as a secondary indicator of sleepiness. RESULTS: The results showed that, for young drivers, sleepiness increased with time in the task with higher levels. The variability of the lateral position and the mean and variability of the blink duration significantly changed when sleepiness increased to KDS >/=20%. Furthermore, there was an increase in the risk of lane departure for KDS >/=30%. CONCLUSIONS: The results suggest that KDS scoring is a reasonable procedure for estimating physiological sleepiness under conditions of driving. The results also indicate that a younger age is associated with greater sensitivity to sleepiness at the wheel.

  • 175. Anund, Anna
    et al.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Vadeby, Anna
    Hjälmdahl, Magnus
    Akerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    The alerting effect of hitting a rumble strip--a simulator study with sleepy drivers.2008In: Accid Anal Prev, ISSN 1879-2057, Vol. 40, no 6, p. 1970-6Article in journal (Refereed)
    Abstract [en]

    The alerting effect of hitting a rumble strip--a simulator study with sleepy drivers.

    Anund A, Kecklund G, Vadeby A, Hjälmdahl M, Akerstedt T.

    Clinical Neuroscience, Karolinska Institutet, SE-177 71 Stockholm, Sweden. anna.anund@vti.se

    A moving base driving simulator experiment was carried out in order to investigate the effects of milled rumble strips on driver fatigue. There were rumble strips both at the edge line and centre line. Four different physical designs of milled rumble strips (yielding noise values from 1.5 to 16 dBA) and two placements on shoulder were used in the experiment. Sound and vibrations from real milled rumble strips were reproduced in the simulator. In total 35 regular shift workers drove during the morning hours after a full night shift. The main results showed an increase in sleepiness indicators (EEG alpha/theta activity, eye closure duration, standard deviation of lateral position, subjective sleepiness) from start to before hitting the rumble strip, an alerting effect in most parameters (not subjective sleepiness) after hitting the strip. The alertness enhancing effect was, however, short and the sleepiness signs returned 5 min after the rumble strip hit. Essentially no effects were seen due to type of strip. It was concluded that various aspects of sleepiness are increased before hitting a rumble strip and that the effect is very short-lived. Type of strip, as used in the present study did not have any effect.

  • 176. Anwar, Muhammad Ikram
    et al.
    Rahman, Moazur
    Ul Hassan, Mahmood
    Stockholm University, Faculty of Social Sciences, Department of Statistics.
    Iqbal, Mazhar
    Prevalence of active hepatitis C virus infections among general public of Lahore, Pakistan2013In: Virology Journal, ISSN 1743-422X, E-ISSN 1743-422X, Vol. 10, article id 351Article in journal (Refereed)
    Abstract [en]

    Background: To find out the prevalence of active hepatitis C virus (HCV) infections among general public in Lahore city, since data concerning the prevalence of active HCV in this city is currently unavailable. Methods: Blood samples were collected randomly from individuals visiting different clinical laboratories in Lahore. Serum was separated and processed by nested PCR qualitative assay for the detection of HCV RNA. The samples were categorized into different age groups on the basis of pre-test questionnaires in order to record the age-wise differences regarding the prevalence of active HCV. Data were analyzed statistically using Chi-Square test. Results: Out of the 4246 blood samples analyzed in this study, 210 were confirmed to be positive for active HCV infection. Gender-wise active HCV prevalence revealed no significant difference [OR = 1.10 CI = (0.83-1.46), p > 0.05]. However, among the age groups the highest prevalence was observed in the age groups 20-29 (7.7%) and 30-39 years (6.4%) with odds of prevalence of 14.8% (OR = 2.48, CI = (1.40-4.38), p < 0.05) and 10.3% (OR = 2.03, CI = (1.10-3.71), respectively. In age groups above 40 years (40-49, 50-59 and >59 years), a decrease in levels of active HCV prevalence was observed. Conclusions: Among tested samples, 4.9% of the subjects were confirmed to harbour active HCV infections and the middle aged population in Lahore was found to be at a higher risk of the HCV ailments compared to both their younger and older peers.

  • 177. Appelberg, Jonas
    et al.
    Janson, Christer
    Lindberg, Eva
    Pavlenko, Tatjana
    Stockholm University, Faculty of Social Sciences, Department of Statistics.
    Hedenstierna, Göran
    Lung aeration during sleep in patients with obstructive sleep apnoea2010In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 30, no 4, p. 301-307Article in journal (Refereed)
    Abstract [en]

