Constructing a clinical radiographic knee osteoarthritis database using artificial intelligence tools with limited human labor: A proof of principle.

OBJECTIVE: To create a scalable and feasible retrospective consecutive knee osteoarthritis (OA) radiographic database with limited human labor using commercial and custom-built artificial intelligence (AI) tools. METHODS: We applied four AI tools, two commercially available and two custom-built tools, to analyze 6 years of clinical consecutive knee radiographs from patients aged 35-79 at the University of Copenhagen Hospital, Bispebjerg-Frederiksberg Hospital, Denmark. The tools provided Kellgren-Lawrence (KL) grades, joint space widths, patella osteophyte detection, radiographic view detection, knee joint implant detection, and radiographic marker detection. RESULTS: In total, 25,778 knee radiographs from 8575 patients were included in the database after excluding inapplicable radiographs, and 92.5% of the knees had a complete OA dataset. Using the four AI tools, we saved about 800 hours of radiologist reading time and only manually reviewed 16.0% of the images in the database. CONCLUSIONS: This study shows that clinical knee OA databases can be built using AI with limited human reading time for uniform grading and measurements. The concept is scalable temporally and across geographic regions and could help diversify further OA research by efficiently including radiographic knee OA data from different populations globally. We can prevent data dredging and overfitting OA theories on existing trite cohorts by including various gene pools and continuous expansion of new clinical cohorts. Furthermore, the suggested tools and applied approaches provide an ability to retest previous hypotheses and test new hypotheses on real-life clinical data with current disease prevalence and trends.

Developing a prediction model to identify people with severe mental illness without regular contact to their GP - a study based on data from the Danish national registers.

INTRODUCTION: People with severe mental illness (SMI) face a higher risk of premature mortality due to physical morbidity compared to the general population. Establishing regular contact with a general practitioner (GP) can mitigate this risk, yet barriers to healthcare access persist. Population initiatives to overcome these barriers require efficient identification of those persons in need. OBJECTIVE: To develop a predictive model to identify persons with SMI not attending a GP regularly. METHOD: For individuals with psychotic disorder, bipolar disorder, or severe depression between 2011 and 2016 (n = 48,804), GP contacts from 2016 to 2018 were retrieved. Two logistic regression models using demographic and clinical data from Danish national registers predicted severe mental illness without GP contact. Model 1 retained significant main effect variables, while Model 2 included significant bivariate interactions. Goodness-of-fit and discriminating ability were evaluated using Hosmer-Lemeshow (HL) test and area under the receiver operating characteristic curve (AUC), respectively, via cross-validation. RESULTS: The simple model retained 11 main effects, while the expanded model included 13 main effects and 10 bivariate interactions after backward elimination. HL tests were non-significant for both models (p = 0.50 for the simple model and p = 0.68 for the extended model). Their respective AUC values were 0.789 and 0.790. CONCLUSION: Leveraging Danish national register data, we developed two predictive models to identify SMI individuals without GP contact. The extended model had slightly better model performance than the simple model. Our study may help to identify persons with SMI not engaging with primary care which could enhance health and treatment outcomes in this group.

Combination therapy with immune check point inhibitors and acute kidney injury.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of metastatic renal cell carcinoma and malignant melanoma but are also associated with a risk of severe side effects. Nephrotoxicity is an immune checkpoint inhibitor-related adverse effect, but acute kidney injury (AKI) can also be caused by other more common conditions. This study aimed to describe the incidence and causes of AKI in patients treated with combination therapy of immune checkpoint inhibitors. MATERIAL AND METHODS: This retrospective cohort study included 200 patients receiving ipilimumab and nivolumab for either metastatic renal cell carcinoma or malignant melanoma at the Department of Oncology at Copenhagen University Hospital, Herlev between 1 January 2019 and 31 December 2020. The incidence and cause of AKI within 6 months after treatment was determined. RESULTS: In the 96 patients treated for malignant melanoma 15 patients (16%) had an episode of AKI. Two of these patients had potential immune checkpoint inhibitor-related AKI both of which received treatment with a proton pump inhibitor (PPI). Of the 104 included patients with metastatic renal cell carcinoma 26 patients (25%) developed AKI. Five of these patients had potential immune checkpoint inhibitor-related AKI. Treatment with PPI before the development of AKI occurred in 4 out of these 5 patients. CONCLUSION: Patients receiving combination therapy with checkpoint inhibitors are at high risk of AKI, but different causes of AKI should always be considered. Use of PPI concurrently with ICIs is likely to increase the risk of AKI.

