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1.  Bone mineral density in patients with multiple sclerosis, hereditary ataxia or hereditary spastic paraplegia after at least 10 years of disease - a case control study 
BMC Neurology  2016;16:252.
Background
Although disability is considered the main cause of low bone mineral density (BMD) in multiple sclerosis (MS), other factors related to the disease process or treatment could also be involved. The aim of this study was to assess whether patients with MS are more likely to develop low BMD (osteopenia or osteoporosis) than patients with the non-inflammatory neurological diseases Hereditary Spastic Paraplegia (HSP) and Hereditary Ataxia (HA).
Methods
We performed a case control study comparing BMD (spine, hip and total body) and biochemical measures of bone metabolism in 91 MS patients and 77 patients with HSP or HA, matched for age, gender and disability. Both patient groups had lived with the disease for at least 10 years.
Results
In total 74.7% of the patients with MS and 75.3% of the patients with HSP or HA had osteopenia (−2.5 < T- score < −1.0) or osteoporosis (T- score ≤ −2.5) in one or more sites. Osteoporosis was more common in patients with MS than with HSP/HA (44.0 vs 20.8%, p =0.001). This difference was not significant after correction for confounders (p = 0.07), nor were any of the biochemical markers.
Conclusion
Most patients with disabling neurological diseases like MS and HSP/HA develop osteopenia or osteoporosis. MS patients had osteoporosis more frequently than HA/HSP patients, though the difference was not significant after adjusting for confounders. Osteoporosis and bone health should be considered in all patients with both inflammatory and degenerative chronic neurological diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-016-0771-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12883-016-0771-4
PMCID: PMC5139093  PMID: 27919248
Bone Mineral Density; Case control; Hereditary Ataxia; Hereditary Spastic Paraparesis; Multiple Sclerosis; Osteoporosis
2.  First quality score for referral letters in gastroenterology—a validation study 
BMJ Open  2016;6(10):e012835.
Objective
To create and validate an objective and reliable score to assess referral quality in gastroenterology.
Design
An observational multicentre study.
Setting and participants
25 gastroenterologists participated in selecting variables for a Thirty Point Score (TPS) for quality assessment of referrals to gastroenterology specialist healthcare for 9 common indications. From May to September 2014, 7 hospitals from the South-Eastern Norway Regional Health Authority participated in collecting and scoring 327 referrals to a gastroenterologist.
Main outcome measure
Correlation between the TPS and a visual analogue scale (VAS) for referral quality.
Results
The 327 referrals had an average TPS of 13.2 (range 1–25) and an average VAS of 4.7 (range 0.2–9.5). The reliability of the score was excellent, with an intra-rater intraclass correlation coefficient (ICC) of 0.87 and inter-rater ICC of 0.91. The overall correlation between the TPS and the VAS was moderate (r=0.42), and ranged from fair to substantial for the various indications. Mean agreement was good (ICC=0.47, 95% CI (0.34 to 0.57)), ranging from poor to good.
Conclusions
The TPS is reliable, objective and shows good agreement with the subjective VAS. The score may be a useful tool for assessing referral quality in gastroenterology, particularly important when evaluating the effect of interventions to improve referral quality.
doi:10.1136/bmjopen-2016-012835
PMCID: PMC5073635  PMID: 27855107
PRIMARY CARE
3.  Urine biomarkers give early prediction of acute kidney injury and outcome after out-of-hospital cardiac arrest 
Critical Care  2016;20:314.
Background
Post-resuscitation care after out-of-hospital cardiac arrest (OHCA) is challenging due to the threat of organ failure and difficult prognostication. Our aim was to examine whether urine biomarkers could give an early prediction of acute kidney injury (AKI) and outcome.
Methods
This was a prospective observational study of comatose OHCA patients at Oslo University Hospital Ullevål, Norway. Risk factors were clinical parameters and biomarkers measured in spot urine (cystatin C, neutrophil gelatinase-associated lipocalin (NGAL) and the product of tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7)) at admission and day 3. Outcome variables were AKI within 3 days using the Kidney Disease Improving Global Outcomes definition, 6-month mortality, and poor neurological outcome (PNO) defined as cerebral performance category 3–5.
