Climate footprint assessment of plastic waste pyrolysis and impacts on the Danish waste management system.

Increased plastic recycling is necessary to reduce environmental impacts related to manufacturing and end-of-life of plastic products, however, mechanical recycling (MR) - currently the most widespread recycling option for plastic waste - is limited by quality requirements for inputs and reduced quality of outputs. In this study, pyrolysis of plastic waste is assessed against MR, municipal solid waste incineration (MSWI) and fuel substitution through climate footprint assessment (CFA) based on primary data from pyrolysis of plastic waste sourced from Danish waste producers. Results of the CFA are scaled to the Danish plastic waste resource in an impact assessment of current Danish plastic waste management, and scenarios are constructed to assess reductions through utilization of pyrolysis. Results of the CFA show highest benefits utilizing pyrolysis for monomer recovery (-1400 and -4800 kg CO2e per ton polystyrene (PS) and polymethyl methacrylate (PMMA), respectively) and MR for single polymer polyolefins (-1000 kg CO2e per ton PE). The two management options perform similarly with mixed plastic waste (200 kg CO2e per ton plastic waste). MSWI has the highest impact (1600-2200 kg CO2e per ton plastic waste) and should be avoided when alternatives are available. Scaling the results of the CFA to the full Danish plastic waste resource reveals an impact of 0.79 Mt CO2e in year 2020 of current plastic waste management. Utilizing pyrolysis to manage MR residues reduces the system impact by 15%. Greater reductions are possible through increased separation of plastic from residual waste. The best performance is achieved through a combination of MR and pyrolysis.

Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Evaluation of an individually tailored smoking-cessation intervention for patients with rheumatoid arthritis in an outpatient clinic.

OBJECTIVE: The aim of this study was to evaluate an individually tailored smoking-cessation intervention delivered in rheumatology care and compare the characteristics of patients who quit smoking with those who did not. METHOD: This was an open single-group prospective intervention study over 24 months, with assessments at baseline and at 6, 12, 18, and 24 months. Current smokers with rheumatoid arthritis (RA) were invited to a smoking-cessation programme including behavioural change support, with or without pharmacotherapy. Data on disease activity, medical treatment, and patient-reported outcomes were retrieved from the Swedish Rheumatology Quality Register. The primary outcome was the proportion of patients at month 24 who reported having quit smoking with self-reported 7 day smoking abstinence. RESULTS: In total, 99 patients participated in the study. Median age was 58 years (interquartile range 50-64); 69% were female and 88% rheumatoid factor and/or anti-cyclic citrullinated peptide positive. At 24 months, 21% of the patients had quit smoking. At 6, 12, and 18 months, 12%, 12%, and 14% of patients, respectively, had quit smoking. For patients still smoking at 24 months, the median number of cigarettes per day was significantly reduced from 12 to 6 (p ≤ 0.001). Among patients who had quit smoking at 24 months, a smaller proportion reported anxiety at baseline compared to those still smoking (28% vs 58%, p = 0.02). CONCLUSION: A smoking-cessation intervention including behavioural change support with or without pharmacotherapy can be helpful for a substantial number of RA patients. Anxiety is associated with lower smoking-cessation success rates.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

Subclinical hyperthyroidism is associated with increased risk of vertebral fractures in older men.

In elderly men included in MrOS-Sweden, subclinical hyperthyroidism (SHyper) was markedly associated with increased risk of vertebral fractures. INTRODUCTION: Overt hyperthyroidism is associated with increased risk of fractures. However, only a few studies have investigated whether SHyper is associated with fracture risk in elderly men. We therefore investigated if SHyper was a risk factor for fractures in Swedish men. METHODS: We followed (median 9.8 years) elderly men (n = 1856; mean age 75, range 69-81 years) participating in the Gothenburg and Malmö subcohorts of the prospective, population-based MrOS-Sweden study. The statistical analyses included Cox proportional hazards regression. SHyper was defined as serum thyroid-stimulating hormone (TSH) < 0.45 mIU/L (n = 38). RESULTS: SHyper was associated with increased risk of all fractures [n = 456; hazard ratio (HR) adjusted for age, study center, and levothyroxine treatment = 1.99, 95% confidence interval (CI): 1.20-3.32], major osteoporotic fractures (MOF, n = 338; HR 2.44, 95% CI: 1.42-4.21), and vertebral fractures (n = 176; HR 3.79, 95% CI: 2.02-7.11). These associations remained after full adjustment for covariates including total hip bone mineral density and in subanalyses including only men with serum free thyroxine ≤ the upper normal limit. However, after exclusion of men receiving levothyroxine treatment, the associations with all fractures and MOF lost significance. CONCLUSIONS: In elderly Swedish men, there was a strong association between SHyper and increased risk of vertebral fractures, whereas the associations with all incident fractures and MOF need to be confirmed in further studies.

