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ASXL1 is one of the most commonly mutated genes in myeloid malignancies, including Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). In order to further our understanding of the role of ASXL1 lesions in malignant hematopoiesis, we generated a novel knock-in mouse model carrying the most frequent ASXL1 mutation identified in MDS patients, p.G643WfsX12. Mutant mice did not display any major hematopoietic defects nor developed any apparent hematological disease. In AML patients, ASXL1 mutations co-occur with mutations in CEBPA and we therefore generated compound Cebpa and Asxl1 mutated mice. Using a transplantation model, we found that the mutated Asxl1 allele significantly accelerated disease development in a CEBPA mutant context. Importantly, we demonstrated that, similar to the human setting, Asxl1 mutated mice responded poorly to chemotherapy. This model therefore constitutes an excellent experimental system for further studies into the clinically important question of chemotherapy resistance mediated by mutant ASXL1.

Summary Recent advances in sequencing technologies have allowed for the identification of recurrent mutations in acute myeloid leukaemia (AML). The transcription factor CCAAT enhancer binding protein alpha (CEBPA) is frequently mutated in AML, and biallelic CEBPA‐mutant AML was recognised as a separate disease entity in the recent World Health Organization classification. However, CEBPA mutations are co‐occurring with other aberrations in AML, and together these lesions form the clonal hierarchy that comprises the leukaemia in the patient. Here, we aim to review the current understanding of co‐occurring mutations in CEBPA‐mutated AML and their implications for disease biology and clinical outcome. We will put emphasis on patterns of cooperation, how these lesions cooperate with CEBPA mutations and the underlying potential molecular mechanisms. Finally, we will relate this to patient outcome and future options for personalised medicine.

HIV-2 is less pathogenic compared to HIV-1. Still, disease progression may develop in aviremic HIV-2 infection, but the driving forces and mechanisms behind such development are unclear. Here, we aimed to reveal the immunophenotypic pattern associated with CD8 T-cell pathology in HIV-2 infection, in relation to viremia and markers of disease progression. The relationships between pathological differences of the CD8 T-cell memory population and viremia were analyzed in blood samples obtained from an occupational cohort in Guinea-Bissau, including HIV-2 viremic and aviremic individuals. For comparison, samples from HIV-1- or dually HIV-1/2-infected and seronegative individuals were obtained from the same cohort. CD8 T-cell exhaustion was evaluated by the combined expression patterns of activation, stimulatory and inhibitory immune checkpoint markers analyzed using multicolor flow cytometry and advanced bioinformatics. Unsupervised multidimensional clustering analysis identified a cluster of late differentiated CD8 T-cells expressing activation (CD38+, HLA-DRint/high), co-stimulatory (CD226+/-), and immune inhibitory (2B4+, PD-1high, TIGIThigh) markers that distinguished aviremic from viremic HIV-2, and treated from untreated HIV-1-infected individuals. This CD8 T-cell population displayed close correlations to CD4%, viremia, and plasma levels of IP-10, sCD14 and beta-2 microglobulin in HIV-2 infection. Detailed analysis revealed that aviremic HIV-2-infected individuals had higher frequencies of exhausted TIGIT+ CD8 T-cell populations lacking CD226, while reduced percentage of stimulation-receptive TIGIT-CD226+ CD8 T-cells, compared to seronegative individuals. Our results suggest that HIV-2 infection, independent of viremia, skews CD8 T-cells towards exhaustion and reduced co-stimulation readiness. Further knowledge on CD8 T-cell phenotypes might provide help in therapy monitoring and identification of immunotherapy targets.

Backgroundcognitive impairment is common among older adults, necessitating the use of collateral sources in epidemiological studies involving this age group. The objective of this study was to evaluate agreement between self- and proxy-reports of cardiovascular disorders and diabetes mellitus in a population-based sample of 80-year-olds. Further, both self- and proxy-reports were compared with hospital register data.Methodsdata were obtained from the Gothenburg H70 Birth Cohort Studies in Sweden. The study had a cross-sectional design and information was collected through semi-structured interviews in 2009–2012 from participants born in 1930 (N = 419) and their proxy informants. The National Patient Register provided diagnoses registered during hospital stays. Agreement was measured with Kappa values (K).Resultsagreement between self- and proxy-reports was substantial for diabetes mellitus (K = 0.79), atrial fibrillation (K = 0.61), myocardial infarction (K = 0.75), angina pectoris (K = 0.73) and hypertension (K = 0.62), and fair for intermittent claudication (K = 0.38) and heart failure (K = 0.40). Compared to the National Patient Register, a large proportion of those with a hospital discharge diagnosis were also self- and proxy-reported.Conclusionsproxy informants can be an important source of information, at least for well-defined conditions such as myocardial infarction, angina pectoris and diabetes mellitus.

Background Many studies investigating daily chlorhexidine gluconate (CHG) bathing as an infection control intervention to decrease health care–associated infections have focused on reduction of infection and colonization; few studies have assessed CHG bathing compliance, work system factors, facilitators, and barriers to implementation. Methods This is a combination retrospective/prospective pilot study conducted at a large academic teaching hospital that implemented daily CHG bathing across all inpatient units. CHG compliance and patient refusal were calculated on the basis of documentation in the electronic medical record. We used the health belief model to guide semistructured interviews with patients about knowledge and barriers related to CHG bathing. Results Of the 31 patients interviewed, 74% reported using CHG soap during their stay. Average compliance documented in the electronic medical record was 78% with a range of 57%-91% among all hospital units. Sixteen percent of patients declined CHG bathing, and refusal ranged from 3%-29% among all units. Major themes about CHG bathing from patient interviews include low perceived susceptibility to infection, high degree of trust in medical professionals, low knowledge of benefits of CHG, and low perceived self-efficacy in preventing HAIs. Conclusions Educating patients about CHG bathing appears to be a critical factor in decreasing patient refusal of CHG bathing.