Results
Among 195 included patients (85 % males, mean age 60 years), 88 (45 %) died, 96 (49 %) had PNO, and 88 (45 %) developed AKI. In univariate analysis, increased urine cystatin C and NGAL concentration sampled at admission and day 3 were independent risk factors for AKI, mortality and PNO. Increased urine TIMP-2 × IGFBP7 levels was associated with AKI only at admission. In multivariate analyses combining clinical parameters and biomarker concentrations, the area under the receiver operating characteristics curve (AuROC) with 95 % confidence interval (CI) were 0.774 (0.700–0.848), 0.812 (0.751–0.873), and 0.819 (0.759–0.878) for AKI, mortality and PNO, respectively.
Conclusions
In comatose OHCA patients, urine levels of cystatin C and NGAL at admission and day 3 were independent risk factors for AKI, 6-month mortality and PNO.
Trial registration
Clinicaltrials.gov NCT01239420. Registered 10 November 2010.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-016-1503-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-016-1503-2
PMCID: PMC5052716  PMID: 27716377
Acute kidney injury; Cardiac arrest; Biomarker; Outcome; Prognosis
4.  Vitamin D Status and Long-Term Mortality in Community-Acquired Pneumonia: Secondary Data Analysis from a Prospective Cohort 
PLoS ONE  2016;11(7):e0158536.
Background
Low vitamin D status has been associated with short-term (30-day) mortality in hospitalized adults with community-acquired pneumonia (CAP). Data on its prevalence in these patients are scarce, and impact on long-term prognosis is unknown. We examined the prevalence of vitamin D deficiency and inadequacy and their effect on long-term mortality in hospitalized adults with CAP.
Methods
Secondary follow-up analysis of data from a prospectively recruited (January 2008–January 2011) well-defined cohort of 241 hospital survivors of CAP (Norway, latitude 60°N). Serum 25-hydroxyvitamin D levels, demographic, clinical, and laboratory data were measured within 48 hours of admission. The etiology of CAP was established in 63% of patients through extensive microbiological investigations. Mortality data were obtained from the national Cause of Death Registry. Explanatory strategy and Cox regression models were used to explore the association between vitamin D status and all-cause mortality.
Results
Median age was 66 years. Eighty-seven (36%) patients were vitamin D deficient (<30 nmol/L), 81 (34%) were inadequate (30–49 nmol/L), and 73 (30%) were sufficient (≥50 nmol/L). Seventy-two patients died over a median of 1839 days (range 1–2520 days), corresponding to cumulative 5-year survival rates of 66.2% (95% CI 56.2–76.2%), 77.0% (67.6–86.4%), and 77.8% (67.8–87.8%) for vitamin D deficient, inadequate, and sufficient patients, respectively. After adjusting for confounders (age, chronic obstructive pulmonary disease, immunocompromization and season), vitamin D deficiency, but not inadequacy, was significantly associated with higher mortality compared to patients with sufficiency (HR 1.91, 95% CI 1.06–3.45; P = .031).
Conclusions
There is a high prevalence of vitamin D deficiency and inadequacy among hospitalized adults with CAP. The results of this study also suggest that vitamin D deficiency is associated with an increased risk of mortality way beyond the short-term in these patients.
doi:10.1371/journal.pone.0158536
PMCID: PMC4930204  PMID: 27367810
5.  Eliciting Patient Risk Willingness in Clinical Consultations as a Means of Improving Decision‐Making of Aortic Valve Replacement 
Background
Treatment decisions for aortic valve replacement (AVR) should be sensitive to patient preferences. However, we lack knowledge of patient preferences and how to obtain them.