High platelet count is associated with low bone mineral density: The MrOS Sweden cohort.

In elderly ambulatory men, high platelet and high neutrophil counts are related to low bone mineral density (BMD), after adjustment for relevant covariates. Low hemoglobin (hgb) is even associated with low BMD, but this relationship seems to be dependent on estradiol and osteocalcin. PURPOSE: Blood and bone cells exist in close proximity to each other in the bone marrow. Accumulating evidence, from both preclinical and clinical studies, indicates that these cell types are interconnected. Our hypothesis was that BMD measurements are associated with blood count variables and bone remodeling markers. METHODS: We analyzed blood count variables, bone remodeling markers, and BMD, in subjects from the MrOS cohort from Gothenburg, Sweden. Men with at least one blood count variable (hgb, white blood cell count, or platelet count) analyzed were included in the current analysis (n = 1005), median age 75.3 years (range 69-81 years). RESULTS: Our results show that high platelet counts were related to low BMD at all sites (total hip BMD; r = - 0.11, P = 0.003). No statistically significant association was seen between platelet counts and bone remodeling markers. Neutrophil counts were negatively associated with total body BMD (r = - 0.09, P = 0.006) and total hip BMD (r = - 0.08, P = 0.010), and positively related to serum ALP (r = 0.15, P < 0.001). Hgb was positively related to total hip BMD (r = 0.16, P < 0.001), and negatively to serum osteocalcin (r = - 0.13, P < 0.001). The association between platelet and neutrophil counts and total hip BMD was statistically significant after adjustments for other covariates, but the association between hgb and total hip BMD was dependent on estradiol and osteocalcin. CONCLUSIONS: Our observations support the hypothesis of an interplay between blood and bone components.

Risk for hip fracture before and after total knee replacement in Sweden.

We studied the risk for hip fracture before and after total knee replacement (TKR) in the entire population in Sweden. Women and men had a low risk for hip fracture before TKR but an increased risk the first year after TKR. PURPOSE: It is known that osteoarthritis is associated with high bone mass. We therefore studied the risk of hip fracture before and after total knee replacement (TKR), risk of different hip fracture types, and risk subdivided in genders and age groups. METHODS: We followed the total Swedish population born between 1902 and 1952 (n = 4,258,934) during the period 1987-2002 and identified all patients with TKR due to primary OA (n = 39,291), and all patients with hip fracture (n = 195,860) in the Swedish National Inpatient Register. The risk time analyses were based on Poisson regression models. RESULTS: The hazard ratio (HR) for hip fracture the last year before TKR was 0.86 (95% CI 0.74 to 1.00) and the first year after 1.26 (95% CI 1.11 to 1.42) compared to individuals without TKR. The HR for femoral neck fracture 0-10 years after TKR was 0.95 (95% CI 0.89 to 1.01) and for trochanteric fracture was 1.13 (95% CI 1.06 to 1.21). The HR for hip fracture in the age group 50-74 was 1.28 (95% CI 1.14 to 1.43) and in the age group 75-90 years was 0.99 (95% CI 0.94 to 1.04) 0-10 years after TKR, compared to individuals without TKR. CONCLUSION: Individuals had a low risk for hip fracture before TKR but an increased risk the first year after TKR. The risk in individuals below age 75 years and for trochanteric fractures was increased after TKR. Possible explanations include changed knee kinematics after a TKR, physical activity level, fall risk, and other unknown factors.

Increased risk for hip fracture after death of a spouse-further support for bereavement frailty?