Labour market attachment dynamics in patients with concussion: a Danish nationwide register-based cohort study.

BACKGROUND: Concussion may lead to persisting post-concussive symptoms affecting work ability and employment. This study examined the transitions between labour market states an individual can experience after the acute phase of concussion. The aim was to describe the incidence of favourable and adverse transitions between different labour market states (e.g., employment, sick leave) in relation to socioeconomic and health characteristics in individuals with concussion relative to matched controls. METHODS: This Danish nationwide register-based cohort study extracted 18-60-year-old individuals between 2003-2007 with concussion from the Danish National Patient Register (ICD-10 S06.0). Controls were matched on age, sex, and municipality. Patients and controls were followed for 5 years starting three months after injury. Exclusion criteria were neurological injuries and unavailability to the labour market in the inclusion period (2003-2007) and 5-years before injury (1998-2002). Labour market states were defined from transfer income data in the Danish Register for Evaluation of Marginalization. Incidence rates of transitions between these labour market states were analysed in multistate models. Transitions were bundled in favourable and adverse transitions between labour market states and the difference in incidence rates between individuals with concussion relative to matched controls were assessed with hazard ratios from Cox regression models. RESULTS: Persons with concussion (n = 15.580) had a lower incidence of favourable transitions (HR 0.88, CI 0.86-0.90) and a higher incidence of adverse transitions (HR 1.30, CI 1.27-1.35), relative to matched controls (n = 16.377). The effect of concussion differed depending on health and socioeconomic characteristics. Notably, individuals between 30-39 years (HR 0.83, CI 0.79-0.87), individuals with high-income (200.000-300.000 DKK) (HR 0.83, CI 0.80-0.87), and wage earners with management experience (HR 0.60, CI 0.44-0.81) had a markedly lower incidence of favourable transitions compared to controls. Additionally, individuals with high income also had a higher incidence of adverse transitions (HR 1.46, CI 1.34-1.58) compared to controls. CONCLUSIONS: Concussion was associated with enhanced risk of adverse transitions between labour market states and lower occurrence of favourable transitions, indicating work disability, potentially due to persistent post-concussive symptoms. Some age groups, individuals with high income, and employees with management experience may be more affected.

A cross-sectional study of the association between family conflicts and children's health: Lolland-Falster Health Study.

BACKGROUND: Few family interaction processes are more detrimental to children's health than family conflicts. Conflictual relationships in childhood predict a host of adverse health outcomes across the life course. The current study examines associations between household conflicts and the health of children aged 6-12 years and explores to which extent this may vary by socioeconomic status (SES) and multimorbidity (MM) in the household. METHODS: Cross-sectional study using questionnaire data gathered between 2016 and 2020 as part of the Lolland-Falster Health Study (LOFUS) combined with routine register data on health care use and socio-demography from the Danish nationwide administrative databases. The study sample consisted of 1065 children 6-12 years old, who answered LOFUS4 or LOFUS11, from 777 households for which at least one adult answered LOFUS18. Main outcome was children's health complaints, defined as headache, abdominal pain, back pain, and sleep difficulties. Covariates included MM, SES, and conflicts, all three measured at household level. Multivariable logistic regression models were used. RESULTS: Conflicts were negatively associated with children's health. This was most pronounced for general conflicts in the household, with increased complaints of abdominal pain, back pain, and sleep difficulties. The associations varied when we stratified the households according to MM and SES. Significant associations were found within households without MM for abdominal pain, and within households with MM and low SES, and without MM and with high SES for sleep difficulties. While the higher level of abdominal pain for the above indicated households were found for both internal and external conflicts in the household, the higher level in sleep difficulties was mostly driven by internal conflicts. CONCLUSION: Children reporting frequent health complaints have a higher future health care use compared with children without such complaints. Our results indicate that growing up in a household with a high conflict level might be a predisposing factor.

