Does the association between adiposity measures and pre-frailty among older adults vary by social position? Findings from the Tromsø study 2015/2016.

INTRODUCTION: Pre-frailty provides an ideal opportunity to prevent physical frailty and promote healthy ageing. Excess adiposity has been associated with an increased risk of pre-frailty, but limited studies have explored whether the association between adiposity measures and pre-frailty varies by social position. METHODS: We used data from the seventh survey of the Tromsø Study (Tromsø7) conducted in 2015-2016. Our primary sample consisted of 2,945 women and 2,794 men aged ≥ 65 years. Pre-frailty was defined as the presence of one or two of the five frailty components: low grip strength, slow walking speed, exhaustion, unintentional weight loss and low physical activity. Adiposity was defined by body mass index (BMI), waist circumference (WC), fat mass index (FMI) and visceral adipose tissue (VAT) mass. Education and subjective social position were used as measures of social position. Poisson regression with robust variance was used to assess the association between adiposity measures and pre-frailty, and the interaction term between adiposity measures and social position measures were utilised to explore whether the association varied by social position. RESULTS: In our sample, 28.7% of women and 25.5% of men were pre-frail. We found sub-multiplicative interaction of BMI-defined obesity with education in women and subjective social position in men with respect to development of pre-frailty. No other adiposity measures showed significant variation by education or subjective social position. Regardless of the levels of education or subjective social position, participants with excess adiposity (high BMI, high WC, high FMI and high VAT mass) had a higher risk of pre-frailty compared to those with low adiposity. CONCLUSION: We consistently observed that women and men with excess adiposity had a greater risk of pre-frailty than those with low adiposity, with only slight variation by social position. These results emphasize the importance of preventing excess adiposity to promote healthy ageing and prevent frailty among all older adults across social strata.

Dietary sulfur amino acid restriction in humans with overweight and obesity: Evidence of an altered plasma and urine sulfurome, and a novel metabolic signature that correlates with loss of fat mass and adipose tissue gene expression.

BACKGROUND: In animals, dietary sulfur amino acid restriction (SAAR) improves metabolic health, possibly mediated by altering sulfur amino acid metabolism and enhanced anti-obesogenic processes in adipose tissue. AIM: To assess the effects of SAAR over time on the plasma and urine SAA-related metabolites (sulfurome) in humans with overweight and obesity, and explore whether such changes were associated with body weight, body fat and adipose tissue gene expression. METHODS: Fifty-nine subjects were randomly allocated to SAAR (∼2 g SAA, n = 31) or a control diet (∼5.6 g SAA, n = 28) consisting of plant-based whole-foods and supplemented with capsules to titrate contents of SAA. Sulfurome metabolites in plasma and urine at baseline, 4 and 8 weeks were measured using HPLC and LC-MS/MS. mRNA-sequencing of subcutaneous white adipose tissue (scWAT) was performed to assess changes in gene expression. Data were analyzed with mixed model regression. Principal component analyses (PCA) were performed on the sulfurome data to identify potential signatures characterizing the response to SAAR. RESULTS: SAAR led to marked decrease of the main urinary excretion product sulfate (p < 0.001) and plasma and/or 24-h urine concentrations of cystathionine, sulfite, thiosulfate, H2S, hypotaurine and taurine. PCA revealed a distinct metabolic signature related to decreased transsulfuration and H2S catabolism that predicted greater weight loss and android fat mass loss in SAAR vs. controls (all pinteraction < 0.05). This signature correlated positively with scWAT expression of genes in the tricarboxylic acid cycle, electron transport and ß-oxidation (FDR = 0.02). CONCLUSION: SAAR leads to distinct alterations of the plasma and urine sulfurome in humans, and predicted increased loss of weight and android fat mass, and adipose tissue lipolytic gene expression in scWAT. Our data suggest that SAA are linked to obesogenic processes and that SAAR may be useful for obesity and related disorders. TRIAL IDENTIFIER: https://clinicaltrials.gov/study/NCT04701346.

A heavy-tailed model for analyzing miRNA-seq raw read counts.