Death of a spouse is associated with poorer physical and mental health. We followed all married individuals, born from 1902 to 1942, during the period from 1987 to 2002, and found that widows and widowers had higher risk for hip fracture, compared with still married women and men. INTRODUCTION: Spousal bereavement can lead to poorer physical and mental health. We aimed to determine whether married women and men had an elevated risk of hip fracture after death of a spouse. METHODS: In a retrospective cohort study, we followed all Swedish married individuals aged 60 to 100 years (n = 1,783,035), from 1987 to 2002. Data are presented as mean with 95% confidence interval (CI). RESULTS: During the follow-up period, 21,305 hip fractures among widows and 6538 hip fractures among widowers were noted. The hazard ratio (HR) for hip fracture in widows compared with married women was 1.34 (95% CI 1.31 to 1.37) and for widowers compared with married men 1.32 (95% CI 1.29 to 1.35). The HR for hip fracture in the first 6 months after death of a spouse was in widows compared with married women 1.62 (95% CI 1.53 to 1.71) and in widowers compared with married men 1.84 (95% CI 1.68 to 2.03). The elevated risk was especially prominent in young widowers in the age range 60-69 years. During the first 6 months they showed a HR of 2.76 (95% CI 1.66 to 4.58) for a hip fractvure compared with age matched married men. Widows aged 60-69 years showed a HR of 1.59 (95% CI 1.26 to 1.99) compared with age matched married women. CONCLUSION: Our observation of a higher hip fracture risk in both genders in connection with the death of a spouse indicates a possible effect of bereavement on frailty.

Plant species affects establishment of Escherichia coli O157:H7 gfp+ on leafy vegetables.

AIMS: Greenhouse trials were conducted with different cultivars of baby leaf spinach, rocket and Swiss chard and inoculation of Escherichia coli O157:H7 gfp+, to determine whether plant species and cultivar have an impact on the establishment of this strain. METHODS AND RESULTS: Three cultivars each of spinach, rocket and Swiss chard were spray inoculated with E. coli O157:H7 gfp+ at doses of log 7 CFU per ml. Due to the different lengths of growing period spinach and Swiss chard were spray inoculated three times and rocket five times, with final inoculation performed 3 days prior to harvest. After a growing period of 26-33 days, E. coli O157:H7 gfp+ was recovered from the leaf surface in mean populations between log 1 and 6 CFU per gram. The lowest occurrence of E. coli O157:H7 gfp+ was found on rocket leaves and the highest on spinach. There was no significant difference in the establishment of E. coli O157:H7 gfp+ between cultivars, but there were differences between plant species. Indigenous phyllosphere bacteria were pure cultured and identified with 16S rRNA gene sequencing. CONCLUSIONS: Despite the same high inoculation dose of E. coli O157:H7 gfp+ on leaves, the establishment rate differed between plant species. However, plant cultivar did not affect establishment. Pantoea agglomerans dominated the identified bacterial isolates. SIGNIFICANCE AND IMPACT OF THE STUDY: As previous studies are inconclusive on choice of model plant species and cultivar, we studied whether plant species or cultivar determines the fate of E. coli O157:H7 gfp+ on leafy vegetables. The findings indicate that plant species is a key determinant in the establishment of E. coli O157:H7 gfp+.

Effects of fibrinogen supplementation on clot formation in blood samples from cardiac surgery patients before and after tranexamic acid administration.