Background: The comprehensive geriatric assessment (CGA) designed to manage frail older people requiring acute medical care, is responsible for diagnostics, assessment, treatment, and planning while addressing a person&rsquo, s medical, psychological, social, and functional capabilities. The aim was to investigate if CGA had an impact on frail older people&rsquo, s activities of daily living (ADL) status, self-rated health, and satisfaction with hospital care. Methods: A two-armed design with frail people aged 75 or older who required an unplanned hospital admission were randomized to either the CGA ward or to an acute medical ward. Analyses were made based on the intention-to-treat principle (ITT). The primary outcome was ADL. Data were analyzed using Chi-square and odds ratio. A subgroup analysis was performed due to non-adherence and contamination. Results: One-hundred and fifty-five people participated in the study, 78 in the intervention and 77 in the control. Participants in the intervention group had a higher odds ratio of reporting having received written information and felt that care met their needs during their hospital stay. No additional statistically significant results for the primary or secondary outcomes in the ITT analysis were achieved. Conclusion: Participants felt that the care they received with the CGA ward met their needs. The lack of additional results supporting the CGA could be due to difficulties performing pragmatic intervention trials in clinical hospital settings, and because a CGA during one hospital stay is probably not enough to have long-term effects.

Humans have a notable capacity to withstand the ravages of infectious diseases. Smallpox killed millions of people but drove Jenner's invention of vaccination, which eventually led to the annihilation of this virus, declared in 1980. To investigate the history of smallpox, Mühlemann et al. obtained high-throughput shotgun sequencing data from 1867 human remains ranging from >31,000 to 150 years ago (see the Perspective by Alcamí). Thirteen positive samples emerged, 11 of which were northern European Viking Age people (6th to 7th century CE). Although the sequences were patchy and incomplete, four could be used to infer a phylogenetic tree. This showed distinct Viking Age lineages with multiple gene inactivations. The analysis pushes back the date of the earliest variola infection in humans by ∼1000 years and reveals the existence of a previously unknown virus clade. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution.

Introduction Female sex workers (FSW) are considered a key group for HIV transmissions in sub-Saharan Africa. The HIV Care Continuum and HIV drug resistance (HIVDR) among FSW has not been well studied in most countries in West Africa. In the current study we describe the HIV Care continuum and prevalence of HIVDR among FSW in Guinea-Bissau. Methods A venue-based recruitment and peer-referral of FSW was used in seven cities in Guinea-Bissau from October 2014 to September 2017. We administered a questionnaire, performed discriminatory HIV-testing and collected blood specimens for CD4 count, viral load and HIVDR genotyping. Results The survey included 440 FSW. The overall HIV-prevalence among FSW was 26.8%. Of the HIV-1 (HIV-1 single- or dually HIV-1/HIV-2) infected FSW (N = 104), 58.7% were previously diagnosed with HIV-1 at enrolment and 41.4% reported taking antiretroviral therapy (ART) compared to 28.6% of the HIV-2 single-infected FSW (N = 14). Among HIV-1 infected FSW on ART (N = 43), 55.8% were virally suppressed ( Conclusion The majority of FSW who knew their HIV status received ART, however a large proportion of FSW were not aware of their HIV positive status. This translated into a great majority of the HIV-infected FSW not being virally suppressed. Amongst treatment naïve FSW nearly a tenth had HIVDR, suggesting that sexual transmission of HIVDR is occurring in this at-risk-population.

The aim of the study is to evaluate the effects of the Comprehensive Geriatric Assessment (CGA) for frail older people in Swedish acute hospital settings - the CGA-Swed study. In this study protocol, we present the study design, the intervention and the outcome measures as well as the baseline characteristics of the study participants. The study is a randomised controlled trial with an intervention group receiving the CGA and a control group receiving medical assessment without the CGA. Follow-ups were conducted after 1, 6 and 12 months, with dependence in activities of daily living (ADL) as the primary outcome measure. The study group consisted of frail older people (75 years and older) in need of acute medical hospital care. The study design, randomisation and process evaluation carried out were intended to ensure the quality of the study. Baseline data show that the randomisation was successful and that the sample included frail older people with high dependence in ADL and with a high comorbidity. The CGA contributed to early recognition of frail older peoples needs and ensured a care plan and follow-up. This study is expected to show positive effects on frail older peoples dependence in ADL, life satisfaction and satisfaction with health and social care. Funding Agencies|FORTE [2015-00043]; Swedish government [ALFBGB-530971/-673831/-716571]; Swedish county councils (ALF) [ALFBGB-530971/-673831/-716571]; Region Vastra Gotaland, Department of Research and Development [VGFOUREG-565511/-63881/-736281]; King Gustav and Queen Victoria Freemasons Foundation

SCOPE This study is designed to provide a broad evaluation of the impacts of vitamin A (VA) deficiency on hepatic metabolism in a gerbil model. METHODS AND RESULTS After 28 days of VA depletion, male Mongolian gerbils (Meriones unguiculatus) are randomly assigned to experimental diets for 28 days. Groups are fed a white-maize-based diet with ≈50 µL cottonseed oil vehicle either alone (VA-, n = 10) or containing 40 µg retinyl acetate (VA+, n = 10) for 28 days. Liver retinol is measured by high-performance liquid chromatography. Primary metabolomics, aminomics, lipidomics, bile acids, oxylipins, ceramides, and endocannabinoids are analyzed in post-mortem liver samples by liquid chromatography-mass spectrometry. RESULTS Liver retinol is lower (p

Summary: B cell development depends on the coordinated expression and cooperation of several transcription factors. Here we show that the transcription factor ETS-related gene (ERG) is crucial for normal B cell development and that its deletion results in a substantial loss of bone marrow B cell progenitors and peripheral B cells, as well as a skewing of splenic B cell populations. We find that ERG-deficient B lineage cells exhibit an early developmental block at the pre-B cell stage and proliferate less. The cells fail to express the immunoglobulin heavy chain due to inefficient V-to-DJ recombination, and cells that undergo recombination display a strong bias against incorporation of distal V gene segments. Furthermore, antisense transcription at PAX5-activated intergenic repeat (PAIR) elements, located in the distal region of the Igh locus, depends on ERG. These findings show that ERG serves as a critical regulator of B cell development by ensuring efficient and balanced V-to-DJ recombination. : Søndergaard et al. demonstrate that ERG is a critical transcriptional regulator essential for B cell development. Loss of ERG leads to a marked reduction in V-to-DJ recombination at the Igh locus, precluding B cell progenitors from expressing the pre-B cell receptor, which is required for entering the final stages of B cell development. Keywords: ETS-related gene, ERG, B cell development, V(D)J recombination, pre-BCR, immunoglobulin heavy-chain gene, transcriptional control