This article addresses the limitations of existing statistical models in analyzing and interpreting highly skewed miRNA-seq raw read count data that can range from zero to millions. A heavy-tailed model using discrete stable distributions is proposed as a novel approach to better capture the heterogeneity and extreme values commonly observed in miRNA-seq data. Additionally, the parameters of the discrete stable distribution are proposed as an alternative target for differential expression analysis. An R package for computing and estimating the discrete stable distribution is provided. The proposed model is applied to miRNA-seq raw counts from the Norwegian Women and Cancer Study (NOWAC) and the Cancer Genome Atlas (TCGA) databases. The goodness-of-fit is compared with the popular Poisson and negative binomial distributions, and the discrete stable distributions are found to give a better fit for both datasets. In conclusion, the use of discrete stable distributions is shown to potentially lead to more accurate modeling of the underlying biological processes.

Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial.

BACKGROUND: Dietary sulfur amino acid restriction (SAAR) improves metabolic health in animals. In this study, we investigated the effect of dietary SAAR on body weight, body composition, resting metabolic rate, gene expression profiles in white adipose tissue (WAT), and an extensive blood biomarker profile in humans with overweight or obesity. METHODS: N = 59 participants with overweight or obesity (73% women) were randomized stratified by sex to an 8-week plant-based dietary intervention low (~ 2 g/day, SAAR) or high (~ 5.6 g/day, control group) in sulfur amino acids. The diets were provided in full to the participants, and both investigators and participants were blinded to the intervention. Outcome analyses were performed using linear mixed model regression adjusted for baseline values of the outcome and sex. RESULTS: SAAR led to a ~ 20% greater weight loss compared to controls (ß 95% CI - 1.14 (- 2.04, - 0.25) kg, p = 0.013). Despite greater weight loss, resting metabolic rate remained similar between groups. Furthermore, SAAR decreased serum leptin, and increased ketone bodies compared to controls. In WAT, 20 genes were upregulated whereas 24 genes were downregulated (FDR < 5%) in the SAAR group compared to controls. Generally applicable gene set enrichment analyses revealed that processes associated with ribosomes were upregulated, whereas processes related to structural components were downregulated. CONCLUSION: Our study shows that SAAR leads to greater weight loss, decreased leptin and increased ketone bodies compared to controls. Further research on SAAR is needed to investigate the therapeutic potential for metabolic conditions in humans. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04701346, registered Jan 8th 2021, https://www. CLINICALTRIALS: gov/study/NCT04701346.

Euthanasia of animals - association with veterinarians' suicidal thoughts and attitudes towards assisted dying in humans: a nationwide cross-sectional survey (the NORVET study).

BACKGROUND: Veterinarians are an occupational group with an increased suicide risk. Euthanasing animals may influence both veterinarians' views on assisted dying in humans and their suicide risk. We investigated (I) attitudes towards assisted dying, (II) whether the field of work and the frequency of euthanasing animals were associated with positive attitudes towards human euthanasia, and (III) whether frequently euthanasing animals was associated with serious suicidal thoughts. METHODS: We conducted a nationwide cross-sectional study among veterinarians in Norway (response rate: 75%). Logistic regression models were used to calculate the odds ratios for both positive attitudes towards human euthanasia and serious suicidal thoughts. The analyses were adjusted for socio-demographic and work-related factors. RESULTS: Fifty-five percent of the veterinarians agreed that euthanasia should be permitted for humans with a fatal disease and short life expectancy. Working with companion animals was independently associated with positive attitudes towards human euthanasia (OR = 1.66 (95% CI: 1.23-2.23)), while veterinarians' frequency of euthanasing animals was not. Frequency of euthanasing animals was independently associated with serious suicidal thoughts, OR = 2.56 (95% CI: 1.35-4.87). CONCLUSIONS: Veterinarians' attitudes towards assisted dying in humans did not differ from those of the general population. Veterinarians' frequency of euthanasing animals was not associated with positive attitudes towards euthanasia in humans. However, veterinarians working in companion animal practices were more likely to have positive attitudes towards euthanasia in humans. Moreover, euthanising animals five times or more a week was associated with serious suicidal thoughts. We need more research to infer about causality in these findings.

Fish intake and pre-frailty in Norwegian older adults - a prospective cohort study: the Tromsø Study 1994-2016.