OBJECTIVES: To investigate if supplementation with fibrinogen concentrate to blood samples collected after tranexamic acid administration improve clot formation more than what can be achieved with fibrinogen in the absence of tranexamic acid. BACKGROUND: It is not known if the combination of fibrinogen and tranexamic acid has additional effects than what can be achieved individually. METHODS: Four blood samples were collected from 15 coronary artery bypass patients. Two samples were collected before surgery, before and after 2 g tranexamic acid was administered. The preoperative samples were diluted to haematocrit 21%. Two samples were collected after surgery, before and after a second dose of 2 g tranexamic acid. Fibrinogen concentrate corresponding to a dose of 3 g in a 70-kg patient was added to the samples. Platelet-independent clotting time and maximum clot firmness assessed by thromboelastometry (ROTEM-FIBTEM®) were compared between the samples. RESULTS: Administration of tranexamic acid shortened clotting time marginally (-6%) before surgery, P = 0·029) but did not influence clot firmness. Fibrinogen concentrate shortened clotting time (-14% before and -12% after surgery, both P = 0·003) and increased clot firmness (+51 and +39%, both P < 0·001). The effects of fibrinogen did not differ before and after tranexamic acid administration. Fibrinolysis was not detected in any sample. CONCLUSIONS: The results of this in vitro study suggest that the enhancing effects of fibrinogen on clot firmness in blood samples from cardiac surgery patients are not further increased in the presence of tranexamic acid. Further studies on patients with ongoing bleeding and/or hyperfibrinolysis are necessary to validate the results.

Effect of fruit and host fly species on the associative learning by Fopius arisanus.

Parasitoids, released in augmentative biological control programmes, which display a rapid host-location capacity, have a higher likelihood of successfully controlling target pest species. By learning to associate sensory cues to a suitable oviposition site, might parasitoids used as biological control agents, locate hosts more rapidly, and perhaps increase the efficacity of e.g. Tephritidae fruit fly management. We studied associative learning of Fopius arisanus (Hymenoptera: Braconidae) and tested its range of learning in natural and conditional hosts and host fruits, i.e. Bactrocera dorsalis, Zeugodacus cucurbitae, Ceratitis capitata and Ceratitis cosyra (Diptera: Tephritidae) and on fruits (papaya, tomato, banana). Naïve female F. arisanus were compared with experienced wasps, which had been offered infested and non-infested fruit, and been allowed to oviposit. Preferences for olfactory cues from infested fruits were thereafter assessed in a two-choice olfactometer. Naïve and trained parasitoids preference differed in general and non-responders to infested fruits were higher among naïve parasitoids. The trained wasps preferred the fruit infested in the training more than the control fruit, for all combination, except when C. cosyra infested the fruits, hence avoidance behavioural response was observed towards the odour of the infested fruit. Fopius arisanus was capable of behaviourally respond to the learned information, e.g. associative odour learning was achieved, yet limited depending on interaction level, fruit fly and fruit combination. To create F. arisanus preference of an associated odour, it might hence be needed to ensure oviposition in perceived suitable host and host fruit, for the parasitoid learning to become favourable in a biological control setup.

Handling underlying discrete variables with bivariate mixed hidden Markov models in NONMEM.

Non-linear mixed effects models typically deal with stochasticity in observed processes but models accounting for only observed processes may not be the most appropriate for all data. Hidden Markov models (HMMs) characterize the relationship between observed and hidden variables where the hidden variables can represent an underlying and unmeasurable disease status for example. Adding stochasticity to HMMs results in mixed HMMs (MHMMs) which potentially allow for the characterization of variability in unobservable processes. Further, HMMs can be extended to include more than one observation source and are then multivariate HMMs. In this work MHMMs were developed and applied in a chronic obstructive pulmonary disease example. The two hidden states included in the model were remission and exacerbation and two observation sources were considered, patient reported outcomes (PROs) and forced expiratory volume (FEV1). Estimation properties in the software NONMEM of model parameters were investigated with and without random and covariate effect parameters. The influence of including random and covariate effects of varying magnitudes on the parameters in the model was quantified and a power analysis was performed to compare the power of a single bivariate MHMM with two separate univariate MHMMs. A bivariate MHMM was developed for simulating and analysing hypothetical COPD data consisting of PRO and FEV1 measurements collected every week for 60 weeks. Parameter precision was high for all parameters with the exception of the variance of the transition rate dictating the transition from remission to exacerbation (relative root mean squared error [RRMSE] > 150%). Parameter precision was better with higher magnitudes of the transition probability parameters. A drug effect was included on the transition rate probability and the precision of the drug effect parameter improved with increasing magnitude of the parameter. The power to detect the drug effect was improved by utilizing a bivariate MHMM model over the univariate MHMM models where the number of subject required for 80% power was 25 with the bivariate MHMM model versus 63 in the univariate MHMM FEV1 model and > 100 in the univariate MHMM PRO model. The results advocates for the use of bivariate MHMM models when implementation is possible.