OBJECTIVES: Vitamin A (VA) is an essential micronutrient with key roles in many biological processes, including growth, vision, reproduction, and immunity. While VA deficiency effects these physiological roles, the impact on many metabolic pathways are poorly studied. Since VA deficiency is a leading cause of morbidity and mortality throughout the world, a more comprehensive understanding of deficiency-associated metabolic alterations is needed. Here we investigate changes in metabolism associated with VA status in a rodent model using targeted metabolomics. METHODS: Male Mongolian gerbils (n = 8/group) were group housed (2−3/cage) during VA depletion and treatment (2/cage). After 28 d depletion, remaining gerbils were weight-matched and allocated to treatment groups. The VA positive group (VA+) was fed white maize and 40 µg retinyl acetate in ∼50 µL cottonseed oil daily, while the VA deficient group (VA-) received white maize and ∼50 µL cottonseed oil. Liver retinol concentrations were measured by HPLC. Liver samples were analyzed by LC-MS using six targeted assays for primary metabolomics, aminomics, bile acids, oxylipins, endocannabinoids, and sphingoid bases. RESULTS: Hepatic retinol concentrations were lower in the VA- group (P

Background: HIV type 2 (HIV-2) is considered more benign and has fewer pathogenic consequences than HIV type 1 (HIV-1) for most infected individuals. However, reliable estimates of time to AIDS and mortality among those with HIV-2 infection are absent. We therefore aimed to compare the time to AIDS and mortality, and the CD4 T-cell dynamics between those infected with HIV-1 and HIV-2. Methods: We did a prospective open cohort study. We included all police officers with regular employment from police stations in both urban and rural areas of Guinea-Bissau since Feb 6, 1990. We continued to include participants until Sept 28, 2009, and follow-up of HIV-1-positive and HIV-2-positive individuals continued until Sept 28, 2013. We collected blood samples at enrolment and at scheduled annual follow-up visits at police stations. We analysed longitudinal data from individuals infected with HIV-1 and HIV-2 according to time to AIDS, time to death, and T-cell dynamics. Time of HIV infection was estimated as the mid-timepoint between last HIV-seronegative and first HIV-seropositive sample. Data from an additional 2984 HIV-uninfected individuals from the same population were analysed to assess the effect of natural mortality on HIV-related mortality. Findings: 872 participants tested HIV positive during the 23-year study period: 408 were infected with HIV-1 (183 infected before and 225 infected after enrolment) and 464 were infected with HIV-2 (377 before and 87 after enrolment). The median time from HIV infection to development of AIDS was 6·2 years (95% CI 5·4–7·1) for HIV-1 infection and 14·3 years (10·7–18·0) for HIV-2 infection (p

2-Methoxyestradiol (2ME2), a metabolite of 17β-estradiol (E2), exerts bone sparing effects in animal models. We hypothesized that the underlying mechanism is back conversion of 2ME2 to E2, which subsequently acts via estrogen receptor (ER)α. We measured serum E2 levels in orchidectomized wild-type (WT) mice treated with 2ME2 66.6 μg/d or placebo. In placebo-treated animals, E2 was below the detection limit. In 2ME2-treated mice, the serum E2 level was 4.97 ± 0.68 pg/mL. This corresponds to the level found in diesterus in cycling female mice. Next, we investigated bone parameters in orchidectomized WT and ERα knockout mice treated with 2ME2 or placebo for 35 days. 2ME2 (6.66 μg/d) preserved trabecular and cortical bone in WT mice. Trabecular volumetric-bone mineral density was 64 ± 20%, and trabecular bone volume/total volume was 60 ± 20% higher in the metaphyseal region of the femur in the 2ME2 group, compared with placebo (P < .01). Both trabecular number and trabecular thickness were increased (P < .01). Cortical bone mineral content in the diaphyseal region of the femur was 31 ± 3% higher in the 2ME2 group, compared with placebo (P < .001). This was due to larger cortical area (P < .001). Three-point bending showed an increased bone strength in WT 2ME2-treated animals compared with placebo (maximum load [Fmax] +19±5% in the 2ME2 group, P < .05). Importantly, no bone parameter was affected by 2ME2 treatment in ERα knockout mice. In conclusion, 2ME2 treatment of orchidectomized mice results in increased serum E2. ERα mediates the bone sparing effects of 2ME2. The likely mediator of this effect is E2 resulting from back conversion of 2ME2.

We aimed to evaluate effects of the intervention on self-rated health, experiences of security/safety and symptoms. A non-blinded controlled trial was performed with participants randomised to either the intervention group or a control group, with follow-ups at 3, 6 and 12 months. The intervention involved collaboration between a nurse with geriatric competence at the emergency department, the hospital wards and a multi-professional team for care and rehabilitation of older adults, with a case manager from the municipality as the hub. Older people who sought care at the emergency department at Sahlgrenska University Hospital/Mölndal and who were discharged to their own homes in the Mölndal municipality were asked to participate. Inclusion criteria were age 80 years and older, or 65 to 79 years with at least one chronic disease and dependency in at least one activity of daily living. Analyses were conducted on the basis of the intention-to-treat principle. Outcome measures were self-rated health, experiences of security/safety and symptoms. These were analysed using Svensson’s method. Of 161 participants, 76 were allocated to the control group and 85 to the intervention group. Positive effects of the intervention were observed for frail older adult’s symptoms and self-rated health.

To describe fluocinolone acetonide implant dissociations in the Multicenter Uveitis Steroid Treatment (MUST) Trial.Randomized clinical trial with extended follow-up.Review of data collected on the first implant in the eye(s) of participants. Dissociation was defined as the drug pellet no longer being affixed to the strut and categorized as spontaneous or surgically related.A total of 250 eyes (146 patients) had at least 1 implant placed. Median follow-up time after implant placement was 6 years (range 0.5-9.2 years). Thirty-four dissociations were reported in 30 participants. There were 22 spontaneous events in 22 participants; 6-year cumulative risk of a spontaneous dissociation was 4.8% (95% confidence interval [CI]: 2.4%-9.1%). The earliest event occurred 4.8 years after placement. Nine of 22 eyes with data had a decline in visual acuity ≥5 letters temporally related to the dissociation. Thirty-nine implant removal surgeries were performed, 33 with replacement. Twelve dissociations were noted during implant removal surgeries in 10 participants (26%, 95% CI 15%-48%); 5 of these eyes had a decline in visual acuity ≥5 letters after surgery. The time from implant placement to removal surgery was longer for the surgeries at which dissociated implants were identified than for those without one (5.7 vs 3.7 years, P.001). Overall, visual acuity declined 15 or more letters from pre-implant values in 22% of affected eyes; declines were frequently associated with complications of uveitis or its treatment.There is an increasing risk of dissociation of Retisert implants during follow-up; the risk is greater with removal/exchange surgeries, but the risk of both spontaneous and surgically related events increases with longevity of the implants. In 22% of affected eyes visual acuity declined by 15 letters. In the context of eyes with moderate to severe uveitis for years, this rate is not unexpected.