Methods and Results
We assessed the mortality risk patients were willing to accept when undergoing AVR by using the Standard Gamble method and aimed to show how this risk willingness was affected by level of disease burden. We report findings from 439 patients, aged >18 years with severe aortic stenosis who were referred for evaluation of AVR to our institution. The vast majority of patients accepted a mortality risk regarded as high or prohibitive according to current guidelines. Of the 439 patients, 51% patients were willing to forego surgery with high mortality risk (8–50%) and 19% were willing accept a prohibitive mortality risk (>50%) as defined in current guidelines. However, the risk willingness varied considerably. Acceptance of prohibitive risk willingness (>50%) was associated with reporting of 3 to 5 different restricting symptoms, with an odds ratio of 4.07 (95% CI 1.56–10.59) opposed by increasing score on EuroQol–Visual Analog Scale, with an odds ratio of 0.99 (95% CI 0.97–1.00). The poor ability to predict risk willingness based on available clinical variables and health status suggests that other factors may be important advocating the need for tools for soliciting patient's preferences individually.
Conclusion
When undergoing AVR, patients were willing to accept considerably higher perioperative risk than what is considered acceptable in current guidelines and practice. Patient preferences varied considerably, and they should be directly assessed and taken into account in decision‐making and guidelines.
Clinical Trial Registration
URL: https://clinicaltrials.gov/. Unique identifier: NCT01794832.
doi:10.1161/JAHA.115.002828
PMCID: PMC4943260  PMID: 26994130
aortic stenosis; cardiovascular diseases; patients; shared decision‐making; surgery; valves; Valvular Heart Disease; Aortic Valve Replacement/Transcather Aortic Valve Implantation; Health Services; Statements and Guidelines
6.  Risk Factors for Long-Term Mortality after Hospitalization for Community-Acquired Pneumonia: A 5-Year Prospective Follow-Up Study 
PLoS ONE  2016;11(2):e0148741.
Background
Contributors to long-term mortality in patients with community-acquired pneumonia (CAP) remain unclear, with little attention paid to pneumonia etiology. We examined long-term survival, causes of death, and risk factors for long-term mortality in adult patients who had been hospitalized for CAP, with emphasis on demographic, clinical, laboratory, and microbiological characteristics.
Methods
Two hundred and sixty-seven consecutive patients admitted in 2008–2011 to a general hospital with CAP were prospectively recruited and followed up. Patients who died during hospital stay were excluded. Demographic, clinical, and laboratory data were collected within 48 hours of admission. Extensive microbiological work-up was performed to establish the etiology of CAP in 63% of patients. Mortality data were obtained from the Norwegian Cause of Death Registry. Cox regression models were used to identify independent risk factors for all-cause mortality.
Results
Of 259 hospital survivors of CAP (median age 66 years), 79 (30.5%) died over a median of 1,804 days (range 1–2,520 days). Cumulative 5-year survival rate was 72.9% (95% CI 67.4–78.4%). Standardized mortality ratio was 2.90 for men and 2.05 for women. The main causes of death were chronic obstructive pulmonary disease (COPD), vascular diseases, and malignancy. Independent risk factors for death were the following (hazard ratio, 95% CI): age (1.83 per decade, 1.47–2.28), cardiovascular disease (2.63, 1.61–4.32), COPD (2.09, 1.27–3.45), immunocompromization (1.98, 1.17–3.37), and low serum albumin level at admission (0.75 per 5g/L higher, 0.58–0.96), whereas active smoking was protective (0.32, 0.14–0.74); active smokers were younger than non-smokers (P < 0.001). Microbial etiology did not predict mortality.
Conclusions
Results largely confirm substantial comorbidity-related 5-year mortality after hospitalization for CAP and the impact of several well-known risk factors for death, and extend previous findings on the prognostic value of serum albumin level at hospital admission. Pneumonia etiology had no prognostic value, but this remains to be substantiated by further studies using extensive diagnostic microbiological methods in the identification of causative agents of CAP.
doi:10.1371/journal.pone.0148741
PMCID: PMC4746118  PMID: 26849359
7.  Soluble RAGE and atherosclerosis in youth with type 1 diabetes: a 5-year follow-up study 
Background
Advanced glycation end products (AGEs) play a role in the development of late complications and atherosclerosis in diabetes by engaging the receptor for advanced glycation end products, RAGE. Receptor binding leads to activation of the vascular endothelium and increased inflammation in the vessel wall. The soluble variants of the receptor, endogenous secretory RAGE (esRAGE) and the cleaved cell-surface part of RAGE, which together comprise soluble RAGE (sRAGE), are suggested to have a protective effect acting as decoys for RAGE. We aimed to test whether high levels of soluble variants of RAGE could be protective against atherosclerosis development.