Extended physical education in children aged 6-15 years was associated with improved academic achievement in boys.

AIM: Physical activity (PA) has been associated with enhanced cognition, brain development and concentration. This study evaluated whether increased physical education (PE) improved academic achievement. METHODS: We recruited 304 children (55% boys) from a Swedish school in Skane County in 1998-2002 when they were six to seven years of age and followed them through all nine mandatory school years. Their PE level was increased from 60 to 200 minutes per week, and their results were compared with 73 885 control children (51% boys) in the county who graduated in the same years and did the standard 60 minutes of PE per week. Their academic achievements were measured as their final grade scores and the proportion of students eligible for upper secondary school. RESULTS: The eligibility for further education increased in the intervention boys by 6.8 percentage points and the mean grade score by 12.1 points, while in the control group as a whole, the eligibility rate decreased by 0.7 percentage points and the mean grade score increased by 1.7 points. No changes in eligibility rates or mean grade scores were seen in the intervention girls. CONCLUSION: Increasing weekly PE over nine years was associated with improved academic achievement in boys.

Reduced and optimized trial designs for drugs described by a target mediated drug disposition model.

Monoclonal antibodies against soluble targets are often rich and include the sampling of multiple analytes over a lengthy period of time. Predictive models built on data obtained in such studies can be useful in all drug development phases. If adequate model predictions can be maintained with a reduced design (e.g. fewer samples or shorter duration) the use of such designs may be advocated. The effect of reducing and optimizing a rich design based on a published study for Omalizumab (OMA) was evaluated as an example. OMA pharmacokinetics were characterized using a target-mediated drug disposition model considering the binding of OMA to free IgE and the subsequent formation of an OMA-IgE complex. The performance of the reduced and optimized designs was evaluated with respect to: efficiency, parameter uncertainty and predictions of free target. It was possible to reduce the number of samples in the study by 30% while still maintaining an efficiency of almost 90%. A reduction in sampling duration by two-thirds resulted in an efficiency of 75%. Omission of any analyte measurement or a reduction of the number of dose levels was detrimental to the efficiency of the designs (efficiency ≤ 51%). However, other metrics were, in some cases, relatively unaffected, showing that multiple metrics may be needed to obtain balanced assessments of design performance.

Low physical activity is related to clustering of risk factors for fracture-a 2-year prospective study in children.

The study investigates the effect of physical activity (PA) on a composite score for fracture risk in pre-pubertal children. Low PA in children is related to the composite score for fracture risk and the pre-pubertal years seem to be a period when PA positively affects the score. INTRODUCTION: This study evaluates if PA in children is related to clustering of risk factors for fracture. Research questions are the following: (i) What is the effect of physical activity (PA) on single traits and a composite score for fracture risk? (ii) Could this score be used to identify the level of PA needed to reach beneficial effects? METHODS: This prospective population-based study included 269 children, aged 7-9 years at baseline while 246 attended the 2-year follow-up. We estimated duration of PA by questionnaires and measured traits that independently predict fractures. We then calculated gender specific Z-scores for each variable. The mean Z-score of all traits was used as a composite score for fracture risk. We tested correlation between duration of PA, each trait, and the composite score and group differences between children in different quartiles of PA. RESULTS: At baseline, we found no correlation between duration of PA and any of the traits or the composite score. At follow-up, we found a correlation between PA and the composite score. Physical activity had an effect on composite score, and children in the lowest quartiles of PA had unbeneficial composite score compared to children in the other quartiles. CONCLUSION: Low PA in children is related to clustering of risk factors for fracture, and the pre-pubertal years seem to be a period when PA positively affects the composite score.

Increased risk of hip fracture among spouses-evidence of a homogamy effect.