Physical activity paradox: could inflammation be a key factor?

OBJECTIVE: The aim of this study was to test the extent to which physical activity performed during work and leisure is associated with systemic inflammation. METHODS: Data regarding job history and high-sensitivity C reactive protein (hs-CRP) levels, as well as potential confounders, came from the Copenhagen Aging and Midlife Biobank. The participants' self-reported job history was combined with a job exposure matrix to give a more valid assessment of cumulated occupational physical activity compared with conventional self-reported activity. Occupational physical activity was measured as cumulative ton-years (lifting 1000 kg each day for a year). Current leisure time physical activity was self-reported into four different categories. We analysed the association between occupational physical activity, current leisure time physical activity and hs-CRP level in a multivariable linear regression model with adjustment for age, sex, smoking history, number of chronic diseases, body mass index and alcohol. RESULTS: In unadjusted analysis, higher occupational physical activity was associated with increased hs-CRP levels, while higher leisure time physical activity was associated with lower hs-CRP levels. In adjusted analysis, lower leisure time physical activity resulted in 12% higher hs-CRP levels while higher occupational physical activities showed a 6% increase in hs-CRP. When we analysed occupational and leisure time physical activity as continuous variables, only leisure time physical activity affected hs-CRP. CONCLUSION: This study indicates that the relationship between physical activity and hs-CRP depends on the setting of physical activity, with lower hs-CRP related to leisure time physical activity and higher hs-CRP related to occupational physical activity. The results suggest that systemic inflammation may explain the physical activity paradox.

TG01/GM-CSF and adjuvant gemcitabine in patients with resected RAS-mutant adenocarcinoma of the pancreas (CT TG01-01): a single-arm, phase 1/2 trial.

BACKGROUND: TG01 is the first cancer immunotherapy targeting KRAS oncogenic mutations. This study assessed the safety and efficacy of TG01/GM-CSF in patients with resected pancreatic adenocarcinoma. METHODS: Patients with stage I or II pancreatic adenocarcinoma who had undergone surgical resection (R0 or R1) received adjuvant gemcitabine with TG01/GM-CSF using two schedules of vaccination. Immune response was defined as a positive delayed-type hypersensitivity (DTH) response and/or positive T-cell proliferation assay. RESULTS: Thirty-two patients were enrolled between February 2013 and May 2016. Nineteen were treated with the high antigen burden, with four serious adverse reactions considered possibly related to TG01 treatment, including three allergic reactions. On this basis, a further 13 patients received a modified vaccination schedule with reduced antigen burden, with no serious adverse events related to TG01. Ninety-five percent patients in the main cohort and 92% in the modified cohort had a positive immune response. Median overall survival (OS) was 33.1 months, and median disease-free survival (DFS) was 13.9 months for the main cohort. For the modified cohort, the median OS was 34.3 months and median DFS was 19.5 months. CONCLUSIONS: TG01/GM-CSF with gemcitabine was well tolerated, with high levels of immune activation. OS and DFS compare favourably with published data for adjuvant gemcitabine. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at ClinicalTrials.gov (NCT02261714).

Chimeric oncolytic Ad5/3 virus replicates and lyses ovarian cancer cells through desmoglein-2 cell entry receptor.