Testosterone deficiency in men is associated with increased risk for autoimmunity and increased B cell numbers through unknown mechanisms. Here we show that testosterone regulates the cytokine BAFF, an essential survival factor for B cells. Male mice lacking the androgen receptor have increased splenic B cell numbers, serum BAFF levels and splenic Baff mRNA. Testosterone deficiency by castration causes expansion of BAFF-producing fibroblastic reticular cells (FRCs) in spleen, which may be coupled to lower splenic noradrenaline levels in castrated males, as an α-adrenergic agonist decreases splenic FRC number in vitro. Antibody-mediated blockade of the BAFF receptor or treatment with the neurotoxin 6-hydroxydopamine revert the increased splenic B cell numbers induced by castration. Among healthy men, serum BAFF levels are higher in men with low testosterone. Our study uncovers a previously unrecognized regulation of BAFF by testosterone and raises important questions about BAFF in testosterone-mediated protection against autoimmunity., Testosterone deficiency is associated with autoimmunity and increased B cell numbers, but the underlying mechanism is unclear. Here the authors show that testosterone may modulate the production of B cell survival factor BAFF by fibroblastic reticular cells via regulation of splenic neurotransmitter levels.

Supplemental Digital Content is available in the text., Objective— Androgen deprivation therapy has been associated with increased cardiovascular risk in men. Experimental studies support that testosterone protects against atherosclerosis, but the target cell remains unclear. T cells are important modulators of atherosclerosis, and deficiency of testosterone or its receptor, the AR (androgen receptor), induces a prominent increase in thymus size. Here, we tested the hypothesis that atherosclerosis induced by testosterone deficiency in male mice is T-cell dependent. Further, given the important role of the thymic epithelium for T-cell homeostasis and development, we hypothesized that depletion of the AR in thymic epithelial cells will result in increased atherosclerosis. Approach and Results— Prepubertal castration of male atherosclerosis-prone apoE−/− mice increased atherosclerotic lesion area. Depletion of T cells using an anti-CD3 antibody abolished castration-induced atherogenesis, demonstrating a role of T cells. Male mice with depletion of the AR specifically in epithelial cells (E-ARKO [epithelial cell-specific AR knockout] mice) showed increased thymus weight, comparable with that of castrated mice. E-ARKO mice on an apoE−/− background displayed significantly increased atherosclerosis and increased infiltration of T cells in the vascular adventitia, supporting a T-cell–driven mechanism. Consistent with a role of the thymus, E-ARKO apoE−/− males subjected to prepubertal thymectomy showed no atherosclerosis phenotype. Conclusions— We show that atherogenesis induced by testosterone/AR deficiency is thymus- and T-cell dependent in male mice and that the thymic epithelial cell is a likely target cell for the antiatherogenic actions of testosterone. These insights may pave the way for new therapeutic strategies for safer endocrine treatment of prostate cancer.

Summary: Hematopoietic stem cells (HSCs) are considered a heterogeneous cell population. To further resolve the HSC compartment, we characterized a retinoic acid (RA) reporter mouse line. Sub-fractionation of the HSC compartment in RA-CFP reporter mice demonstrated that RA-CFP-dim HSCs were largely non-proliferative and displayed superior engraftment potential in comparison with RA-CFP-bright HSCs. Gene expression analysis demonstrated higher expression of RA-target genes in RA-CFP-dim HSCs, in contrast to the RA-CFP reporter expression, but both RA-CFP-dim and RA-CFP-bright HSCs responded efficiently to RA in vitro. Single-cell RNA sequencing (RNA-seq) of >1,200 HSCs showed that differences in cell cycle activity constituted the main driver of transcriptional heterogeneity in HSCs. Moreover, further analysis of the single-cell RNA-seq data revealed that stochastic low-level expression of distinct lineage-affiliated transcriptional programs is a common feature of HSCs. Collectively, this work demonstrates the utility of the RA-CFP reporter line as a tool for the isolation of superior HSCs. : HSCs are considered a functional heterogeneous population. Lauridsen et al. use scRNA-seq to demonstrate that most transcriptional heterogeneity within the HSC compartment is associated with differences in cell cycle status. They further use an RA-CFP reporter mouse line to isolate slow-cycling HSCs characterized by superior engraftment potential. Keywords: hematopoietic stem cells, single-cell RNA-sequencing, retinoic acid, transcriptional heterogeneity, hematopoiesis

Testosterone has profound immune-modulatory actions, which may be important for the sexual dimorphism in immune-related disorders, such as autoimmune diseases. A well-known effect of androgens is inhibition of bone marrow B lymphopoiesis; however, a plausible target cell for this effect has not yet been presented. The aim of this study was to determine the target cell for androgen-mediated regulation of bone marrow B lymphopoiesis in males. We confirm higher number of bone marrow B cells in male mice with global inactivation of the androgen receptor (AR) and these global AR knockout (G-ARKO) mice had increased number of B cell precursors from the pro-B stage. Because osteoblast-lineage cells are known to support B lymphopoiesis at the pro-B stage, we investigated the effect on B lymphopoiesis in osteoblast-lineage cell-specific ARKO (O-ARKO) mice; O-ARKO mice had increased number of B cells in the bone marrow, and the number of B cell precursors was increased from the pro-B stage, demonstrating that O-ARKO mimics the bone marrow B lymphopoiesis pattern of G-ARKO mice. By contrast, O-ARKO mice displayed only minor changes in B cell numbers in the splenic compartment compared with G-ARKO. Further, O-ARKO mice had moderately reduced number of bone trabeculae in the vertebrae, whereas cortical bone was unaffected. In conclusion, androgens exert inhibitory effects on bone marrow B lymphopoiesis in males by targeting the AR in osteoblast-lineage cells. The identification of the likely target cell for androgen-mediated regulation of bone marrow B lymphopoiesis will contribute to elucidation of the mechanisms by which androgens modulate immune-related disorders.

Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)–dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)–deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (−41%; thoracic aorta), subcutaneous fat mass (−44%), and cholesterol levels (−35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.—Fagman, J. B., Wilhelmson, A. S., Motta, B. M., Pirazzi, C., Alexanderson, C., De Gendt, K., Verhoeven, G., Holmäng, A., Anesten, F., Jansson, J.-O., Levin, M., Borén, J., Ohlsson, C., Krettek, A., Romeo, S., Tivesten, A. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.

Aim The aim of this study was to analyse the explanatory power of variables measuring health-strengthening factors for self-rated health among community-living frail older people. Background Frailty is commonly constructed as a multi-dimensional geriatric syndrome ascribed to the multi-system deterioration of the reserve capacity in older age. Frailty in older people is associated with decreased physical and psychological well-being. However, knowledge about the experiences of health in frail older people is still limited. Design The design of the study was cross-sectional. Method The data were collected between October 2008 and November 2010 through face-to-face structured interviews with older people aged 65–96 years (N = 161). Binary logistic regression was used to analyse whether a set of explanatory relevant variables is associated with self-rated health. Results The results from the final model showed that satisfaction with one's ability to take care of oneself, having 10 or fewer symptoms and not feeling lonely had the best explanatory power for community-living frail older peoples' experiences of good health. Conclusion The results indicate that a multi-disciplinary approach is desirable, where the focus should not only be on medical problems but also on providing supportive services to older people to maintain their independence and experiences of health despite frailty.

Background Individuals with limited health literacy have barriers to patient−physician communication. Problems in communication are known to contribute to malpractice litigation. Concern exists, however, about the feasibility and patient acceptance of a health literacy assessment. This study was performed to determine the feasibility of health literacy assessment in surgical practice and its effect on patient satisfaction. Study design Every patient seen in a Breast Surgery Clinic during a 2-year period was asked to undergo a health literacy assessment with the Newest Vital Sign (NVS) as part of the routine history and physical examination. During the year before routine NVS assessments and during the 2-year study period, all patients were asked to rate their “overall satisfaction with clinic visit” on a 5-point scale. Results A total of 2,026 of 2,097 patients (96.6%) seen during the study were eligible for the health literacy assessment. Of those, no patients refused assessment, and only one patient was missed. Therefore, 2,025 of 2,026 eligible patients (99.9%) underwent the assessment. The average time for NVS assessment was 2:02 minutes. Only 19% of patients had adequate health literacy. Patient satisfaction ratings were slightly greater during the first year of the health literacy assessment (3.8 vs 3.7, P = .049) compared with the year prior to health literacy assessment and greater during the second year of health literacy assessment (4.1 vs 3.7, P Conclusion Routine health literacy assessment is feasible in surgical practice and results in no decrease in patient satisfaction. In fact, satisfaction was greater during the years when health literacy assessments were performed.

To analyse frail older people's views of quality of care when receiving a comprehensive continuum of care intervention, compared with those of people receiving the usual care (control group). The intervention included early geriatric assessment, case management, interprofessional collaboration, support for relatives and organising of care-planning meetings in older people's own homes.Prior studies indicate that tailored/individualised care planning conducted by a case manager/coordinator often led to greater satisfaction with care planning among older people. However, there is no obvious evidence of any effects of continuum of care interventions on older people's views of quality of care.Randomised controlled study.Items based on a validated questionnaire were used in face-to-face interviews to assess older people's views of quality of care at three, six and 12 months after baseline.Older people receiving a comprehensive continuum of care intervention perceived higher quality of care on items about care planning (p ≤ 0·005), compared with those receiving the usual care. In addition, they had increased knowledge of whom to contact about care/service, after three and 12 months (p0·03).The study gives evidence of the advantages of a combination of components such as organising care-planning meetings in older people's own homes, case management and interprofessional teamwork.The results have implications for policymakers, managers and professionals in the area of health and social care for older people to meet individual needs of frail older people.

Intimal hyperplasia is a vascular pathological process involved in the pathogenesis of atherosclerosis. Data suggest that T, the most important sex steroid hormone in males, protects men from atherosclerotic cardiovascular disease. T mainly acts via the androgen receptor (AR), and in this study we evaluated formation of intimal hyperplasia in male AR knockout (ARKO) mice using a vascular injury model. Two weeks after ligation of the carotid artery, male ARKO mice showed increased intimal area and intimal thickness compared with controls. After endothelial denudation by an in vivo scraping injury, there was no difference in the reendothelialization in ARKO compared with control mice. Ex vivo, we observed increased outgrowth of vascular smooth muscle cells from ARKO compared with control aortic tissue explants; the number of outgrown cells was almost doubled in ARKO. In vitro, stimulation of human aortic vascular smooth muscle cells with a physiological T concentration inhibited both migration and proliferation of the cells. Analyzing the expression of central regulators of cell proliferation and migration, we found that mRNA and protein levels of p27 were lower in uninjured arteries from ARKO mice and that T replacement to castrated male mice increased p27 mRNA in an AR-dependent manner. In conclusion, AR deficiency in male mice increases intimal hyperplasia in response to vascular injury, potentially related to the effects of androgens/AR to inhibit proliferation and migration of smooth muscle cells.

Although it is acknowledged that exercising self-determination in daily activities affects older people's health and well-being, few studies have focused on the explanatory factors for self-determination in daily life.To investigate explanatory factors for self-determination in the context of community-dwelling older persons.This cross-sectional study combined two sets of data that included community-dwelling persons 80 years and older (n = 456). A bivariate logistic regression was performed to analyse the association of self-determination and a set of explanatory factors.The final bivariate logistic regression model revealed five explanatory factors that were significantly associated with perceiving reduced self-determination: high education (OR = 2.83), frailty (OR = 2.70), poor self-rated health (OR = 2.54), dissatisfaction with physical health (OR = 6.50), and receiving help from public homecare service (OR = 2.46).Several explanatory factors related to the ageing body and environmental aspects were associated with reduced self-determination. To help older people maintain self-determination, healthcare professionals should consider using a person-centred and capability approach to care.