    P>Background: Previous studies have indicated that patients with obstructive sleep apnoea (OSA) have altered ventilation and lung volumes awake and the results suggest that this may be a determinant of severity of desaturations during sleep. However, little is known about regional lung aeration during sleep in patients with OSA. Methods: Twelve patients with OSA were included in the study. Computed tomography was used to study regional lung aeration during wakefulness and sleep. Lung aeration was calculated in ml gas/g lung tissue in four different regions of interest (ROI1-4), along the border of the lung from ventral to dorsal. Results: Lung aeration in the dorsal (dependent) lung region (ROI4) was lower during sleep compared to wakefulness 0 center dot 78 +/- 0 center dot 19 versus 0 center dot 88 +/- 0 center dot 19 (mean +/- SD) ml gas/g lung tissue (P = 0 center dot 005). Associations were found between awake expiratory reserve volume and change in lung aeration from wakefulness to sleep in ROI4 (r = -0 center dot 69; P = 0 center dot 012). In addition, the change in lung aeration in the dorsal region correlated to sleep time (r = 0 center dot 69; P = 0 center dot 014) but not to time in supine position. The difference in lung aeration between inspiration and expiration (i.e. ventilation), was larger in the ventral lung region when expressed as ml gas per g lung tissue. In two patients it was noted that, during on-going obstructive apnoea, lung aeration tended to be increased rather than decreased. Conclusions: Aeration in the dorsal lung region is reduced during sleep in patients with OSA. The decrease is related to lung volume awake and to sleep time.

  • 178.
    Apraiz Larrucea, Itxaso
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Development and application of a proteomic approach to the assessment of pollution in the marine environment2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Today, assessment of the health of coastal waters is recognized as being important for both the conservation of nature and well-being of humans. Anthropogenic pollution has been the focus of extensive research for some time and a variety of programs for the monitoring and assessment of environmental pollution have been developed. Determination of the levels of pollution in sensitive ‘sentinels’ such as mussels, allows monitoring of these levels in a given area over a prolonged period of time. Furthermore, the biological effects of pollution are reflected in a series of biomarkers, none of which provides a general picture of the sentinel’s state of health and all of which are individually specific for certain pollutants and influenced by both biotic and abiotic factors.

    In an attempt to improve biomonitoring of marine pollution, we have developed two proteomic approaches here. In the first portion of the thesis, a proteomic analysis was performed on peroxisomes isolated from mussels exposed either to one of three model anthropogenic pollutants, or two different types of crude oil, or from mussels exposed to the Prestige oil spill. Application of two-dimensional electrophoresis (2-DE) provided protein expression signatures (PES) for exposure to these different pollutants.Furthermore, several individual protein components of these PES could be putatively identified.

    In the second portion of this work, such analysis of subproteomes was developed further in order to improve the applicability of this approach to biomonitoring. A simple fractionation procedure in combination with liquid chromatography and 2-DE provided samples from mussels residing in different regions of a pollution gradient around the harbor of Gothenburg, as well as from mussels exposed to two types of fuel oil similar to that of the Prestige that were suitable for environmental proteomics. In addition, we constructed a model for this approach that can be cross-validated in the future and applied to assess sources of fuel oil pollution in connection with biomonitoring programs.

  • 179.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Boström, Stephanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Varani, Stefania
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Interethnic Differences in Antigen-Presenting Cell Activation and TLR Responses in Malian Children during Plasmodium falciparum Malaria2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. e18319-Article in journal (Refereed)
    Abstract [en]

    The Fulani ethnic group from West Africa is relatively better protected against Plasmodium falciparum malaria as compared to other sympatric ethnic groups, such as the Dogon. However, the mechanisms behind this lower susceptibility to malaria are largely unknown, particularly those concerning innate immunity. Antigen-presenting cells (APCs), and in particular dendritic cells (DCs) are important components of the innate and adaptive immune systems. Therefore, in this study we investigated whether APCs obtained from Fulani and Dogon children exhibited differences in terms of activation status and toll-like receptor (TLR) responses during malaria infection. Lower frequency and increased activation was observed in circulating plasmacytoid DCs and BDCA-3+ myeloid DCs of infected Fulani as compared to their uninfected counterparts. Conversely, a higher frequency and reduced activation was observed in the same DC subsets obtained from peripheral blood of P. falciparum-infected Dogon children as compared to their uninfected peers. Moreover, infected individuals of both ethnic groups exhibited higher percentages of both classical and inflammatory monocytes that were less activated as compared to their non-infected counterparts. In line with APC impairment during malaria infection, TLR4, TLR7 and TLR9 responses were strongly inhibited by P. falciparum infection in Dogon children, while no such TLR inhibition was observed in the Fulani children. Strikingly, the TLR-induced IFN-γ release was completely abolished in the Dogon undergoing infection while no difference was seen within infected and non-infected Fulani. Thus, P. falciparum infection is associated with altered activation status of important APC subsets and strongly inhibited TLR responses in peripheral blood of Dogon children. In contrast, P. falciparum induces DC activation and does not affect the innate response to specific TLR ligands in Fulani children. These findings suggest that DCs and TLR signalling may be of importance for the protective immunity against malaria observed in the Fulani.

  • 180. Arama, Charles
    et al.
    Maiga, Bakary
    Dolo, Amagana
    Kouriba, Bourema
    Traore, Boubacar
    Crompton, Peter D.
    Pierce, Susan K.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Miller, Louis H.
    Doumbo, Ogobara K.
    Ethnic differences in susceptibility to malaria: What have we learned from immuno-epidemiological studies in West Africa?2015In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 146, p. 152-156Article, review/survey (Refereed)
    Abstract [en]

    There are many fundamental aspects of the immunobiology of Plasmodium falciparum infections that are not fully understood, therefore limiting our comprehension of how people become immune to malaria and why some ethnic groups living in malaria endemic areas are less susceptible than others. The complexity of parasite-host interactions and the genetic diversity of the parasites as well as the human host complicate our strategy to address this issue. In this mini-review we discuss and summarize what we have learned about African ethnic differences in susceptibility to malaria from immuno-epidemiological studies. Additionally, we suggest research topics that might be of great value for dissecting the mechanisms of protection by providing new insights into molecular interactions between the parasite and the host.