Despite new therapies, the estimated 229 875 women living with ovarian cancer have a 5-year survival rate of 47.6%. This cavity-localized cancer lends itself to local administration of modalities, such as the oncolytic adenovirus (Ad) Ad5/3-D24-granulocyte-macrophage colony-stimulating factor virus (ONCOS-102). Its repeated administration to a patient with chemotherapy-refractory ovarian cancer induced CD8+ antitumor immune responses with the overall survival reaching 40 months. Here we probe the dominant receptor used by ONCOS-102 in four established epithelial ovarian cancer cell lines. Ad3 can use the desmoglein-2 (DSG2) and CD46 receptors on susceptible cells. DSG2 was nearly absent in A2780 cells but was expressed in more than 90% of OAW42, OVCAR3, and OV-90 cells. After 96 hours, ONCOS-102 treatment showed significant oncolytic activity (≧50%) in OAW42, OVCAR3, and OV-90 cells, but minimal activity in A2780 cells, suggesting DSG2 as the dominant receptor for ONCOS-102. Furthermore, retrospective analyses of phase I clinical trial of ONCOS-102 treatment of 12 patients with varied tumors indicated a correlation between viral genomes in blood and DSG2 RNA expression. These data support the role of DSG2 expression on cancer cells in virus infectivity and the continued development of ONCOS-102 for ovarian cancer treatment.

Five-Year Trends in Marital Stability, Academic Achievement, and Socioeconomic Indicators After Concussion: A National Register Study.

OBJECTIVE: To examine long-term trends in marital stability, academic achievement, income, and socioeconomic status in patients with concussion. DESIGN AND SETTING: Danish national register-based cohort study with 5 years of follow-up. PARTICIPANTS: A total of 23 549 hospital-admitted or emergency-treated patients between 18 and 60 years of age with concussion (International Classification of Diseases, Tenth Revision [ICD-10] diagnosis S06.0) and 22 228 matching controls. MAIN MEASURES: Outcomes were the differences between patients with concussion and controls in the change from injury date to 5 years postinjury in the dichotomized outcomes-martial stability, academic achievement, income, and socioeconomic status. RESULTS: Fewer patients had high education (19.43%) compared with controls (23.96%) and the adjusted odds ratio (OR) of high education beyond the difference in prevalence at baseline became even lower at 5 years of follow-up (OR: 0.93, 95% confidence interval [CI]: 0.90-0.95). Patients were to a lesser extent gainfully employed (67.05%) compared with controls (77.32%) and had lower odds of being gainfully employed (OR: 0.83, 95% CI: 0.79-0.88), self-employed, leaders, or managers (OR: 0.89, 95% CI: 0.84-0.95) at 5 years postinjury, beyond differences at baseline. CONCLUSIONS: Academic achievement and socioeconomic status are affected by concussion. There is no evidence that marital stability and income are affected. Supporting interventions should be considered those at risk of persistent symptoms.

Exploring targeted preventive health checks in a socially disadvantaged neighborhood in Denmark.

Recently studies have focused on how health promotion interventions sometimes sideline issues of social context, framing health as a matter of individual choice and, by implication, a personal responsibility. Part of this criticism is that health promotion interventions often do not draw on situated understandings of the contextual aspects of health and illness practices. Theoretically, this study departs in practice theory and contemporary public heath discussions on targeted health promotion. Based on semi-structured interviews with 18 people living in a social housing association we explored the significance of participating in a preventive health check and how participation configured into everyday life. All participants in our study had been identified with a 'risk' health profile. Overall, we found that they were well aware of their health risks and challenges, and that they reflected a great deal on how their health status was intrinsically linked with their lifestyle and health practices, such as lack of exercise or smoking. The health checks were, however, not able to support or improve their general health, and did not seem to address the challenges the participants seemed to struggle with in life. By way of conclusion, we suggest that we implement a more practice-oriented form of public health that focus on the 'lives' that people live, and the problems that they face. Moreover, attention should be paid to how and to whom health promotion initiatives are offered, in order to ensure the relevance of targeted interventions.

Abscopal effect when combining oncolytic adenovirus and checkpoint inhibitor in a humanized NOG mouse model of melanoma.