To examine independence in activities of daily living (ADL) at the 1- and 2-year follow-ups of the health-promoting study Elderly Persons in the Risk Zone.A randomized, three-armed, single-blind, and controlled study. A representative sample of 459 independent and community-dwelling older adults, 80 years and older, were included. A preventive home visit was compared with four weekly multiprofessional senior group meetings including a follow-up home visit.Analysis showed a significant difference in favor of the senior meetings in postponing dependence in ADL at the 1-year follow-up (odds ratio [OR] = 1.92, 95% confidence interval [CI] = 1.19-3.10) and also in reducing dependence in three (OR = 0.52, 95% CI = 0.31-0.86) and four or more ADL (OR = 0.40, 95% CI = 0.22-0.72) at the 2-year follow-up. A preventive home visit reduced dependence in two (OR = 0.40, 95% CI = 0.24-0.68) and three or more ADL (OR = 0.37, 95% CI = 0.17-0.80) after 1 year.A long-term evaluation of Elderly Persons in the Risk Zone showed that both senior meetings and a preventive home visit reduced the extent of dependence in ADL after 1 year. The senior meetings were superior to a preventive home visit since additional significant effects were seen after 2 years. To further enhance the long-term effects of the senior meetings and support the process of self-change in health behavior, it is suggested that booster sessions might be a good way of reinforcing the intervention.

Estradiol is converted to the biologically active metabolite 2-methoxyestradiol via the activity of the enzyme catechol-O-methyltransferase (COMT). Exogenous administration of both estradiol and 2-methoxyestradiol reduces experimental atherosclerosis and neointima formation, and COMT-dependent formation of 2-methoxyestradiol likely mediates the antimitogenic effect of estradiol on smooth muscle cells in vitro. This study evaluated whether 2-methoxyestradiol mediates the vasculoprotective actions of estradiol in vivo. Wild-type (WT) and COMT knockout (COMTKO) mice on an apolipoprotein E-deficient background were gonadectomized and treated with estradiol or placebo. Exogenous estradiol reduced atherosclerotic lesion formation in both females (WT, 78%; COMTKO, 82%) and males (WT, 48%; COMTKO, 53%) and was equally effective in both genotypes. We further evaluated how exogenous estradiol affected neointima formation after ligation of the carotid artery in ovariectomized female mice; estradiol reduced intimal hyperplasia to a similar extent in both WT (80%) and COMTKO (77%) mice. In ovarianintact female COMTKO mice, atherosclerosis was decreased (25%) compared with WT controls. In conclusion, the COMT enzyme is dispensable for vascular protection by exogenous estradiol in experimental atherosclerosis and neointima formation in vivo. Instead, COMT deficiency in virgin female mice with intact endogenous production of estradiol results in relative protection against atherosclerosis. (Endocrinology 152: 4683–4690, 2011)

Positive margins occur in 15 to 69 per cent of patients undergoing lumpectomy. The current study was performed to evaluate intraoperative ultrasound in patients undergoing lumpectomy for palpable breast cancer. A retrospective chart review was performed of patients with palpable cancer who underwent lumpectomy with intraoperative ultrasound from 2004 to 2009. Each patient was matched with two patients who underwent lumpectomy alone over the same time period. Matching criteria included tumor size, clinical stage, body mass index, age at diagnosis, and lymphovascular invasion or extensive intraductal component. Twenty-two consecutive patients who underwent lumpectomy with intraoperative ultrasound were matched with 44 patients who underwent lumpectomy without intraoperative ultrasound. In addition to matching criteria, the patients were similar with respect to ethnicity, insurance status, weight, predominant histology, estrogen receptor, progesterone receptor, and Her2 status. Patients who underwent lumpectomy with intraoperative ultrasound were significantly less likely to have an involved margin (41 vs 9%, P = 0.01) and less likely to require a re-excision (34 vs 9%, P = 0.04). The lumpectomy volumes in the intraoperative ultrasound group were smaller than the volumes in the lumpectomy alone group. Intraoperative ultrasound can decrease the rate of positive margins and re-excision lumpectomy in patients with palpable breast cancers.

Wire guided breast procedures are the most commonly used breast conserving operation for nonpalpable cancers. We did a retrospective review of all patients who underwent the wire guided breast procedure at a county hospital with an associated surgical residency program. Twenty-eight patients underwent the procedure with intraoperative ultrasound from June 2009 to March 2010. Breast cancer patients who underwent a wire-guided lumpectomy with intraoperative ultrasound had a lower rate of positive margins (9% vs 26%, P = 0.28) and a smaller volume of tissue removed (126 cm3 vs 146 cm3, P = 0.57). For wire guided excisional biopsy, the volume of tissue removed was smaller in the intraoperative ultrasound group (30 cm3 vs 44 cm3, P = 0.17) and the targeted area was more likely to be removed in one specimen (1.1 vs 1.5, P = 0.03). Intraoperative ultrasound can improve surgical outcomes of the wire guided breast procedure.

Background: Wire guided breast procedures (WGBP) are the most commonly used breast conserving operation for non-palpable cancers. Suboptimal needle placement can result in a larger amount of tissue removed and increased difficulty in removal of the lesion. The use of intraoperative ultrasound can improve the execution of wire guided breast procedures by more precisely demonstrating the direction and depth of the wire as well as the location of the wire hook and radiographic clip. These benefits allow a more appropriately located incision and smaller volume of tissue removed. Methods: A retrospective review of all patients who underwent the WGBP at a county hospital with associated surgical residency program. 28 patients underwent the procedure with intraoperative ultrasound from June 2009 to March 2010. Results: Breast cancer patients who underwent a wire-guided lumpectomy with intraoperative ultrasound had a lower rate of positive margins (9% vs. 26%, p = 0.28) and a smaller volume of tissue removed (126 cm3 vs. 146 cm3, p = 0.57) compared to patients who underwent wire guided lumpectomy alone. In patients who underwent wire guided excisional biopsy for diagnostic purposes, the volume of tissue removed was smaller in the intraoperative ultrasound group (30 cm3 vs. 44 cm3, p = 0.17) and the targeted area was more likely to be removed in one specimen (1.1 vs. 1.5, p = 0.03) compared to those who underwent the procedure without intraoperative ultrasound. Two illustrative cases with figures are presented. The first demonstrates the benefit when the distance from skin entry point of the wire to the target area is great. The hook can be localized with ultrasound for optimal placement of the incision. The second demonstrates potential benefit when wire placement is suboptimal and the wire hook is distant from the target. The surgeon may use the wire location to identify the approximate area of the lesion and then the exact location of the radiographic clip can be localized with intraoperative ultrasound. Conclusions: Intraoperative ultrasound can improve surgical outcomes of the wire guided breast procedure. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-10-12.