Spouses tend to share habits and therefore have an increased risk of same diseases. We followed all married couples in Sweden, born 1902 to 1942, in hospital records from 1987 to 2002, and found that individuals whose spouse had a hip fracture had an increased risk of hip fracture. INTRODUCTION: The purpose of this study was to determine whether spouses of hip fracture patients have an elevated risk of hip fracture. METHODS: We performed a retrospective cohort study of all couples married for at least 5 years in Sweden and born between 1902 and 1942 (n = 904,451) and all patients registered with a hip fracture (n = 218,285) in the National Inpatients Register in Sweden from 1987 to 2002. RESULTS: During the period 1987 to 2002 hip fractures occurred among spouses in 4212 married couples. The hazard ratio (HR) for hip fracture in a married woman following hip fracture in the husband was 1.11 (95 % confidence interval 1.07 to 1.16) compared to a woman whose husband did not have hip fracture. The corresponding HR for a married man was 1.20 (1.15 to 1.26) compared to a man whose wife did not have hip fracture. The risk was significantly elevated over the age range 60 to 90 years. The increased risk for hip fracture among spouses remained after adjustments for income, education, geographical latitude and urbanisation. In a common model with spouses and their siblings, the HR for spousal effect were 1.63 (1.01 to 2.64) and for sibling effect 2.18 (1.55 to 3.06) compared to married with spouse and sibling respectively without hip fracture. CONCLUSION: The novel finding of an increased risk for hip fracture among spouses provides evidence indicating that there is a homogamy effect due to common social and lifestyle factors but could also be due to assortative mating.

Model averaging for robust assessment of QT prolongation by concentration-response analysis.

Assessing the QT prolongation potential of a drug is typically done based on pivotal safety studies called thorough QT studies. Model-based estimation of the drug-induced QT prolongation at the estimated mean maximum drug concentration could increase efficiency over the currently used intersection-union test. However, robustness against model misspecification needs to be guaranteed in pivotal settings. The objective of this work was to develop an efficient, fully prespecified model-based inference method for thorough QT studies, which controls the type I error and provides satisfactory test power. This is achieved by model averaging: The proposed estimator of the concentration-response relationship is a weighted average of a parametric (linear) and a nonparametric (monotonic I-splines) estimator, with weights based on mean integrated square error. The desired properties of the method were confirmed in an extensive simulation study, which demonstrated that the proposed method controlled the type I error adequately, and that its power was higher than the power of the nonparametric method alone. The method can be extended from thorough QT studies to the analysis of QT data from pooled phase I studies.

Preventing sickness absenteeism among employees with common mental disorders or stress-related symptoms at work: Design of a cluster randomized controlled trial of a problem-solving based intervention versus care-as-usual conducted at the Occupational Health Services.

BACKGROUND: Common mental disorders (CMDs) are among the leading causes of sick leave in Sweden and other OECD countries. They result in suffering for the individual and considerable financial costs for the employer and for society at large. The occupational health service (OHS) can offer interventions in which both the individual and the work situation are taken into account. The aim of this paper is to describe the design of a study evaluating the effectiveness of an intervention given at the OHS to employees with CMDs or stress-related symptoms at work. In addition, intervention fidelity and its relation to the outcome will be assessed in a process analysis. METHODS: The study is designed as a cluster randomized trial in which the participating OHS consultants are randomized into either delivering the intervention or performing care as usual. Employees with CMDs or stress-related symptoms at work are recruited consecutively by the OHS consultants. The intervention aims to improve the match between the employee and the job situation. Interviews are held individually with the employee and the nearest supervisor, after which a joint meeting with both the employee and the supervisor takes place. A participatory approach is applied by which the supervisor and the employee are guided by the OHS consultant and encouraged to actively take part in problem solving concerning the work situation. Outcomes will be assessed at baseline and at six and 12 months. A long-term follow-up at 3 years will also be performed. The primary outcome is registered sickness absence during a 1-year period after study inclusion. Secondary outcomes are mental health and work ability. The intervention's cost effectiveness, compared to treatment as usual, both for society and for the employer will be evaluated. A process evaluation by both the OHS consultants and the employee will be carried out. DISCUSSION: The study includes analyses of the effectiveness of the intervention (clinical and economic) as well as an analysis of its implementation at the participating OHSs. Possible methodological challenges such as selection bias and risk of contamination between OHS consultants delivering the experimental condition and consultants giving usual care are discussed. TRIAL REGISTRATION: ClinicalTrials NCT02563743 Sep 28 2015.