  • 181. Arama, Charles
    et al.
    Quin, Jaclyn E.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kouriba, Bourema
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Doumbo, Ogobara K.
    Epigenetics and Malaria Susceptibility/Protection: A Missing Piece of the Puzzle2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 1733Article, review/survey (Refereed)
    Abstract [en]

    A better understanding of stable changes in regulation of gene expression that result from epigenetic events is of great relevance in the development of strategies to prevent and treat infectious diseases. Histone modification and DNA methylation are key epigenetic mechanisms that can be regarded as marks, which ensure an accurate transmission of the chromatin states and gene expression profiles over generations of cells. There is an increasing list of these modifications, and the complexity of their action is just beginning to be understood. It is clear that the epigenetic landscape plays a fundamental role in most biological processes that involve the manipulation and expression of DNA. Although the molecular mechanism of gene regulation is relatively well understood, the hierarchical order of events and dependencies that lead to protection against infection remain largely unknown. In this review, we propose that host epigenetics is an essential, though relatively under studied, factor in the protection or susceptibility to malaria.

  • 182. Arama, Charles
    et al.
    Skinner, Jeff
    Doumtabe, Didier
    Portugal, Silvia
    Tran, Tuan M.
    Jain, Aarti
    Traore, Boubacar
    Doumbo, Ogobara K.
    Davies, David Huw
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Dolo, Amagana
    Felgner, Philip L.
    Crompton, Peter D.
    Genetic Resistance to Malaria Is Associated With Greater Enhancement of Immunoglobulin (Ig)M Than IgG Responses to a Broad Array of Plasmodium falciparum Antigens2015In: Open forum infectious diseases, ISSN 2328-8957, Vol. 2, no 3Article in journal (Refereed)
    Abstract [en]

    Background. People of the Fulani ethnic group are more resistant to malaria compared with genetically distinct ethnic groups, such as the Dogon people, in West Africa, and studies suggest that this resistance is mediated by enhanced antibody responses to Plasmodium falciparum antigens. However, prior studies measured antibody responses to < 0.1% of P falciparum proteins, so whether the Fulani mount an enhanced and broadly reactive immunoglobulin (Ig) M and IgG response to P falciparum remains unknown. In general, little is known about the extent to which host genetics influence the overall antigen specificity of IgM and IgG responses to natural infections. Methods. In a cross-sectional study in Mali, we collected plasma from asymptomatic, age-matched Fulani (n = 24) and Dogon (n = 22) adults with or without concurrent P falciparum infection. We probed plasma against a protein microarray containing 1087 P falciparum antigens and compared IgM and IgG profiles by ethnicity. Results. We found that the breadth and magnitude of P falciparum-specific IgM and IgG responses were significantly higher in the malaria-resistant Fulani versus the malaria-susceptible Dogon, and, unexpectedly, P falciparum-specific IgM responses more strongly distinguished the 2 ethnic groups. Conclusions. These findings point to an underappreciated role for IgM in protection from malaria, and they suggest that host genetics may influence the antigen specificity of IgM and IgG responses to infection.

  • 183.
    Arat, Arzu
    et al.
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Karolinska Institute, Sweden.
    Östberg, Viveca
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Burström, Bo
    Hjern, Anders
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Karolinska Institute, Sweden.
    ADHD medication in offspring of immigrants - does the income level of the country of parental origin matter?2018In: BMC Psychiatry, ISSN 1471-244X, E-ISSN 1471-244X, Vol. 18, no 1, article id 3Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Child psychiatric treatment facilities vary greatly worldwide and are virtually non-existent in many low-income countries. One of the most common psychiatric disorders in childhood is ADHD, with an estimated prevalence of 3-5% in Sweden. Previous studies have shown a similar prevalence of ADHD in minority and majority children in Sweden and the UK. However, clinical studies demonstrated that children from immigrant families living in Sweden received less psychiatric care than those of native-born parents. We tested the hypothesis that the consumption of child psychiatric care in immigrant families would be determined by the availability of such treatment in the parents' country of origin. Patterns of medication for attention-deficit hyperactivity disorder (ADHD) were studied as a proxy for child psychiatric care.

    METHODS: This was a register study of dispensed stimulant medication during 2013-2014 in Swedish national birth cohorts from 1995-2009. The study population, consisting of nearly 1.4 million children, was divided by national income of the parental country of origin and whether the parents were native Swedes, European immigrants, non-European immigrants or a mixture. Logistic regression was used to calculate the odds ratios of having been dispensed at least one ADHD drug during 2013, with adjustments for gender, family status indicating whether the child is living with both parents, household income and area of residence.