BACKGROUND: Pre-frailty is an intermediate, potentially reversible state before the onset of frailty. Healthy dietary choices may prevent pre-frailty. Fish is included in most healthy diets, but little is known about the association between long-term habitual fish intake and pre-frailty. We aimed to elucidate the longitudinal association between the frequency of fish intake and pre-frailty in a cohort of older adults in Norway. METHODS: 4350 participants (52% women, ≥65 years at follow-up) were included in this prospective cohort study. Data was obtained from three waves of the population-based Tromsø Study in Norway; Tromsø4 (1994-1995), Tromsø6 (2007-2008) and Tromsø7 (follow-up, 2015-2016). Frailty status at follow-up was defined by a modified version of Fried's phenotype. Fish intake was self-reported in the three surveys and assessed as three levels of frequency of intake: low (0-3 times/month), medium (1-3 times/week) and high (≥ 4 times/week). The fish-pre-frailty association was analysed using multivariable logistic regression in two ways; (1) frequency of intake of lean, fatty and total fish in Tromsø6 and pre-frailty at follow-up, and (2) patterns of total fish intake across the three surveys and pre-frailty at follow-up. RESULTS: At follow-up, 28% (n = 1124) were pre-frail. Participants with a higher frequency of lean, fatty and total fish intake had 28% (odds ratio (OR) = 0.72, 95% confidence interval (CI) = 0.53, 0.97), 37% (OR = 0.63, 95% CI = 0.43, 0.91) and 31% (OR = 0.69, 95% CI = 0.52, 0.91) lower odds of pre-frailty 8 years later compared with those with a low intake, respectively. A pattern of stable high fish intake over 21 years was associated with 41% (OR = 0.59, 95% CI = 0.38, 0.91) lower odds of pre-frailty compared with a stable low intake. CONCLUSIONS: A higher frequency of intake of lean, fatty and total fish, and a pattern of consistent frequent fish intake over time, were associated with lower odds of pre-frailty in older community-dwelling Norwegian adults. These results emphasise the important role of fish in a healthy diet and that a frequent fish intake should be promoted to facilitate healthy ageing.

Maternal prenatal cholesterol levels predict offspring weight trajectories during childhood in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: Numerous intrauterine factors may affect the offspring's growth during childhood. We aimed to explore if maternal and paternal prenatal lipid, apolipoprotein (apo)B and apoA1 levels are associated with offspring weight, length, and body mass index from 6 weeks to eight years of age. This has previously been studied to a limited extent. METHODS: This parental negative control study is based on the Norwegian Mother, Father and Child Cohort Study and uses data from the Medical Birth Registry of Norway. We included 713 mothers and fathers with or without self-reported hypercholesterolemia and their offspring. Seven parental metabolites were measured by nuclear magnetic resonance spectroscopy, and offspring weight and length were measured at 12 time points. Data were analyzed by linear spline mixed models, and the results are presented as the interaction between parental metabolite levels and offspring spline (age). RESULTS: Higher maternal total cholesterol (TC) level was associated with a larger increase in offspring body weight up to 8 years of age (0.03 ≤ Pinteraction ≤ 0.04). Paternal TC level was not associated with change in offspring body weight (0.17 ≤ Pinteraction ≤ 0.25). Higher maternal high-density lipoprotein cholesterol (HDL-C) and apoA1 levels were associated with a lower increase in offspring body weight up to 8 years of age (0.001 ≤ Pinteraction ≤ 0.005). Higher paternal HDL-C and apoA1 levels were associated with a lower increase in offspring body weight up to 5 years of age but a larger increase in offspring body weight from 5 to 8 years of age (0.01 ≤ Pinteraction ≤ 0.03). Parental metabolites were not associated with change in offspring height or body mass index up to 8 years of age (0.07 ≤ Pinteraction ≤ 0.99). CONCLUSIONS: Maternal compared to paternal TC, HDL-C, and apoA1 levels were more strongly and consistently associated with offspring body weight during childhood, supporting a direct intrauterine effect.

Research Integrity Attitudes and Behaviors are Difficult to alter: Results from a ten Year Follow-up Study in Norway.