Low serum vitamin D is associated with higher cortical porosity in elderly men.

BACKGROUND: Bone loss at peripheral sites in the elderly is mainly cortical and involves increased cortical porosity. However, an association between bone loss at these sites and 25-hydroxyvitamin D has not been reported. OBJECTIVE: To investigate the association between serum levels of 25-hydroxyvitamin D, bone microstructure and areal bone mineral density (BMD) in elderly men. METHODS: A population-based cohort of 444 elderly men (mean ± SD age 80.2 ± 3.5 years) was investigated. Bone microstructure was measured by high-resolution peripheral quantitative computed tomography, areal BMD by dual-energy X-ray absorptiometry and serum 25-hydroxyvitamin D and parathyroid hormone levels by immunoassay. RESULTS: Mean cortical porosity at the distal tibia was 14.7% higher (12.5 ± 4.3% vs. 10.9 ± 4.1%, P < 0.05) whilst cortical volumetric BMD, area, trabecular bone volume fraction and femoral neck areal BMD were lower in men in the lowest quartile of vitamin D levels compared to the highest. In men with vitamin D deficiency (<25 nmol L-1 ) or insufficiency [25-49 nmol L-1 , in combination with an elevated serum level of parathyroid hormone (>6.8 pmol L-1 )], cortical porosity was 17.2% higher than in vitamin D-sufficient men (P < 0.01). A linear regression model including age, weight, height, daily calcium intake, physical activity, smoking vitamin D supplementation and parathyroid hormone showed that 25-hydroxyvitamin D independently predicted cortical porosity (standardized ß = -0.110, R2 = 1.1%, P = 0.024), area (ß = 0.123, R2 = 1.4%, P = 0.007) and cortical volumetric BMD (ß = 0.125, R2 = 1.4%, P = 0.007) of the tibia as well as areal BMD of the femoral neck (ß = 0.102, R2 = 0.9%, P = 0.04). CONCLUSION: Serum vitamin D is associated with cortical porosity, area and density, indicating that bone fragility as a result of low vitamin D could be due to changes in cortical bone microstructure and geometry.

High plasma osteocalcin is associated with low blood haemoglobin in elderly men: the MrOS Sweden Study.

BACKGROUND: It has been suggested that osteoblasts are involved in the regulation of haematopoietic stem cells. Whether osteocalcin, which is derived from osteoblasts and is metabolically active, influences blood haemoglobin (Hb) levels is not known. OBJECTIVE: To determine whether plasma osteocalcin is a determinant of Hb in elderly men. METHODS: A total of 993 men (mean age 75.3 ± 3.2 years) participated in the population-based MrOS (osteoporotic fractures in men) study. Plasma osteocalcin concentration was evaluated in relation to Hb and adjustments were made for potential confounders (i.e. age, body mass index, erythropoietin, total oestradiol, fasting insulin, adiponectin, ferritin and cystatin C). RESULTS: Hb correlated (age adjusted) negatively with osteocalcin in the total study group (r = -0.12, P < 0.001) as well as in the subgroup of nondiabetic men (r = -0.16, P < 0.001). In nondiabetic men with higher osteocalcin levels, it was more likely that Hb would be in the lowest quartile (odds ratio per SD decrease in osteocalcin 1.32, 95% confidence interval 1.13-1.53). Quartiles of Hb were negatively associated (age adjusted) with osteocalcin (P < 0.001). Anaemic men (47/812) (Hb <130 g L(-1) ) had significantly higher mean osteocalcin levels than nonanaemic men (33.9 vs. 27.1 µg L(-1) , P < 0.001). In multiple stepwise linear regression analyses (adjusted for age, body mass index, total oestradiol, adiponectin, erythropoietin, fasting insulin, cystatin C, leptin, ferritin and holotranscobalamin), osteocalcin was an independent predictor of Hb concentration in nondiabetic men (P < 0.05). CONCLUSIONS: These data add further support to the evidence indicating that the bone-specific protein osteocalcin has several endocrine functions targeting the pancreas, testes, adipocytes, brain. An additional novel finding is that osteocalcin may also have a paracrine function as a regulator of haematopoiesis.