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Abstract Many patients with chronic thromboembolic pulmonary disease (CTEPD) suffer from exertional dyspnea. It is unclear if CTEPD is associated with exercise pulmonary hypertension (ePH). This cross‐sectional study aimed to determine the occurrence of ePH in patients with CTEPD and to identify the haemodynamic changes during exercise. We recruited 36 patients with persistent dyspnoea and residual perfusion defects by ventilation/perfusion scintigraphy from a large cohort of patients with previous pulmonary embolism. All patients underwent exercise right heart catheterization before being classified into the following groups: (1) CTEPD without ePH; comprising patients with normal mean pulmonary artery pressure (mPAP) of ≤20 mmHg, but with mPAP/cardiac output (CO) slope of ≤3 mmHg/L/min, (2) CTEPD with ePH (CTEPD‐ePH); those with CTEPD with an mPAP/CO slope of >3 mmHg/L/min, (3) chronic thromboembolic pulmonary hypertension (CTEPH); those with mPAP >20 mmHg, pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg and pulmonary vascular resistance >2 WU. The postcapillary contribution during exercise was considered present if the PAWP/CO slope of >2 mmHg/L/min. CTEPD without resting pulmonary hypertension (PH) was present in 29 (81%) of the 36 patients, of whom six (21%) had ePH, while five (14%) had CTEPH. Two patients had unclassified PH. Two (33%) of the six patients with CTEPD‐ePH had a PAWP/CO slope of >2 mmHg/L/min, compared with two (40%) of the five of those with CTEPH. In conclusion, about 20% of patients with CTEPD and exertional dyspnoea had ePH. Exercise right heart catheterization revealed a notable proportion of patients with postcapillary contribution.

Abstract Background COVID-19 has been associated with cardiac troponin T (cTnT) elevations and changes in cardiac structure and function, but the link between cardiac dysfunction and high-sensitive cardiac troponin T (hs-cTnT) in the acute and convalescent phase is unclear. Objective To assess whether hs-cTnT concentrations are associated with cardiac dysfunction and structural abnormalities after hospitalization for COVID-19, and to evaluate the performance of hs-cTnT to rule out cardiac pathology. Methods Patients hospitalized with COVID-19 had hs-cTnT measured during the index hospitalization and after 3-and 12 months, when they also underwent an echocardiographic study. A subset also underwent cardiovascular magnetic resonance imaging (CMR) after 6 months. Cardiac abnormalities were defined as left ventricular hypertrophy or dysfunction, right ventricular dysfunction, or CMR late gadolinium. Results We included 189 patients with hs-cTnT concentrations measured during hospitalization for COVID-19, and after 3-and 12 months: Geometric mean (95%CI) 13 (11–15) ng/L, 7 (6–8) ng/L and 7 (6–8) ng/L, respectively. Cardiac abnormalities after 3 months were present in 45 (30%) and 3 (8%) of patients with hs-cTnT ≥ and

Abstract Aims The aim of this study was to determine microvascular function in the acute phase of Takotsubo syndrome (TTS) and to identify inflammatory mediators that could reflect TTS‐induced pathology. Methods and results The study included 20 females [median age 65 years; interquarile range (IQR) = 58–70 years] with TTS according to the Mayo diagnostic criteria. During heart catheterization, we determined the index of microvascular resistance (IMR) and drew blood samples almost simultaneously from the aorta and coronary sinus. Cardiac magnetic resonance imaging (MRI) was done in the acute phase. We present descriptive coronary physiology and cardiac MRI data and compare inflammatory biomarkers between samples from the aorta, coronary sinus, and venous samples after 3 months using the Wilcoxon signed‐rank test. For comparison, we also analysed the actual biomarkers in venous blood from 15 healthy female controls. A supplementary analysis explored Spearman's rank correlation between the inflammatory biomarkers, IMR, MRI data, and cardiac biomarkers. The median IMR was 16.5 mmHg·s (IQR = 10.5–28.2 mmHg·s), which was only slightly higher than that in the reference populations. Seven (35%) of the study subjects had IMR > 25 mmHg·s, suggesting a microvascular dysfunction. IMR was not affected by time from symptom onset. According to MRI, the apical region of the left ventricle was affected in 65% of the subjects. The median ejection fraction was 41% (IQR = 31–48%). Biomarker analyses revealed elevation of markers for extracellular matrix remodelling and fibrosis, inflammation, immune activation, and upstream inflammation as compared with healthy controls. Only the levels of interleukin (IL)‐1 receptor antagonist and soluble T‐cell immunoglobulin mucin domain‐3 (sTIM‐3) were higher in the coronary sinus than in the aorta. No variable was significantly correlated with IMR. The IL‐6 level in the aorta was inversely correlated with the left ventricular ejection fraction. Growth differentiation factor‐15, osteoprotegerin, and von Willebrand factor levels in both aorta and coronary sinus were positively correlated with N‐terminal‐pro‐brain‐natriuretic peptide, while the correlations of IL‐6 and sTIM‐3 with N‐terminal‐pro‐brain‐natriuretic peptide were restricted to the aorta and coronary sinus, respectively. While most of the markers were within normal limits after 3 months, matrix metalloproteinase‐9 increased during follow‐up to reach levels higher than those in the healthy controls. Conclusion The median IMR was only slightly elevated in this study, but about one‐third of the patients had values indicating microvascular dysfunction. The present study supports the involvement of several inflammatory pathways in TTS, including monocyte/macrophage activation, with sTIM‐3 as a potential novel marker.