Background: Research integrity has obtained much attention in research communities, but also in the general public. To improve research integrity is difficult as it involves complex systems of knowledge, attitudes, and practices. The objective of this study is to investigate the knowledge, attitudes, and practices of cohorts of PhD candidates at one faculty (of medicine) over time and compare this to finished PhDs of the same cohorts. Material and method: Researchers (n = 186) awarded the degree PhD at the Faculty of Medicine at the University of Oslo in 2019 were invited to answer a questionnaire about knowledge, attitudes and actions related to scientific dishonesty. 94 responded (50.5%). The results were compared with results among first-year PhD candidates who responded to the same questionnaire during 2010-20 (n = 536) and to those who finished PhDs in 2016 (n = 86). Results: For the years 2010-2020 1.1% of the PhD candidates report to have engaged in severe scientific misconduct (FFP) while 0.9% report to have presented results in a misleading way. 2.3% report that they know of persons at their department who have engaged in FFP the last 12 months. In total 1.5% report to have experienced pressure to engage in severe scientific misconduct (FFP) while 2.1% report to have experienced pressure to present results in a misleading way. On average 12.8% report to have been exposed to unethical pressure concerning inclusion or ordering of authors during the last 12 months, and 28.8% report to have knowledge about their department's written policies about research integrity. While some attitudes improve over the years, attitudes in general are not much changed from 2010-2020. None of the PhDs that received a PhD from the Faculty of Medicine at the University of Oslo in 2019 reported to have engaged in FFT or having experienced pressure to do so.1.1% experienced pressure to present results in other misleading ways, while 26.6% of respondents had experienced unethical pressure in relation to authorship during the course of the PhD fellowship. 4.3% knew about someone at their department who had presented results in a misleading manner. Some attitudes were not in line with traditional conceptions of research integrity, but most agreed that their research environment displayed research integrity. Conclusion: This long-term follow up study shows that few PhD-candidates report to engage in severe scientific misconduct, that they experience little pressure to do so, and with some exceptions, attitudes in in line with good research integrity. However, pressure in relation to authorship is relatively common. There is some improvement in research integrity from PhD candidates to recently finished PhDs, but in general research integrity is stable over time.

Stability of distinct symptom experiences in patients with chronic obstructive pulmonary disease (COPD).

PURPOSE: This study aimed to examine reclassification rates among classes of chronic obstructive pulmonary disease (COPD) patients based on their distinct symptom experiences and to assess how these subgroups differed in symptom scores and health-related quality of life (HRQoL) outcomes over one year. Moreover, we wished to assess how these subgroups differed in demographic and clinical characteristics at 12 months. PATIENTS AND METHODS: This is a follow-up study of 267 patients with moderate, severe, and very severe COPD. Based on their distinct symptom experiences using the Memorial Symptom Assessment Scale (MSAS), three subgroups (i.e., "high", "intermediate", and "low") were identified at baseline. In the present study, transitions between the subgroups at three, six, nine, and 12 months were investigated and calculated as reclassification rates. Differences among the subgroups in symptom scores and HRQoL at each time point and demographic and clinical characteristics at 12 months were evaluated using analysis of variance with post hoc comparisons. RESULTS: Almost 65% were still in the "high" class after 12 months. At 12 months, pairwise comparisons for respiratory function measurements were not significantly different. Compared to the "intermediate" and "low" class, patients in the "high" class were more likely to be women and had significantly more comorbidities, reported a significantly higher number of symptoms at all time points, and worse HRQoL scores. CONCLUSION: Our findings suggest that the pattern of a high symptom burden in COPD is consistent over time. The patients' individual symptom experiences should be the primary focus of treatment.

Mortality, Causes of Death, and Predictors of Death among Patients On and Off Opioid Agonist Treatment: Results from a 19-Year Cohort Study.