    RESULTS: Having parents born in low-income (OR [95% confidence interval] 0.27 [0.24-0.29]) or middle-income (European: OR 0.23 [0.20-0.26], non-European: OR 0.39 [0.34-0.41]) countries was associated with lower ADHD treatment levels than having parents born in high-income countries (European: OR 0.60 [0.54-0.66], non-European: OR 0.68 [0.59-0.79]), when compared to children of parents born in Sweden. In families with a background in low or middle income countries, there was no significant association between household income and ADHD medication, while in children with Swedish and mixed backgrounds high level of disposable income was associated with lower levels of ADHD medication.

    CONCLUSION: The use of child psychiatric care by immigrant families in Sweden was largely associated with the income level of the country of origin.

  • 184. Arbesu Valdivia, Alejandro
    et al.
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Romero Batista, Yamilet
    Kumar, Saroj
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Characterization of recombinant antibodies for cancer therapy by infrared spectroscopy2013In: Biologicals (Print), ISSN 1045-1056, E-ISSN 1095-8320, Vol. 41, no 2, p. 104-110Article in journal (Refereed)
    Abstract [en]

    Fourier transform infrared (FTIR) spectroscopy was used to study the structure of the recombinant antibodies 1E10, anti-CD20 and hR3, which are used as anti-cancer therapeutic drugs. We tested their sensitivity against different conditions and treatments such as pH, temperature, freeze-thaw cycles and drying, which are relevant for the practical usefulness of the drugs. All antibodies were stable against moderate temperature increases (up to 50 degrees C) and pH changes (range 5-9). 1E10 was sensitive to extreme pH values (pH 3 and 12), whereas hR3 was most sensitive to temperature (at and above 60 degrees C). We did not observe any significant changes upon freeze-thaw and drying treatments. The secondary structure content of all three antibodies was estimated to be similar to that of IgG with similar to 64% beta-sheet, 0% alpha-helix and similar to 36% other structure. (C) 2012 The International Alliance for Biological Standardization.

  • 185.
    Ardenfors, Oscar
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    Lillhök, Jan
    Persson, Linda
    Gudowska, Irena
    Stockholm University, Faculty of Science, Department of Physics.
    Out-of-field doses from secondary radiation produced in proton therapy and the associated risk of radiation-induced cancer from a brain tumor treatment2018In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 53, p. 129-136Article in journal (Refereed)
    Abstract [en]

    Purpose: To determine out-of-field doses produced in proton pencil beam scanning (PBS) therapy using Monte Carlo simulations and to estimate the associated risk of radiation-induced second cancer from a brain tumor treatment. Methods: Simulations of out-of-field absorbed doses were performed with MCNP6 and benchmarked against measurements with tissue-equivalent proportional counters (TEPC) for three irradiation setups: two irradiations of a water phantom using proton energies of 78-147 MeV and 177-223 MeV, and one brain tumor irradiation of a whole-body phantom. Out-of-field absorbed and equivalent doses to organs in a whole-body phantom following a brain tumor treatment were subsequently simulated and used to estimate the risk of radiation-induced cancer. Additionally, the contribution of absorbed dose originating from radiation produced in the nozzle was calculated from simulations. Results: Out-of-field absorbed doses to the TEPC ranged from 0.4 to 135 mu Gy/Gy. The average deviation between simulations and measurements of the water phantom irradiations was about 17%. The absorbed dose contribution from radiation produced in the nozzle ranged between 0 and 70% of the total dose; the contribution was however small in absolute terms. The absorbed and equivalent doses to the organs ranged between 0.2 and 60 mu Gy/Gy and 0.5-151 mu Sv/Gy. The estimated lifetime risk of radiation-induced second cancer was approximately 0.01%. Conclusions: The agreement of out-of-field absorbed doses between measurements and simulations was good given the sources of uncertainties. Calculations of out-of-field organ doses following a brain tumor treatment indicated that proton PBS therapy of brain tumors is associated with a low risk of radiation-induced cancer.

  • 186.
    Ardenfors, Oscar
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Gudowska, Irena
    Stockholm University, Faculty of Science, Department of Physics.
    Flejmer, Anna Maria
    Dasu, Alexandru
    IMPACT OF IRRADIATION SETUP IN PROTON SPOT SCANNING BRAIN THERAPY ON ORGAN DOSES FROM SECONDARY RADIATION2018In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 180, no 1-4, p. 261-266Article in journal (Refereed)
    Abstract [en]

    A Monte Carlo model of a proton spot scanning pencil beam was used to simulate organ doses from secondary radiation produced from brain tumour treatments delivered with either a lateral field or a vertex field to one adult and one paediatric patient. Absorbed doses from secondary neutrons, photons and protons and neutron equivalent doses were higher for the vertex field in both patients, but the differences were low in absolute terms. Absorbed doses ranged between 0.1 and 43 mu Gy. Gy(-1) in both patients with the paediatric patient receiving higher doses. The neutron equivalent doses to the organs ranged between 0.5 and 141 mu Sv. Gy(-1) for the paediatric patient and between 0.2 and 134 mu Sv. Gy(-1) for the adult. The highest neutron equivalent dose from the entire treatment was 7 mSv regardless of field setup and patient size. The results indicate that different field setups do not introduce large absolute variations in out-of-field doses produced in patients undergoing proton pencil beam scanning of centrally located brain tumours.