Methods
Participants in the prospective atherosclerosis and childhood diabetes study were examined at baseline (aged 8–18) and at follow-up after 5 years. Both sRAGE and esRAGE were measured by immunoassay in 299 patients with type 1 diabetes and 112 healthy controls at baseline and 241 patients and 128 controls at follow-up. The AGEs methylglyoxal-derived hydroimidazolone-1 (MG-H1) and carboxymethyllysine (CML) were measured by immunoassay. The surrogate markers of atherosclerosis assessed were carotid intima-media thickness (cIMT), C-reactive protein (CRP) and Young’s modulus, measures of arterial wall thickness, inflammation and arterial stiffness, respectively.
Results
Levels of sRAGE and esRAGE correlated strongly both at baseline and at follow-up in both diabetes patients and controls. With increasing age, mean values of both variants declined, independent of gender, diabetes or pubertal stage. In the diabetes group, multiple regression analysis showed a positive association between both variants of soluble RAGE and cIMT. There was no significant relationship with Young’s modulus, but a negative association between sRAGE at baseline and CRP at follow-up. The ratios between the AGEs and the variants of soluble RAGE were increased in diabetes patients compared to controls.
Conclusions
The results show a possible protective effect of high levels of sRAGE at baseline against inflammation 5 years later, but not on arterial stiffness or wall thickness, in this cohort of adolescents and young adults with T1D.
doi:10.1186/s12933-015-0292-2
PMCID: PMC4582642  PMID: 26408307
Advanced glycation end products; Receptor for advanced glycation end products; sRAGE; esRAGE; Atherosclerosis; Type 1 diabetes; CRP
8.  Associations between circulating endostatin levels and vascular organ damage in systemic sclerosis and mixed connective tissue disease: an observational study 
Introduction
Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are chronic immune-mediated disorders complicated by vascular organ damage. The aim of this study was to examine the serum levels of the markers of neoangiogenesis: endostatin and vascular endothelial growth factor (VEGF), in our unselected cohorts of SSc and MCTD.
Methods
Sera of SSc patients (N = 298) and MCTD patients (N = 162) from two longitudinal Norwegian cohorts were included. Blood donors were included as controls (N = 100). Circulating VEGF and endostatin were analyzed by enzyme immunoassay.
Results
Mean endostatin levels were increased in SSc patients 93.7 (37) ng/ml (P < .001) and MCTD patients 83.2 (25) ng/ml (P < .001) compared to controls 65.1 (12) ng/ml. Median VEGF levels were elevated in SSc patients 209.0 (202) pg/ml compared to MCTD patients 181.3 (175) pg/ml (P = .017) and controls 150.0 (145) pg/ml (P < .001). Multivariable analysis of SSc subsets showed that pulmonary arterial hypertension (coefficient 15.7, 95 % CI: 2.2–29.2, P = .023) and scleroderma renal crisis (coefficient 77.6, 95 % CI: 59.3–100.0, P < .001) were associated with elevated endostatin levels. Multivariable analyses of MCTD subsets showed that digital ulcers were associated with elevated endostatin levels (coefficient 10.5, 95 % CI: 3.2–17.8, P = .005). The risk of death increased by 1.6 per SD endostatin increase (95 % CI: 1.2–2.1, P = .001) in the SSc cohort and by 1.6 per SD endostatin increase (95 % CI: 1.0–2.4, P = .041) in the MCTD cohort after adjustments to known risk factors.