Melanoma, an immunogenic tumor, is the first indication where oncolytic viruses are now becoming part of clinical practice. ONCOS-102, a transgened adenovirus, has shown to act as a primer of relevant tumor targeting immune cells both in preclinical and clinical melanoma studies. Strategies to augment its effectiveness warrant investigation. Combination therapy of ONCOS-102 with the checkpoint inhibitor (CPI) pembrolizumab was evaluated in a quasi-human animal model, the humanized NOG mouse model. A dosing schedule of the combination, beginning the CPI concurrently with the oncolytic viral therapy and continuing the CPI treatment, appeared to induce an abscopal effect in untreated tumor lesions. Concurrent combination therapy with checkpoint inhibitors may improve the induction of antitumor immune responses of ONCOS-102.

Cumulative physical workload and mobility limitations in middle-aged men and women: a population-based study with retrospective assessment of workload.

PURPOSE: To assess the association between exposure to physical workload throughout working life and risk of mobility limitations in midlife in a population-based Danish cohort. METHODS: The study was cross-sectional with a retrospective exposure assessment, and data were from a questionnaire used in the Copenhagen Aging and Biobank. Cumulative physical workload was estimated by combining information about the participants' employments and data from a job exposure matrix. Daily amount of lifting was standardised in ton-years (lifting 1000 kg/day/year) and grouped in 5 exposure groups (no/minor (1-2 ton-years)/low (3-10 ton-years)/moderate (11-20 ton-years)/high exposure (> 20 ton-years)). The outcome was self-reports of mobility limitations (running 100 m, walking 400 m, and climbing stairs to the 2nd floor) in midlife. The association between exposure and outcome was analysed using logistic regression models. RESULTS: We included 4996 men and 2247 women, mean age 56 years. 21% of men and 10% of women were in the highest exposure-group (> 20 ton-years). Higher cumulative exposure was associated with higher odds for mobility limitations. Exposure to more than 20 ton-years compared to no exposure increased the odds for limitations in walking, age-adjusted odds ratio (OR) 3.2 (95% CI: 2.4-4.3) for men, 2.3 (1.4-3.8) for women. Corresponding results for running: 2.5 (2.2-3.0) for men, 1.6 (1.2-2.2) for women, and for limitations in climbing stairs: 4.2 (3.3-5.2) for men, 1.7 (1.2-2.4) for women. Results were attenuated when confounders were added. CONCLUSIONS: Exposure to physical workload throughout working life is associated with higher odds for mobility limitations in midlife.

Optimization of Early Steps in Oncolytic Adenovirus ONCOS-401 Production in T-175 and HYPERFlasks.

Oncolytic adenoviruses can trigger lysis of tumor cells, induce an antitumor immune response, bypass classical chemotherapeutic resistance strategies of tumors, and provide opportunities for combination strategies. A major challenge is the development of scalable production methods for viral seed stocks and sufficient quantities of clinical grade viruses. Because of promising clinical signals in a compassionate use program (Advanced Therapy Access Program) which supported further development, we chose the oncolytic adenovirus ONCOS-401 as a testbed for a new approach to scale up. We found that the best viral production conditions in both T-175 flasks and HYPERFlasks included A549 cells grown to 220,000 cells/cm² (80% confluency), with ONCOS-401 infection at 30 multiplicity of infection (MOI), and an incubation period of 66 h. The Lysis A harvesting method with benzonase provided the highest viral yield from both T-175 and HYPERFlasks (10,887 ± 100 and 14,559 ± 802 infectious viral particles/cell, respectively). T-175 flasks and HYPERFlasks produced up to 2.1 × 108 ± 0.2 and 1.75 × 108 ± 0.08 infectious particles of ONCOS-401 per cm² of surface area, respectively. Our findings suggest a suitable stepwise process that can be applied to optimizing the initial production of other oncolytic viruses.

Antitumor-specific T-cell responses induced by oncolytic adenovirus ONCOS-102 (AdV5/3-D24-GM-CSF) in peritoneal mesothelioma mouse model.