BACKGROUND: Mortality is increased among people with opioid use disorder but reduced while on opioid agonist treatment (OAT). However, the impact of patient and treatment characteristics on mortality and causes of death is insufficiently studied. OBJECTIVES: The objective of this study was to explore mortality and causes of death and examine the impact of patient and treatment characteristics on mortality in an OAT cohort with high retention in treatment. METHODS: Design: longitudinal cohort study. SETTING: Norway. Observation period: time from OAT start as of 1998 until death or end of 2016, 2,508 person-years (PY) in total. SAMPLE: 200 persons starting OAT 1998-2007. DATA SOURCES: hospital records, interviews, the Norwegian Cause of Death Registry, Statistics Norway. RESULTS: Retention: 86.4% of the observation period was on OAT, 9.0% off, 4.6% unknown OAT status. All-cause crude mortality rate per 100 PY during the whole observation period was 1.64 (95% CI: 1.19-2.20), for deaths of somatic cause 0.88 (0.56-1.31), for drug-induced deaths 0.44 (0.23-0.76), and traumatic deaths 0.24 (0.10-0.50). Off-versus-on-OAT all-cause mortality ratio was 2.31 (1.00-4.85). On OAT, 58% of the deaths were of somatic cause and 21% drug-induced; off OAT, 38% of somatic cause and 50% drug-induced. Increasing baseline age and rate of somatic hospital treatment episodes were independently associated with increased all-cause mortality risk, while increasing rate of in-patient psychiatric treatment episodes was associated with reduced risk. Increasing duration of nicotine and cannabis use and alcohol dependence as well as increasing severity of polydrug use were associated with increased all-cause and somatic mortality adjusted for age and sex. CONCLUSION: The long observation period made it possible to demonstrate the importance of long-term retention in OAT to reduce mortality. Further, the preponderance of somatic and reduction of drug-induced causes of death during OAT underlines the need for follow-up of chronic diseases and health-promoting lifestyle changes. These findings add to the knowledge about long-term OAT effects, not least in ageing OAT populations.

Pre-diagnostic DNA methylation in blood leucocytes in cutaneous melanoma; a nested case-control study within the Norwegian Women and Cancer cohort.

The prognosis of cutaneous melanoma depends on early detection, and good biomarkers for melanoma risk may provide a valuable tool to detect melanoma development at a pre-clinical stage. By studying the epigenetic profile in pre-diagnostic blood samples of melanoma cases and cancer free controls, we aimed to identify DNA methylation sites conferring melanoma risk. DNA methylation was measured at 775,528 CpG sites using the Illumina EPIC array in whole blood in incident melanoma cases (n = 183) and matched cancer-free controls (n = 183) in the Norwegian Women and Cancer cohort. Phenotypic information and ultraviolet radiation exposure were obtained from questionnaires. Epigenome wide association (EWAS) was analyzed in future melanoma cases and controls with conditional logistic regression, with correction for multiple testing using the false discovery rate (FDR). We extended the analysis by including a public data set on melanoma (GSE120878), and combining these different data sets using a version of covariate modulated FDR (AdaPT). The analysis on future melanoma cases and controls did not identify any genome wide significant CpG sites (0.85 ≤ padj ≤ 0.99). In the restricted AdaPT analysis, 7 CpG sites were suggestive at the FDR level of 0.15. These CpG sites may potentially be used as pre-diagnostic biomarkers of melanoma risk.

Professional help-seeking behaviour for mental health problems among veterinarians in Norway: a nationwide, cross-sectional study (The NORVET study).

BACKGROUND: Veterinarians have a relatively high prevalence of mental health problems; however, research on professional help-seeking is limited. The main purpose of the present study was to investigate the prevalence of mental health problems and professional help-seeking behaviour for such problems, and the independent factors associated with help-seeking behaviour among veterinarians in Norway. METHOD: This cross-sectional study included all veterinarians in Norway (response rate 75%, 70% women). Logistic regression was used to calculate odds ratios (OR) for professional help-seeking for mental health problems. Analyses were controlled for socio-demographic, individual (personality trait reality weakness, SCL-5, attitudes toward mental illness), and work-related factors (work field, job stress). RESULTS: The prevalence of self-reported mental health problems in need of treatment was 30% (746/2494), significantly higher among women than men (36% vs. 15%). Fifty-four percent had sought professional help, women significantly more often (56%) than men (41%). Among veterinarians with serious suicidal thoughts, 50% (69/139) had sought help. Veterinarians most frequently related mental health problems to work problems (47%), women significantly more often (49%) than men (34%). Factors significantly associated with help-seeking were being female, OR = 2.11 (95% CI: 1.24-3.60), working with production animals, OR = 0.35 (0.13-0.98), public administration, OR = 2.27 (1.15-4.45), academia/research, OR = 4.78 (1.99-11.47) or 'other' fields, OR = 2.79 (1.23-6.32), and attitudes toward mental illness, OR = 1.32 (1.03-1.68). CONCLUSIONS: Thirty percent of veterinarians in Norway reported mental health problems in need of treatment, and only half of them had sought professional help. A low degree of help-seeking was also seen among those with serious suicidal thoughts. Being female, positive attitudes toward treatment of mental illness, working in public administration, academia/research and 'other' field were associated with more help-seeking, while working in production animal practice was associated with less help-seeking. Interventions to increase help-seeking behaviour for mental health problems among veterinarians are warranted.