Conclusions
Endostatin levels were elevated in patients with SSc and MCTD, particularly SSc patients with pulmonary arterial hypertension and scleroderma renal crisis, and MCTD patients with digital ulcers. Elevated endostatin levels were also associated with increased all-cause mortality during follow-up in both groups of patients. We propose that endostatin might indicate the degree of vascular injury in SSc and MCTD patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0756-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-015-0756-5
PMCID: PMC4551562  PMID: 26315510
9.  Are poor set-shifting abilities associated with a higher frequency of body checking in anorexia nervosa? 
Background
The rigid and obsessional features of anorexia nervosa (AN) have led researchers to explore possible underlying neuropsychological difficulties. Numerous studies have demonstrated poorer set-shifting in patients with AN. However, due to a paucity of research on the connection between neuropsychological difficulties and the clinical features of AN, the link remains hypothetical. The main objective of this study was to explore the association between set-shifting and body checking.
Methods
The sample consisted of 30 females diagnosed with AN and 45 healthy females. Set-shifting was assessed using the Wisconsin Card Sorting Test (WCST) and frequency of body checking was assessed using the Body Checking Questionnaire (BCQ).
Results
The analysis showed no significant correlations between any of the WCST scores and the BCQ.
Conclusion
The results suggest that there is no association between set-shifting difficulties and frequency of body checking among patients with AN. An alternative explanation could be that the neuropsychological measure included in this study is not sensitive to the set-shifting difficulties observed in clinical settings. We recommend that future studies include more ecologically valid measures of set-shifting in addition to standard neuropsychological tests.
doi:10.1186/s40337-015-0053-3
PMCID: PMC4403677  PMID: 25897402
Anorexia nervosa; Eating disorders; Body checking; Set-shifting; Cognitive flexibility
10.  Risk Factors for Community-Acquired Urinary Tract Infections Caused by ESBL-Producing Enterobacteriaceae –A Case–Control Study in a Low Prevalence Country 
PLoS ONE  2013;8(7):e69581.
Community-acquired urinary tract infection (CA-UTI) is the most common infection caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, but the clinical epidemiology of these infections in low prevalence countries is largely unknown. A population based case-control study was conducted to assess risk factors for CA-UTI caused by ESBL-producing E. coli or K. pneumoniae. The study was carried out in a source population in Eastern Norway, a country with a low prevalence of infections caused by ESBL-producing Enterobacteriaceae. The study population comprised 100 cases and 190 controls with CA-UTI caused by ESBL-producing and non-ESBL-producing E. coli or K. pneumoniae, respectively. The following independent risk factors of ESBL-positive UTIs were identified: Travel to Asia, The Middle East or Africa either during the past six weeks (Odds ratio (OR) = 21; 95% confidence interval (CI): 4.5–97) or during the past 6 weeks to 24 months (OR = 2.3; 95% CI: 1.1–4.4), recent use of fluoroquinolones (OR = 16; 95% CI: 3.2–80) and β-lactams (except mecillinam) (OR = 5.0; 95% CI: 2.1–12), diabetes mellitus (OR = 3.2; 95% CI: 1.0–11) and recreational freshwater swimming the past year (OR = 2.1; 95% CI: 1.0–4.0). Factors associated with decreased risk were increasing number of fish meals per week (OR = 0.68 per fish meal; 95% CI: 0.51–0.90) and age (OR = 0.89 per 5 year increase; 95% CI: 0.82–0.97). In conclusion, we have identified risk factors that elucidate mechanisms and routes for dissemination of ESBL-producing Enterobacteriaceae in a low prevalence country, which can be used to guide appropriate treatment of CA-UTI and targeted infection control measures.
doi:10.1371/journal.pone.0069581
PMCID: PMC3720588  PMID: 23936052
12.  Early Signs of Atherosclerosis in Diabetic Children on Intensive Insulin Treatment 
Diabetes Care  2010;33(9):2043-2048.
OBJECTIVE
To evaluate early stages of atherosclerosis and predisposing factors in type 1 diabetic children and adolescents compared with age- and sex-matched healthy control subjects.