  • 187.
    Ardenfors, Oscar
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Henry, Thomas
    Stockholm University, Faculty of Science, Department of Physics.
    Gudowska, Irena
    Stockholm University, Faculty of Science, Department of Physics.
    Poludniowski, Gavin
    Dasu, Alexandru
    Organ doses from a proton gantry-mounted cone-beam computed tomography system characterized with MCNP6 and GATE2018In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 53, p. 56-61Article in journal (Refereed)
    Abstract [en]

    Purpose

    To determine organ doses from a proton gantry-mounted cone-beam computed tomography (CBCT) system using two Monte Carlo codes and to study the influence on organ doses from different acquisition modes and repeated imaging.

    Methods

    The CBCT system was characterized with MCNP6 and GATE using measurements of depth doses in water and spatial profiles in air. The beam models were validated against absolute dose measurements and used to simulate organ doses from CBCT imaging with head, thorax and pelvis protocols. Anterior and posterior 190° scans were simulated and the resulting organ doses per mAs were compared to those from 360° scans. The influence on organ doses from repeated imaging with different imaging schedules was also investigated.

    Results

    The agreement between MCNP6, GATE and measurements with regard to depth doses and beam profiles was within 4% for all protocols and the corresponding average agreement in absolute dose validation was 4%. Absorbed doses for in-field organs from 360° scans ranged between 6 and 8 mGy, 15–17 mGy and 24–54 mGy for the head, thorax and pelvis protocols, respectively. Cumulative organ doses from repeated CBCT imaging ranged between 0.04 and 0.32 Gy for weekly imaging and 0.2–1.6 Gy for daily imaging. The anterior scans resulted in an average increase in dose per mAs of 24% to the organs of interest relative to the 360° scan, while the posterior scan showed a 37% decrease.

    Conclusions

    A proton gantry-mounted CBCT system was accurately characterized with MCNP6 and GATE. Organ doses varied greatly depending on acquisition mode, favoring posterior scans.

  • 188.
    Ardenfors, Oscar
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Linköping University, Sweden; Karolinska Institutet, Sweden.
    Josefsson, Dan
    Dasu, Alexandru
    Are IMRT treatments in the head and neck region increasing the risk of secondary cancers?2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 8, p. 1041-1047Article in journal (Refereed)
    Abstract [en]

    Background. Intensity-modulated radiation therapy (IMRT) has been increasingly employed for treating head and neck (H&N) tumours due to its ability to produce isodoses suitable for the complex anatomy of the region. The aim of this study was to assess possible differences between IMRT and conformal radiation therapy (CRT) with regard to risk of radiation-induced secondary malignancies for H&N tumours. Material and methods. IMRT and CRT plans were made for 10 H&N adult patients and the resulting treatment planning data were used to calculate the risk of radiation-induced malignancies in four different tissues. Three risk models with biologically relevant parameters were used for calculations. The influence of scatter radiation and repeated imaging sessions has also been investigated. Results. The results showed that the total lifetime risks of developing radiation-induced secondary malignancies from the two treatment techniques, CRT and IMRT, were comparable and in the interval 0.9-2.5%. The risk contributions from the primary beam and scatter radiation were comparable, whereas the contribution from repeated diagnostic imaging was considerably smaller. Conclusion. The results indicated that the redistribution of the dose characteristic to IMRT leads to a redistribution of the risks in individual tissues. However, the total levels of risk were similar between the two irradiation techniques considered.

  • 189. Arendt, Josephine
    et al.
    Van Someren, Eus J W
    Appleton, Richard
    Skene, Debra J
    Akerstedt, Torbjorn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Clinical update: melatonin and sleep disorders.2008In: Clin Med, ISSN 1470-2118, Vol. 8, no 4, p. 381-3Article in journal (Refereed)
    Abstract [en]

    Clinical update: melatonin and sleep disorders.

    Arendt J, Van Someren EJ, Appleton R, Skene DJ, Akerstedt T.

    Centre for Chronobiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford. j.arendt@surrey.ac.uk

    The hormone melatonin is increasingly used for the treatment of certain sleep disorders, particularly those related to disturbed biological rhythms. This article summarises current knowledge of its mechanism of action and identifies situations where there is good evidence for its efficacy. The authors provide advice, based on their own experience and consistent published data, concerning the dose range of melatonin to be used and the critically important question of the timing of treatment. Anecdotal evidence for the use of melatonin needs to be replaced by data from well-controlled, preferably multi-centre, randomised clinical trials.