Videoconferencing in Pressure Injury: Randomized Controlled Telemedicine Trial in Patients With Spinal Cord Injury.

BACKGROUND: Geographical, financial and travel-related barriers may impact access to necessary health care for people in need of long-term follow-up. OBJECTIVE: The goal of the research was to perform a nonblinded, randomized, controlled trial on health-related quality of life (HRQoL), healing, interaction, and satisfaction of patients with spinal cord injury (SCI) and PI receiving multidisciplinary videoconference consultations from a wound clinic to the participant's home versus regular outpatient care. The multidisciplinary team consisted of a medical doctor, a wound nurse, and an occupational therapist. In both groups, district nurses attended the consultations at the participant's home. METHODS: A total of 56 participants, 28 in each group, were randomized to a videoconference group (VCG) or a regular care group (RCG). Validated questionnaires were used to measure and compare the follow-up effect on HRQoL. Percentage reduction of wound volume was measured at end of the follow-up. A Likert scale was used to measure the satisfaction of the patients and district nurses regarding the interaction between different modalities of care in the 2 groups. RESULTS: The HRQoL did not show significant differences between the 2 groups (P values ranging from .09 to .88) or the rate of PI healing, experienced interaction, and satisfaction in the groups. A total of 67% (37/55) of all PIs healed, 64% (18/28) in the VCG and 70% (19/27) in the RCG. Mean reduction in ulcer volume was 79% in the VCG and 85% in the RCG (P=.32). A Kaplan-Meier plot with a logrank test regarding time to healing did not show any significant difference between the 2 groups. CONCLUSIONS: Videoconference-based care seems to be a safe and efficient way to manage PIs in terms of HRQoL, healing, interaction, and satisfaction compared to conventional care for people with SCI. This should be considered when planning for future care. SCI has a huge impact on the individual, the family, and the health care system. There is an urgent need to improve systems of care so that individuals who live far from specialists and require long-term follow-up for conditions such as PI can get optimal treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02800915; https://clinicaltrials.gov/ct2/show/NCT02800915 and Current Research Information System in Norway (CRISTIN) 545284; https://app.cristin.no/projects/show.jsf?id=545284.

On optimal two-stage testing of multiple mediators.

Mediation analysis in high-dimensional settings often involves identifying potential mediators among a large number of measured variables. For this purpose, a two-step familywise error rate procedure called ScreenMin has been recently proposed. In ScreenMin, variables are first screened and only those that pass the screening are tested. The proposed data-independent threshold for selection has been shown to guarantee asymptotic familywise error rate. In this work, we investigate the impact of the threshold on the finite-sample familywise error rate. We derive a power maximizing threshold and show that it is well approximated by an adaptive threshold of Wang et al. (2016, arXiv preprint arXiv:1610.03330). We illustrate the investigated procedures on a case-control study examining the effect of fish intake on the risk of colorectal adenoma. We also apply our procedure in the context of replicability analysis to identify single nucleotide polymorphisms (SNP) associated with crop yield in two distinct environments.

Effects of patient-level risk factors, departmental allocation and seasonality on intrahospital patient transfer patterns: network analysis applied on a Norwegian single-centre data set.