RESEARCH DESIGN AND METHODS
All children and adolescents with type 1 diabetes, aged 8–18 years in Health Region South-East in Norway were invited to participate in the study (n = 800). A total of 40% (n = 314) agreed to participate and were compared with 118 age-matched healthy control subjects. Carotid artery intima-media thickness (cIMT) and elasticity were measured using standardized methods.
RESULTS
Mean age of the diabetic patients was 13.7 years, mean diabetes duration was 5.5 years, and mean A1C was 8.4%; 97% were using intensive insulin treatment, and 60% were using insulin pumps. Diabetic patients had more frequently elevated cIMT than healthy control subjects: 19.5% were above the 90th centile of healthy control subjects, and 13.1% were above the 95th centile (P < 0.001). Mean cIMT was higher in diabetic boys than in healthy control subjects (0.46 ± 0.06 vs. 0.44 ± 0.05 mm, P = 0.04) but not significantly so in girls. There was no significant difference between the groups regarding carotid distensibility, compliance, or wall stress. None of the subjects had atherosclerotic plaque formation. Although within the normal range, the mean values of systolic blood pressure, total cholesterol, LDL cholesterol, and apolipoprotein B were significantly higher in the diabetic patients than in the healthy control subjects.
CONCLUSIONS
Despite short disease duration, intensive insulin treatment, fair glycemic control, and no signs of microvascular complications, children and adolescents with type 1 diabetes had slightly increased cIMT compared with healthy control subjects, and the differences were more prominent in boys.
doi:10.2337/dc10-0505
PMCID: PMC2928360  PMID: 20530748
13.  Reduction in BMI z-score and improvement in cardiometabolic risk factors in obese children and adolescents. The Oslo Adiposity Intervention Study - a hospital/public health nurse combined treatment  
BMC Pediatrics  2011;11:47.
Background
Weight loss and increased physical fitness are established approaches to reduce cardiovascular risk factors. We studied the reduction in BMI z-score associated with improvement in cardiometabolic risk factors in overweight and obese children and adolescents treated with a combined hospital/public health nurse model. We also examined how aerobic fitness influenced the results.
Methods
From 2004-2007, 307 overweight and obese children and adolescents aged 7-17 years were referred to an outpatient hospital pediatrics clinic and evaluated by a multidisciplinary team. Together with family members, they were counseled regarding diet and physical activity at biannual clinic visits. Visits with the public health nurse at local schools or at maternal and child health centres were scheduled between the hospital consultations. Fasting blood samples were taken at baseline and after one year, and aerobic fitness (VO2peak) was measured. In the analyses, 230 subjects completing one year of follow-up by December 2008 were divided into four groups according to changes in BMI z-score: Group 1: decrease in BMI z-score≥0.23, Group 2: decrease in BMI z-score≥0.1-< 0.23, Group 3: decrease in/stable BMI z-score≥0.0-< 0.1, Group 4: increase in BMI z-score (>0.00-0.55).
Results
230 participants were included in the analyses (75%). Mean (SD) BMI z-score was reduced from 2.18 (0.30) to 2.05 (0.39) (p < 0.001) in the group as a whole. After adjustment for BMI z-score, waist circumference and gender, the three groups with reduced BMI z-score had a significantly greater reduction in HOMA-IR, insulin, total cholesterol, LDL cholesterol and total/HDL cholesterol ratio than the group with increased BMI z-score. Adding change in aerobic fitness to the model had little influence on the results. Even a very small reduction in BMI z-score (group 3) was associated with significantly lower insulin, total cholesterol, LDL and total/HDL cholesterol ratio. The group with the largest reduction in BMI z-score had improvements in HOMA-IR and aerobic fitness as well. An increase in BMI z-score was associated with worsening of C-peptide and total/HDL cholesterol ratio.
Conclusions
Even a modest reduction in BMI z-score after one year of combined hospital/and public health nurse intervention was associated with improvement in several cardiovascular risk factors.
doi:10.1186/1471-2431-11-47
PMCID: PMC3121603  PMID: 21619652

Results 1-13 (13)