Oncolytic adenoviral immunotherapy activates the innate immune system with subsequent induction of adaptive tumor-specific immune responses to fight cancer. Hence, oncolytic viruses do not only eradicate cancer cells by direct lysis, but also generate antitumor immune response, allowing for long-lasting cancer control and tumor reduction. Their therapeutic effect can be further enhanced by arming the oncolytic adenovirus with costimulatory transgenes and/or coadministration with other antitumor therapies. ONCOS-102 has already been found to be well tolerated and efficacious against some types of treatment-refractory tumors, including mesothelin-positive ovarian cancer (NCT01598129). It induced local and systemic CD8+ T-cell immunity and upregulated programmed death ligand 1. These results strongly advocate the use of ONCOS-102 in combination with other therapeutic strategies in advanced and refractory tumors, especially those expressing the mesothelin antigen. The in vivo work presented herein describes the ability of the oncolytic adenovirus ONCOS-102 to induce mesothelin-specific T-cells after the administration of the virus in bagg albino (BALB/c) mice with mesothelin-positive tumors. We also demonstrate the effectiveness of the interferon-γ the enzyme-linked immunospot (ELISPOT) assay to detect the induction of T-cells recognizing mesothelin, hexon, and E1A antigens in ONCOS-102-treated mesothelioma-bearing BALB/c mice. Thus, the ELISPOT assay could be useful to monitor the progress of therapy with ONCOS-102.

Retrospectively assessed physical work environment during working life and risk of sickness absence and labour market exit among older workers.

OBJECTIVE: To determine the prospective association between retrospectively assessed physical work environment during working life and prospectively assessed sickness absence and labour market exit among older workers. METHODS: Using Cox regression analyses we estimated the 4-year to 6-year prospective risk of register-based long-term sickness absence (LTSA), disability pension, early retirement and unemployment from exposure to different physical work environmental factors during working life among 5076 older workers (age 49-63 at baseline) from the Copenhagen Aging and Midlife Biobank cohort. RESULTS: Very hard physical work throughout working life was a risk factor for LTSA (HR 1.66,95% CI 1.32 to 2.07), disability pension (HR 2.21,95% CI 1.04 to 4.72) and early retirement (HR 1.57,95% CI 1.13 to 2.17). Both short-term (<10 years) and long-term (≥20 years) exposures to lifting or carrying of heavy burdens predicted the risk of LTSA (HRs 1.49-1.56) and disability pension (HRs 2.26-3.29). In contrast, exposure to dust was associated with LTSA and disability pension only following 20 or more exposure years. CONCLUSIONS: Retrospectively assessed hard physical work during working life and exposure to several factors in the physical work environment, especially heavy lifting, were important for labour market exit and sickness absence. This study underscores the importance of reducing physical work exposures throughout the working life course for preventing sickness absence and premature exit from the labour market.

Retrospectively assessed psychosocial working conditions as predictors of prospectively assessed sickness absence and disability pension among older workers.

BACKGROUND: The aim was to explore the association between retrospectively assessed psychosocial working conditions during working life and prospectively assessed risk of sickness absence and disability pension among older workers. METHODS: The prospective risk of register-based long-term sickness absence (LTSA) and disability pension was estimated from exposure to 12 different psychosocial work characteristics during working life among 5076 older workers from the CAMB cohort (Copenhagen Aging and Midlife Biobank). Analyses were censored for competing events and adjusted for age, gender, physical work environment, lifestyle, education, and prior LTSA. RESULTS: LTSA was predicted by high levels of cognitive demands (HR 1.31 (95% CI 1.10-1.56)), high levels of emotional demands (HR 1.26 (95% CI 1.07-1.48)), low levels of influence at work (HR 1.30 (95% CI 1.03-1.64)), and high levels of role conflicts (HR 1.34 (95% CI 1.09-1.65)). Disability pension was predicted by low levels of influence at work (HR 2.73 (95% CI 1.49-5.00)) and low levels of recognition from management (HR 2.04 (95% CI 1.14-3.67)). CONCLUSIONS: This exploratory study found that retrospectively assessed high cognitive demands, high and medium emotional demands, low influence at work, low recognition from management, medium role clarity, and high role conflicts predicted LTSA and/or disability pension.

Parental response to severe or lethal prenatal diagnosis: a systematic review of qualitative studies.