  • 190. Arentsen, T.
    et al.
    Qian, Y.
    Gkotzis, Spyridon
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Karolinska Institutet, Sweden.
    Femenia, T.
    Wang, T.
    Udekwu, Klas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Forssberg, H.
    Heijtz, R. Diaz
    The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior2017In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, no 2, p. 257-266Article in journal (Refereed)
    Abstract [en]

    Recent studies have revealed that the gut microbiota modulates brain development and behavior, but the underlying mechanisms are still poorly understood. Here, we show that bacterial peptidoglycan (PGN) derived from the commensal gut microbiota can be translocated into the brain and sensed by specific pattern-recognition receptors (PRRs) of the innate immune system. Using expression-profiling techniques, we demonstrate that two families of PRRs that specifically detect PGN (that is, PGN-recognition proteins and NOD-like receptors), and the PGN transporter PepT1 are highly expressed in the developing brain during specific windows of postnatal development in both males and females. Moreover, we show that the expression of several PGN-sensing molecules and PepT1 in the developing striatum is sensitive to manipulations of the gut microbiota (that is, germ-free conditions and antibiotic treatment). Finally, we used the PGN-recognition protein 2 (Pglyrp2) knockout mice to examine the potential influence of PGN-sensing molecules on brain development and behavior. We demonstrate that the absence of Pglyrp2 leads to alterations in the expression of the autism risk gene c-Met, and sex-dependent changes in social behavior, similar to mice with manipulated microbiota. These findings suggest that the central activation of PRRs by microbial products could be one of the signaling pathways mediating the communication between the gut microbiota and the developing brain.

  • 191.
    Arko-Mensah, John
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Immune evasion and identification of biomarkers associated with mycobacterial infection2007Licentiate thesis, comprehensive summary (Other academic)
  • 192.
    Arko-Mensah, John
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Mycobacterial infection: Immune evasion, host susceptibility and immunological markers of diagnostic importance2008Doctoral thesis, monograph (Other academic)
    Abstract [en]

    IIn the first study, we investigated the functional implications of prolonged TLR signalling on IFN-γ mediated killing of mycobacteria by murine macrophages in vitro. TLR2, but not TLR4 ligation interfered with IFN-γ mediated killing of mycobacteria in macrophages. In terms of mechanisms, neither TNF nor nitric oxide (NO) production was significantly affected, and the refractoriness induced could be reversed with increasing amounts of IFN-γ In the second study, we aimed to identify immunological markers of diagnostic importance in both the respiratory tract and serum during pulmonary mycobacterial infection in mice. We found that increased levels of immunological markers in the respiratory tract, but not serum, correlated better with active mycobacterial infection in the lungs, suggesting that the immune response in the respiratory tract is more reflective of the infection status and pathology than the systemic response. Finally, we investigated the level and nature of immune responses to pulmonary mycobacterial infection in BALB/c and C57BL/6 mice, two mouse strains known to exhibit different susceptibilities to infection with several intracellular pathogens, including mycobacteria. We showed that increased susceptibility of BALB/c mice to early mycobacterial infection was associated with reduced Th1 immune responses, and increased sTNFR secretion in the lung. Moreover, BALB/c mice recruited fewer monocytes/macrophages to the lung, and although IFN-γ stimulation of infected bone marrow derived macrophages in both mouse strains resulted in induction of antimycobacterial activity, BALB/c mice had a reduced capacity to kill ingested bacteria. The work presented in this thesis provide further insight into the mechanisms involved in the host-pathogen interaction; from persistence, to the immunological processes induced by the pathogen, to susceptibility of the host to infection.

  • 193. Arko-Mensah, John
    et al.
    Rahman, Muhammad Jubayer
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Julián, Eshter
    Horner, Gudron
    Singh, Mahavir
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Increased levels of immunological markers in the respiratory tract but not in serum correlate with active pulmonary mycobacterial infection in mice2009In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 15, no 8, p. 777-786Article in journal (Refereed)
    Abstract [en]

    Immunological tests for the diagnosis of tuberculosis (TB) have relied mostly on detection of immune markers in serum or release of cytokines by mononuclear cells in vitro. These tests, although useful, sometimes fail to discriminate between active infection and contact with mycobacteria or vaccination. TB is primarily a disease of the lung, and therefore identification of immunological markers in the respiratory tract will be more likely to reflect the infection status or disease activity. In this study, it is demonstrated that active infection of mice with Mycobacterium bovis bacille Calmette-Guérin (BCG), but not exposure to heat-killed BCG, induced production of interleukin-12 (IL-12), interferon-gamma (IFN-gamma) or soluble tumour necrosis factor receptors (sTNFRs) locally in the lungs, as detected in bronchoalveolar lavage (BAL) fluid. There was a strong correlation between bacterial growth in the lung and levels of sTNFRs, and to some extent IL-12 and IFN-gamma, in BAL fluid. Furthermore, sTNFR levels increased significantly in BAL fluid after reactivation of controlled infection with dexamethasone, and this correlated with increased bacterial growth in the lungs. Finally, infection, but not exposure to non-replicating mycobacteria, induced specific IgG and IgA in BAL fluid. Elevated levels of all biomarkers measured were also detected in the serum, but correlation with infection was not as clear as in the case of BAL fluid. Taken together, the detection of sTNFRs and mycobacterium-specific antibodies, especially IgA, locally in the lungs could be used as immunological markers for the diagnosis of TB.