Emergency physicians are trained to separate "sick" from "not sick" patients during their training. Nevertheless, every emergency physician will face situations in which early intervention is critical to their patient's outcome. Infectious diseases are responsible for many of these potentially poor outcomes. This article discusses early identification and treatment for several rapidly fatal infections, including two newly identified travel-related illnesses.

Testosterone is a crucial regulator of the skeleton, but the role of the androgen receptor (AR) for the maintenance of the adult male skeleton is unclear. In the present study, the role of the AR for bone metabolism and skeletal growth after sexual maturation was evaluated by means of the drug enzalutamide, which is a new AR antagonist used in the treatment of prostate cancer patients. Nine-week-old male mice were treated with 10, 30, or 100 mg/kg·d of enzalutamide for 21 days or were surgically castrated and were compared with vehicle-treated gonadal intact mice. Although orchidectomy reduced the cortical bone thickness and trabecular bone volume fraction in the appendicular skeleton, these parameters were unaffected by enzalutamide. In contrast, both enzalutamide and orchidectomy reduced the bone mass in the axial skeleton as demonstrated by a reduced lumbar spine areal bone mineral density (P < .001) and trabecular bone volume fraction in L5 vertebrae (P < .001) compared with vehicle-treated gonadal intact mice. A compression test of the L5 vertebrae revealed that the mechanical strength in the axial skeleton was significantly reduced by enzalutamide (maximal load at failure −15.3% ± 3.5%; P < .01). The effects of enzalutamide in the axial skeleton were associated with a high bone turnover. In conclusion, enzalutamide reduces the bone mass in the axial but not the appendicular skeleton in male mice after sexual maturation. We propose that the effect of testosterone on the axial skeleton in male mice is mainly mediated via the AR.

Very old persons (80+) are often described as "frail", implying that they are particularly vulnerable to adverse health outcomes. Elderly Persons in the Risk Zone was designed to determine whether a preventive home visit or multiprofessional senior group meetings could postpone deterioration in frailty if the intervention is carried out when the person is not so frail.The study was a RCT with follow-ups at 1 and 2 years. A total of 459 persons (80+), still living at home, were included. Participants were independent in activities of daily life and cognitively intact.Frailty was measured in two complementary ways, with the sum of eight frailty indicators and with the Mob-T Scale measuring tiredness in daily activities.Both interventions showed favorable effects in postponing the progression of frailty measured as tiredness in daily activities for up to 1 year. However, neither of the two interventions was effective in postponing frailty measured with the sum of frailty indicators.The results in this study show the potential of health promotion to older persons. The multiprofessional approach, including a broad spectrum of information and knowledge, might have been an important factor contributing to a more positive view of aging.

It has been shown that frailty is associated with low levels of wellbeing and life satisfaction. Further exploration is needed, however, to better understand which components constitute life satisfaction for frail older people and how satisfaction is related to other life circumstances. The aim of this study was to examine relationships between frail older people’s life satisfaction and their socioeconomic conditions, social networks, and health-related conditions. A cross-sectional study was conducted (n=179). A logistic regression analysis was performed, including life satisfaction as the dependent variable and 12 items as independent variables. Four of the independent variables made statistically significant contributions: financial situation (OR 3.53), social contacts (OR 2.44), risk of depression (OR 2.26), and selfrated health (OR 2.79). This study demonstrates that financial situation, self-rated health conditions and social networks are important components for frail older people’s life satisfaction. Health and social care professionals and policy makers should consider this knowledge in the care and service for frail older people; and actions that benefit life satisfaction − such as social support − should be promoted.

Aims and objectives: The aim of this study was to analyse effects of a comprehensive continuum of care (intervention group) on frail older persons life satisfaction, as compared to those receiving usual care (control group). The intervention included geriatric assessment, case management, interprofessional collaboration, support for relatives and organising of care-planning meetings in older persons own homes. Background: Improvements in older persons subjective well-being have been shown in studies including care planning and coordination by a case manager. However, effects of more complex continuum of care interventions on frail older persons life satisfaction are not well explored. DesignRandomised controlled study. Methods: The validated LiSat-11 scale was used in face-to-face interviews to assess older persons life satisfaction at baseline and at three, six and 12 months after the baseline. The odds ratio for improving or maintaining satisfaction was compared for intervention and control groups from baseline to three-month, three- to six-month as well as six- to 12-month follow-ups. Results: Older persons who received the intervention were more likely to improve or maintain satisfaction than those who received usual care, between 6 and 12 month follow-ups, for satisfaction regarding functional capacity, psychological health and financial situation. Conclusions: A comprehensive continuum of care intervention comprising several components had a positive effect on frail older persons satisfaction with functional capacity, psychological health and financial situation. Relevance to clinical practice: Frail older persons represent a great proportion of the persons in need of support from the health care system. Health care professionals need to consider continuum of care interventions impact on life satisfaction. As life satisfaction is an essential part of older persons well-being, we propose that policy makers and managers promote comprehensive continuum of care solutions. Funding Agencies|Vardalinstitutet, The Swedish Institute for Health Sciences

Self-reported data were collected from 156 self-employed small-scale forestry workers regarding their work, including use of safety gear and number and type of incidents and accidents. About 40% of the respondents reported that during the previous 24 months they had some kind of work-related accident where an injury occurred, and/or experienced in incident, a close call that could have resulted in an injury. Of those injured or involved in an accident, 50% reported that at the time of the accident or incident they were not fully using their safety gear. Sixty-seven percent of the accident victims reported seeking medical attention for their injuries. No significant relationships were found between production level, age, use of safety gear or sensation seeking tendencies and the reports of accidents and incidents. Accidents and incidents were most likely to occur during felling, thinning and transportation activities and were usually caused by unforeseen interactions with falling trees/branches or equipment. Compared to earlier surveys of Swedish small-scale forestry workers, consistent use of all required safety gear was down by 10% to 50%. Protective pants and gloves were the items least likely to be used while ear, eye and foot protection were most likely to be used. The results indicate that better planning during felling processes may be the key to reducing the number of accidents for this population.