OBJECTIVE: A severe or lethal prenatal diagnosis places great demands on prospective parents, who face choices of far-reaching consequences, such as continuing or terminating the pregnancy. How best to support these parents is a clinical challenge. This systematic review aimed to identify and synthesize the qualitative evidence regarding prospective parents' responses to such prenatal diagnoses. METHODS: Following PRISMA guidelines, four databases were systematically searched and 28 studies met the inclusion criteria. Thematic analysis guided data extraction and synthesis of findings. The Confidence in the Evidence for Reviews of Qualitative research assessment tool was utilized to assess confidence in the findings. RESULTS: Prospective parents experienced multiple losses, for example, of the healthy child, normal pregnancy and envisioned future. After diagnosis, they requested timely and reliable information and empathetic continued interaction with clinicians. Prospective parents who continued the pregnancy wished to be acknowledged as parents and engaged in planning to obtain a sense of meaning and control. Selective disclosure and concerns about negative responses were issues both for the parents who terminated and those who continued a pregnancy. CONCLUSION: Clinicians can support parental coping following a severe prenatal diagnosis through continued dialogue and collaboration. Further research is needed on the experiences of parents who choose to terminate a pregnancy following prenatal diagnosis. © 2017 John Wiley & Sons, Ltd.

Influence of physical and psychosocial work environment throughout life and physical and cognitive capacity in midlife on labor market attachment among older workers: study protocol for a prospective cohort study.

BACKGROUND: As average life span increases, elderly will account for an increasing proportion of the total population in most parts of the world. Thus, initiatives to retain older workers at the labor market are becoming increasingly important. This study will investigate the influence of physical and psychosocial work environment throughout working life and physical and cognitive capacity in midlife on labor market attachment among older workers. METHODS/DESIGN: Approximately 5000 participants (aged 50-60 years) from the Copenhagen Aging and Midlife Biobank (CAMB) will be followed prospectively in a national register (DREAM), containing information on a week-to-week basis about social transfer payments for about 5 million Danish residents. Using Cox regression, we will model the risk of long-term sickness absence, disability pension, early retirement and unemployment within a 4 to 6 year period from the baseline measurement as a function of the following predictors: 1) physical work demands throughout working life, 2) psychosocial working conditions throughout working life, 3) physical capacity in midlife, 4) cognitive capacity in midlife. Estimates will be adjusted for age, sex, lifestyle, socioeconomic position, chronic disease and long-term sickness absence prior to baseline. DISCUSSION: The project will generate new knowledge on risk factors for loss of labor market attachment. The results will potentially contribute in identifying factors that could be targeted in future interventions for maintaining a longer and healthier working life among older workers.

Cancers of unknown primary origin (CUP) are characterized by chromosomal instability (CIN) compared to metastasis of know origin.

BACKGROUND: Cancers of unknown primary (CUPs) constitute ~5% of all cancers. The tumors have an aggressive biological and clinical behavior. The aim of the present study has been to uncover whether CUPs exhibit distinct molecular features compared to metastases of known origin. METHODS: Employing genome wide transcriptome analysis, Linear Discriminant Analysis (LDA) and Quadratic Discriminant Analysis (QDA), we defined the putative origins of a large series of CUP and how closely related a particular CUP was to corresponding metastases of known origin. LDA predictions were subsequently used to define a universal CUP core set of differentially expressed genes, that by means of gene set enrichment analysis was exploited to depict molecular pathways characterizing CUP. RESULTS: The analyses show that CUPs are distinct from metastases of known origin. CUPs exhibit inconsistent expression of conventional cancer biomarkers and QDA derived outlier scores show that CUPs are more distantly related to their primary tumor class than corresponding metastases of known origin. Gene set enrichment analysis showed that CUPs display increased expression of genes involved in DNA damage repair and mRNA signatures of chromosome instability (CIN), indicating that CUPs are chromosome unstable compared to metastases of known origin. CONCLUSIONS: CIN may account for the uncommon clinical presentation, chemoresistance and poor outcome in patients with CUP and warrant selective diagnostic strategies and treatment.