  • 194.
    Arnberg, Filip K.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Uppsala University, Sweden.
    Gudmundsdóttir, Ragnhildur
    Butwicka, Agnieszka
    Fang, Fang
    Lichtenstein, Paul
    Hultman, Christina M.
    Valdimarsdóttir, Unnur A.
    Psychiatric disorders and suicide attempts in Swedish survivors of the 2004 southeast Asia tsunami: a 5 year matched cohort study2015In: Lancet psychiatry, ISSN 2215-0374, E-ISSN 2215-0366, Vol. 2, no 9, p. 817-824Article in journal (Refereed)
    Abstract [en]

    Background: Survivors of natural disasters are thought to be at an increased risk of psychiatric disorders, however the extent of this risk, and whether it is linked to pre-existing psychopathology, is not known. We aimed to establish whether Swedish survivors of tsunamis from the 2004 Sumatra-Andaman earthquake had increased risks of psychiatric disorders and suicide attempts 5 years after repatriation.

    Methods: We identified Swedish survivors repatriated from southeast Asia (8762 adults and 3742 children) and 864 088 unexposed adults and 320 828 unexposed children matched for sex, age, and socioeconomic status. We retrieved psychiatric diagnoses and suicide attempts from the Swedish patient register for the 5 years after the tsunami (from Dec 26, 2004, to Jan 31, 2010) and estimated hazard ratios (HRs), then adjusted for pre-tsunami psychiatric disorders, and, for children, for parental pre-tsunami disorders.

    Findings: Exposed adults were more likely than unexposed adults to receive any psychiatric diagnosis (547 [6.2%] vs 47 734 [5.5%]; adjusted HR 1.21, 95% CI 1.11-1.32), particularly stress-related disorders (187 [2.1%] vs 8831 [1.0%]; 2.27, 1.96-2.62) and suicide attempts (38 [0.43%] vs 2752 [0.32%]; 1.54, 1.11-2.13), but not mood or anxiety disorders. Risk of psychiatric diagnoses did not differ between exposed and unexposed children and adolescents (248 [6.6] vs 22 081 [6.9%]; 0.98, 0.86-1.11), although exposed children and adolescents had a higher risk for suicide attempts with uncertain intent (1.43; 1.01-2.02) and stress-related disorders (1.79; 1.30-2.46), mainly during the first 3 months after the tsunami.

    Interpretation: The 2004 tsunami was, independently of previous psychiatric morbidity, associated with an increased risk of severe psychopathology, mainly stress-related disorders and suicide attempts, in children and adults. Survivors of natural disasters should be targeted with early interventions and active long-term follow-up to prevent, detect, and alleviate psychiatric disorders that might follow.

    Funding: The Swedish Council for Working Life and Social Research, Swedish Board of Health and Welfare, Polish Ministry of Science and Higher Education, Swedish Society for Medical Research.

  • 195.
    Arnberg, Filip K.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Uppsala University, Sweden.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Morey, Jennifer N.
    Segerström, Suzanne C.
    Self-rated health and interleukin-6: Longitudinal relationships in older adults2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 54, p. 226-232Article in journal (Refereed)
    Abstract [en]

    Background: Both self-rated health (SRH) and inflammation are implicated in chronic diseases and premature mortality. Better SRH is associated with lower proinflammatory cytokines, but there is little evidence about whether this relationship is more stable or dynamic.

    Objective: To study the between- and within-person associations between SRH and IL-6.

    Methods: Older adults (N=131; Mage=75years) rated their health and provided blood samples for analysis of IL-6 at separate occasions every 6months over a period up to 5years. Age, sex, BMI, neuroticism, and statin use were examined as covariates in multilevel models.

    Results: In bivariate models, better SRH, lower BMI, younger age, and female sex correlated with lower IL-6. In multilevel models, stable SRH (between-person differences; p<.001) but not dynamic SRH (within-person changes; p=.93) correlated with IL-6. The stable relationship persisted with demographic and health covariates in the model.

    Conclusions: Better stable SRH but not dynamic SRH was robustly associated with lower IL-6 among older adults, lending support to previous cross-sectional findings on the relation between inflammatory markers and SRH. The findings suggest that trait-like mechanisms, rather than changes over a time scale of 6-month waves, govern this association. To further investigate the mechanisms behind the SRH-IL-6 association, studies with different measurement frequencies, higher within-person variability, and experimental approaches are warranted.

  • 196.
    Arnberg, Filip K.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Uppsala University, Sweden.
    Michel, Per-Olof
    Lundin, Tom
    Posttraumatic stress in survivors 1 month to 19 years after an airliner emergency landing2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0119732Article in journal (Refereed)
    Abstract [en]

    Posttraumatic stress (PTS) is common in survivors from life-threatening events. Little is known, however, about the course of PTS after life threat in the absence of collateral stressors (e.g., bereavement, social stigma, property loss) and there is a scarcity of studies about PTS in the long term. This study assessed the short- and long-term course of PTS, and the influence of gender, education and age on the level and course of PTS, in survivors from a non-fatal airliner emergency landing caused by engine failure at an altitude of 1 km. There were 129 persons on board. A survey including the Impact of Event Scale was distributed to 106 subjects after 1 month, 4 months, 14 months, and 25 months, and to 95 subjects after 19 years (response rates 64-83%). There were initially high levels of PTS. The majority of changes in PTS occurred from 1 to 4 months after the event. There were small changes from 4 to 25 months but further decrease in PTS thereafter. Female gender was associated with higher levels of PTS whereas gender was unrelated to the slope of the short- and long-term trajectories. Higher education was related to a quicker recovery although not to initial or long-term PTS. Age was not associated with PTS. The present findings suggest that a life-threatening experience without collateral stressors may produce high levels of acute posttraumatic stress, yet with a benign prognosis. The findings further implicate that gender is unrelated to trajectories of recovery in the context of highly similar exposure and few collateral stressors.