OBJECTIVES: Describe patient transfer patterns within a large Norwegian hospital. Identify risk factors associated with a high number of transfers. Develop methods to monitor intrahospital patient flows to support capacity management and infection control. DESIGN: Retrospective observational study of linked clinical data from electronic health records. SETTING: Tertiary care university hospital in the Greater Oslo Region, Norway. PARTICIPANTS: All adult (≥18 years old) admissions to the gastroenterology, gastrointestinal surgery, neurology and orthopaedics departments at Akershus University Hospital, June 2018 to May 2019. METHODS: Network analysis and graph theory. Poisson regression analysis. OUTCOME MEASURES: Primary outcome was network characteristics at the departmental level. We describe location-to-location transfers using unweighted, undirected networks for a full-year study period. Weekly networks reveal changes in network size, density and key categories of transfers over time. Secondary outcome was transfer trajectories at the individual patient level. We describe the distribution of transfer trajectories in the cohort and associate number of transfers with patient clinical characteristics. RESULTS: The cohort comprised 17 198 hospital stays. Network analysis demonstrated marked heterogeneity across departments and throughout the year. The orthopaedics department had the largest transfer network size and density and greatest temporal variation. More transfers occurred during weekdays than weekends. Summer holiday affected transfers of different types (Emergency department-Any location/Bed ward-Bed ward/To-From Technical wards) differently. Over 75% of transferred patients followed one of 20 common intrahospital trajectories, involving one to three transfers. Higher number of intrahospital transfers was associated with emergency admission (transfer rate ratio (RR)=1.827), non-prophylactic antibiotics (RR=1.108), surgical procedure (RR=2.939) and stay in intensive care unit or high-dependency unit (RR=2.098). Additionally, gastrosurgical (RR=1.211), orthopaedic (RR=1.295) and neurological (RR=1.114) patients had higher risk of many transfers than gastroenterology patients (all effects: p<0.001). CONCLUSIONS: Network and transfer chain analysis applied on patient location data revealed logistic and clinical associations highly relevant for hospital capacity management and infection control.

Cardiovascular risk factors in extended family members and birthweight in offspring.

Low birthweight has been related to an increased risk of adult cardiovascular disease (CVD). Transgenerational studies have been used to investigate likely mechanisms underlying this inverse association. However, previous studies mostly examined the association of offspring birthweight with CVD risk factors among parents. In this study, we investigated the association between offspring birthweight and individual CVD risk factors, an index of CVD risk factors, and education in their parents, aunts/uncles, and aunts'/uncles' partners. Birth data (Medical Birth Registry, Norway (MBRN) (1967-2012)) was linked to CVD risk factor data (the County Study, Age 40 Program, and Cohort Norway (CONOR)) for the parents, aunts/uncles, and their partners. For body mass index (BMI), resting heart rate (RHR), systolic blood pressure (SBP), total cholesterol (TC), triglycerides (TG), and a risk factor index, the associations were examined by linear regression. For smoking and education, they were examined by logistic regression. Low birthweight was associated with an unfavorable risk factor profile in all familial relationships. For each kg increase in birthweight, the mean risk factor index decreased by -0.14 units (-0.15, -0.13) in mothers, -0.11 (-0.12, -0.10) in fathers, and -0.02 (-0.05, -0.00) to -0.07 (-0.09, -0.06) in aunts/uncles and their partners. The association in mothers was stronger than fathers, but it was also stronger in aunts/uncles than their partners. Profound associations between birthweight and CVD risk factors in extended family members were observed that go beyond the expected genetic similarities in pedigrees, suggesting that mechanisms like environmental factors, assortative mating, and genetic nurturing may explain these associations.

Bilberry/red grape juice decreases plasma biomarkers of inflammation and tissue damage in aged men with subjective memory impairment -a randomized clinical trial.

BACKGROUND: Few randomized clinical trials have explored the health effects of bilberries in humans. The aim was to test the effect of bilberry and red grape-juice consumption on visual memory, motor speed and dexterity as well as inflammatory and tissue damage biomarkers of plasma in aged men with subjective memory impairment. METHODS: Nine-week double-blind, placebo-controlled, dietary intervention study of aged men (n = 60, age ≥ 67 years) with subjective memory impairment randomized to consume a 50/50 mix of bilberry/red grape-juice or an iso-caloric placebo juice. A selection of Cambridge Cognition Test Battery (CANTAB), Grooved Pegboard tests and blood-sampling for biomarker analysis were performed before and after the intervention. RESULTS: Compared to placebo the selected memory and motor test scores were un-affected by the bilberry/red grape intervention. However, the plasma levels of tissue damage biomarkers decreased significantly more in the bilberry/red grape group. In particular lactate dehydrogenase (LDH) decreased from 362 U/L (median, baseline) to 346 U/L (median, post intervention) in the bilberry/red grape group. Also, several biomarkers of inflammation (EGF, IL6, IL9, IL10 and TNFα) decreased significantly more in the bilberry/red grape group. Furthermore, several plasma polyphenols; p-coumaric acid, hippuric acid, protocatechuic acid, 3HPAA and vanillic acid, increased significantly more in the bilberry/red grape group compared to placebo with the largest increase in p-coumaric acid with 116%; from 2.2 [1.0,5.5] to 4.7 [2.8,8.1] µM/L (median [95% CL]). CONCLUSIONS: The results indicate that a nine-week bilberry/red grape juice intervention has no measurable effects on the selected memory scores in aged men experiencing memory problems but decreases the level of biomarkers of inflammation and tissue damage. Whether the dampening effects on inflammation and tissue damage biomarkers have relevance for neuroinflammatory brain pathology remains to be established. TRIAL REGISTRATION: Registration number ( ClinicalTrials.gov : NCT00972972 ), September 9, 2009.