In the 19 April 1996 Illinois tornado outbreak, cell mergers played a very important role in the convective evolution. With a large number of cells forming within a short time period, the early stages of cell organization were marked by cell merger interactions and cell attrition that led to a pattern of isolated tornadic supercells as described in Part I of this study. Twenty-six mergers were documented and analyzed. Storm-rotation-induced differential cell propagation accounted for 58% of these 26 cell mergers while differing cell speeds prompted 27% of the mergers. Cell merger characterizations were utilized to describe the cell reflectivity coalescence morphology including aspects of new cell development, development along the periphery of an existing cell, or an upward pulse in the cell intensity of a dominant cell. In cases where the merging cells were of similar intensity, a rapidly developing cellular pulse “bridging” the two echoes was often observed. When the relationship between short-term cell intensity changes and cell mergers was examined, it was found that the maximum reflectivity tendency showed a bias toward higher reflectivity for the product storm. Depending upon the radar elevation angle utilized, 27%–44% of mergers were associated with an increase in peak reflectivity while 40%–58% of the storms realized little or no increase. With respect to short-term cell rotation changes, the merger signal was marked. Depending upon the length of the evaluation window, in 44%–60% of the mergers, there was evidence of a merger-associated increase in cell rotation. When considering the association between tornado occurrence and cell mergers, a striking 54% of the tornadoes occurred within 15 min before or after a cell merger. This high percentage is strongly suggestive of a physical relationship between storm mergers and tornadogenesis. A discussion is presented of potential merger scenarios and favorable ambient environmental conditions that may have been conducive to tornadogenesis in this event. Suggestions are presented to raise the awareness level of forecasters to key aspects of cell evolution and interaction in nowcasting severe convection.

Background and aims: Self-reported data and/or medical records are often used to assess the prevalence of illness and impairment in epidemiological studies. However, these two data sources do not always provide the same information. The aim was to compare data from interviews and medical records regarding illness, symptoms and impairment in the elderly, and to analyze the agreement between a consensus from both data sources and data from interviews and medical records, respectively. Methods: We interviewed 130 persons (age range 67–99) regarding socio-demographic background data and physical and mental health. Medical records were reviewed. Illness burden was rated according to the Cumulative Illness Rating Scale for Geriatrics, and was rated in three ways based on: 1) interview data; 2) medical records; 3) information from both interviews and medical records considered to be consensus. Agreement was measured by the Kappa coefficient and the Svensson Paired Rank Measurement. A permutation test tested whether the ratings from interviews and medical records had the same agreement when compared with consensus. Results: Statistically significant differences in agreement were found between interview versus consensus and medical records versus consensus for the vascular system (medical records best), eyes/ears/ nose/throat/larynx and musculoskeletal/integument (interview best). Medical records gave better information concerning specific diseases and diagnoses, whereas interview data provided a better measure of illness, functional impairment and health in a broader sense. Conclusions: Both medical records and interviews yield good information of elderly people’s health status, but they focus on different aspects of health.

Little is known about the extent of work-related accidents occurring during the performance of forestry work by the non-industrial private forest owner or their assistant (hereafter called self-employed NIPF). The absence of an effective accident registration system largely excludes this group from accurate representation in official statistics. In this study, data from 1996 to 2001 were collected from hospital injury records managed by the Umea Accident Analysis Group at the University Hospital in Umea. During that period, it was found that 485 persons in the Umea region were given medical attention due to injuries possibly acquired during self-employed forestry work. Questionnaires about the accidents were sent to each of the 485 injured persons and 80% were returned. Responses revealed that 225 of the respondents were injured during self-employed forestry work. Out of these, 81% performed fewer than 31 days of forestry work annually. Due to the injury, 29% had been on sick leave for some period of time and 42% had persistent symptoms. On average, each injury led to 13 days of sick leave and 24 hours of institutional care. Firewood production was shown to be a key factor behind the large number of accidents for self-employed NIPF. Further studies on the lack of knowledge about how the work should be done and conscious risk taking should be considered as an important link to the development of effective accident prevention strategies.

Cancer patients treated with chemotherapy often become neutropenic, which predisposes for oral and systemic C. albicans infections. The purpose of this feasibility study was to find out if gargling with anti-C. albicans immunoglobulin Y from egg yolk can prevent oral candidiasis in children, treated for acute lymphatic leukemia. Four patients gargled with the antibodies once a day during the induction phase of chemotherapy. None of four patients treated with IgY got any C. albicans infection. In the non-treated control and in a historic group, seven of thirteen patients had suspected C. albicans infection. This study indicates that anti-C. albicans IgY may prevent oral candidiasis in immunocompromized children.

The aim of this study was to describe cohort differences in health indicators among four birth cohorts of 70-year old men and women from Goteborg, Sweden, born in 1901/2, 1905/6, 1911/12, and 1922. With special reference to gender, education, and obesity, it is hypothesized that changes in health among elderly men and women may not be occurring in a uniform manner. The variables studied were: systolic and diastolic blood pressures, triglycerides, cholesterol, height, weight, body mass index, waist-hip ratio, physical inactivity, current smoking, and alcohol consumption, plus selected prevalent diseases. Logistic and linear regression models were used to test for secular trends and effect modification by gender. Most trends in metabolic and lifestyle indicators varied in relation to gender as well as education. For instance, later-born male cohorts were more overweight than earlier-born groups while the later-born female cohorts had similar relative weights but a more centralized fat patterning. These cohort differences further varied by education where later-born men with less education and later-born women with higher education tended to be more overweight, compared to earlier-born cohorts. Finally, significant cohort differences in previously diagnosed myocardial infarction, stroke, and diabetes mellitus at age 70 were observed in men only. Interaction terms revealed that the gender difference was statistically significant only in the case of diabetes mellitus. In conclusion, secular trends in many obesity-related health indicators among 70-year old Swedish cohorts were dependent on both gender and socio-economic factors.