  • 197. Arnetz, Bengt
    et al.
    Frenzel, Lena
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Lisspers, Jan
    The brief fatigue syndrome scale: Validation and utilization in fatigue recovery studies2008In: Fatigue Science for Human Health, Springer , 2008, p. 55-66Chapter in book (Other academic)
  • 198.
    Aronsson, Gunnar
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Astvik, Wanja
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Mälardalen University, Sweden.
    Gustafsson, Klas
    Work conditions, Recovery and Health: A study among workers within Pre-School, Home Care and Social Work2014In: British Journal of Social Work, ISSN 0045-3102, E-ISSN 1468-263X, Vol. 44, no 6, p. 1654-1672Article in journal (Refereed)
    Abstract [en]

    The study investigated the working conditions associated with the accumulation of stress and lack of recovery and how recovery is related to health. The study group was employed in pre-school, home care and social work (n = 193). Recovery was assumed to be an explanatory variable for the relations between work and health. The response rate on a survey was 79 per cent. Cluster analysis identified three groups: the ‘Recovered’ (36 per cent of the total group) and ‘Not Recovered’ (25 per cent) and the ‘In-between’ (39 per cent). The Not Recovered displayed the whole chain of risk factors, involving difficult working conditions to which they responded with increased compensatory strategies. Despite this group having significantly greater reports of ill health, work absenteeism was not greater, which is likely related to their substituting sickness absence with sickness presence. As many as 43 per cent of the social workers were found to belong to the Not Recovered group. Multiple regression analyses controlling for background variables revealed that the Not Recovered group had a significantly higher relative risk for poor self-rated health than those in the Recovered group. Even sharper increases in relative risk existed for the other five symptoms that were analysed. Practical implications and new research questions are discussed.

  • 199.
    Aronsson, Gunnar
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Lundberg, Ulf
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Interventioner för återgång i arbete vid sjukskrivning: En systematisk kunskapsöversikt av metaanalyser med inriktning på muskuloskeletala och psykiska besvär2015In: Arbete och Hälsa, ISSN 0346-7821, ISSN 0346-7821, Vol. 49, no 2, p. 1-50Article, review/survey (Refereed)
  • 200.
    Aronsson, Gunnar
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Work and organizational psychology.
    Theorell, Töres
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Grape, Tom
    Hammarström, Anne
    Hogstedt, Christer
    Marteinsdottir, Ina
    Skoog, Ingmar
    Träskman-Bendz, Lil
    Hall, Charlotte
    A systematic review including meta-analysis of work environment and burnout symptoms2017In: BMC Public Health, ISSN 1471-2458, E-ISSN 1471-2458, Vol. 17, no 1, article id 264Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Practitioners and decision makers in the medical and insurance systems need knowledge on the relationship between work exposures and burnout. Many burnout studies - original as well as reviews - restricted their analyses to emotional exhaustion or did not report results on cynicism, personal accomplishment or global burnout. To meet this need we carried out this review and meta-analyses with the aim to provide systematically graded evidence for associations between working conditions and near-future development of burnout symptoms.

    METHODS: A wide range of work exposure factors was screened. Inclusion criteria were: 1) Study performed in Europe, North America, Australia and New Zealand 1990-2013. 2) Prospective or comparable case control design. 3) Assessments of exposure (work) and outcome at baseline and at least once again during follow up 1-5 years later. Twenty-five articles met the predefined relevance and quality criteria. The GRADE-system with its 4-grade evidence scale was used.

    RESULTS: Most of the 25 studies focused emotional exhaustion, fewer cynicism and still fewer personal accomplishment. Moderately strong evidence (grade 3) was concluded for the association between job control and reduced emotional exhaustion and between low workplace support and increased emotional exhaustion. Limited evidence (grade 2) was found for the associations between workplace justice, demands, high work load, low reward, low supervisor support, low co-worker support, job insecurity and change in emotional exhaustion. Cynicism was associated with most of these work factors. Reduced personal accomplishment was only associated with low reward. There were few prospective studies with sufficient quality on adverse chemical, biological and physical factors and burnout.

    CONCLUSION: While high levels of job support and workplace justice were protective for emotional exhaustion, high demands, low job control, high work load, low reward and job insecurity increased the risk for developing exhaustion. Our approach with a wide range of work exposure factors analysed in relation to the separate dimensions of burnout expanded the knowledge of associations, evidence as well as research needs. The potential of organizational interventions is illustrated by the findings that burnout symptoms are strongly influenced by structural factors such as job demands, support and the possibility to exert control.

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