Replacing Saturated Fat with Polyunsaturated Fat Modulates Peripheral Blood Mononuclear Cell Gene Expression and Pathways Related to Cardiovascular Disease Risk Using a Whole Transcriptome Approach.

SCOPE: The aim of this study is to explore the molecular mechanisms underlying the effect of replacing dietary saturated fat (SFA) with polyunsaturated fat (PUFA) on cardiovascular disease (CVD) risk using a whole transcriptome approach. METHODS AND RESULTS: Healthy subjects with moderate hypercholesterolemia (n = 115) are randomly assigned to a control diet (C-diet) group or an experimental diet (Ex-diet) group receiving comparable food items with different fatty acid composition for 8 weeks. RNA isolated from peripheral blood mononuclear cells (PBMCs) at baseline and after 8 weeks of intervention is analyzed by microarray technology (n = 95). By use of a linear regression model (n = 92), 14 gene transcripts are differentially altered in the Ex-diet group compared to the C-diet group. These include transcripts related to vascular smooth muscle cell proliferation, low-density lipoprotein receptor folding, and regulation of blood pressure. Furthermore, pathways mainly related to immune response and inflammation, signal transduction, development, and cytoskeleton remodeling, gene expression and protein function, are differentially enriched between the groups. CONCLUSION: Replacing dietary SFA with PUFA for 8 weeks modulates PBMC gene expression and pathways related to CVD risk in healthy subjects with moderate hypercholesterolemia.

Integrative, multi-omics, analysis of blood samples improves model predictions: applications to cancer.

BACKGROUND: Cancer genomic studies often include data collected from several omics platforms. Each omics data source contributes to the understanding of the underlying biological process via source specific ("individual") patterns of variability. At the same time, statistical associations and potential interactions among the different data sources can reveal signals from common biological processes that might not be identified by single source analyses. These common patterns of variability are referred to as "shared" or "joint". In this work, we show how the use of joint and individual components can lead to better predictive models, and to a deeper understanding of the biological process at hand. We identify joint and individual contributions of DNA methylation, miRNA and mRNA expression collected from blood samples in a lung cancer case-control study nested within the Norwegian Women and Cancer (NOWAC) cohort study, and we use such components to build prediction models for case-control and metastatic status. To assess the quality of predictions, we compare models based on simultaneous, integrative analysis of multi-source omics data to a standard non-integrative analysis of each single omics dataset, and to penalized regression models. Additionally, we apply the proposed approach to a breast cancer dataset from The Cancer Genome Atlas. RESULTS: Our results show how an integrative analysis that preserves both components of variation is more appropriate than standard multi-omics analyses that are not based on such a distinction. Both joint and individual components are shown to contribute to a better quality of model predictions, and facilitate the interpretation of the underlying biological processes in lung cancer development. CONCLUSIONS: In the presence of multiple omics data sources, we recommend the use of data integration techniques that preserve the joint and individual components across the omics sources. We show how the inclusion of such components increases the quality of model predictions of clinical outcomes.

A robust variable screening procedure for ultra-high dimensional data.

Variable selection in ultra-high dimensional regression problems has become an important issue. In such situations, penalized regression models may face computational problems and some pre-screening of the variables may be necessary. A number of procedures for such pre-screening has been developed; among them the Sure Independence Screening (SIS) enjoys some popularity. However, SIS is vulnerable to outliers in the data, and in particular in small samples this may lead to faulty inference. In this paper, we develop a new robust screening procedure. We build on the density power divergence (DPD) estimation approach and introduce DPD-SIS and its extension iterative DPD-SIS. We illustrate the behavior of the methods through extensive simulation studies and show that they are superior to both the original SIS and other robust methods when there are outliers in the data. Finally, we illustrate its use in a study on regulation of lipid metabolism.