ObjectivesTo investigate changes in chest CT between 3 and 12 months and associations with disease severity in patients hospitalized for COVID-19 during the first wave in 2020.Materials and methodsLongitudinal cohort study of patients hospitalized for COVID-19 in 2020. Chest CT was performed 3 and 12 months after admission. CT images were evaluated using a CT severity score (CSS) (0-12 scale) and recoded to an abbreviated version (0-3 scale). We analyzed determinants of the abbreviated CSS with multivariable mixed effects ordinal regression.Results242 patients completed CT at 3 months, and 124 (mean age 62.3±13.3, 78 men) also at 12 months. Between 3 and 12 months (n = 124) CSS (0-12 scale) for ground-glass opacities (GGO) decreased from median 3 (25th-75th percentile: 0-12) at 3 months to 0.5 (0-12) at 12 months (pConclusionsGGO and mosaicism decreased, while parenchymal bands increased from 3 to 12 months. Persistent GGO were associated with initial COVID-19 severity and age ≥60 years.

Abstract Objectives Complications after CT-guided lung biopsy is a burden both for the individual patient and for the overall healthcare. Pneumothorax is the most common complication. This study determined the association between lung function tests and pneumothorax and chest drainage following CT-guided lung biopsy in consecutive patients in a large university hospital. Results We prospectively registered 875 biopsy procedures from 786 patients in one institution from January 27th 2012 to March 1st 2017 and recorded complications including pneumothorax with or without chest drainage. Lung function data from 637 patients undergoing 710 of the procedures were available. The association of lung function measures with pneumothorax with or without chest drainage was assessed using multivariable logistic regression analyses. Diffusion capacity for carbon monoxide (DLCO) below 4.70 mmol/min/kPa was associated with increased occurrence of pneumothorax and chest drainage after CT guided lung biopsy. We found no association between FEV1, RV and occurrence of pneumothorax and chest drainage. We found low DLCO to be a risk factor of pneumothorax and chest drainage after CT-guided lung biopsy. This should be taken into account in planning and performing the procedure.

BackgroundDurvalumab is an immune checkpoint Inhibitor (ICIs) that is used in the treatment of malignant tumors, such as lung cancer and melanoma. ICIs are associated with immune-related adverse events including autoimmune encephalitis, although both paraneoplastic phenomena and ICI treatment may lead to autoimmunity.Case presentationWe describe a 72-year old male patient with small-cell lung cancer, who during adjuvant treatment with Durvalumab developed GABABR1 and GAD65 antibodies and both diabetes and autoimmune limbic encephalitis. Because he was followed prospectively as part of a treatment study, we had access to repeated serum samples and cognitive assessments over time prior to developing encephalitis and diabetes, in addition to later assessments. A high titer of GABABR1 antibodies appeared early, while GAD65 antibodies appeared later with a lower titer in parallel with the development of diabetes. As he subsequently developed clinical signs of encephalitis, verified by EEG and brain MRI, he also had CSF GABABR1 antibodies. Durvalumab was discontinued and steroid treatment with subsequent plasmapheresis were started, resulting in reduction of both CSF and serum antibody levels. Clinical signs of encephalitis gradually improved.ConclusionThis case illustrates the importance of being aware of possible serious autoimmune adverse reactions, including neurological syndromes such as encephalitis, when treating patients with high risk of para-neoplasia with ICIs. In addition, the case shows the development of autoantibodies over time.

COVID-19 primarily affects the respiratory system. We aimed to evaluate how pulmonary outcomes develop after COVID-19 by assessing participants from the first pandemic wave prospectively 3 and 12 months following hospital discharge. Pulmonary outcomes included self-reported dyspnoea assessed with the modified Medical Research Council dyspnoea scale, 6-min walk distance (6MWD), spirometry, diffusing capacity of the lung for carbon monoxide (DLCO), body plethysmography and chest computed tomography (CT). Chest CT was repeated at 12 months in participants with pathological findings at 3 months. The World Health Organization (WHO) ordinal scale for clinical improvement defined disease severity in the acute phase. Of 262 included COVID-19 patients, 245 (94%) and 222 (90%) participants attended the 3- and 12-month follow-up, respectively. Self-reported dyspnoea and 6MWD remained unchanged between the two time points, while DLCO and total lung capacity improved (0.28 mmol·min−1·kPa−1, 95% CI 0.12–0.44, and 0.13 L, 95% CI 0.02–0.24, respectively). The prevalence of fibrotic-like findings on chest CT at 3 and 12 months in those with follow-up chest CT was unaltered. Those with more severe disease had worse dyspnoea, DLCO and total lung capacity values than those with mild disease. There was an overall positive development of pulmonary outcomes from 3 to 12 months after hospital discharge. The discrepancy between the unaltered prevalence of self-reported dyspnoea and the improvement in pulmonary function underscores the complexity of dyspnoea as a prominent factor of long-COVID. The lack of increase in fibrotic-like findings from 3 to 12 months suggests that SARS-CoV-2 does not induce a progressive fibrotic process in the lungs.

Background and aim Several factors can influence measured lung function over time. The aim of this study was to investigate period and cohort effects on spirometric measures in a large general population sample in Norway during the 20th century, using Global Lung Function Initiative (GLI-2012) equations as a reference. Methods 36 466 subjects (born 1894–1969) from four cross-sectional surveys conducted between 1965 and 1999 were included, with harmonised data on smoking habits, respiratory symptoms, lung diseases, education and spirometry. Changes in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) z-scores in healthy subjects across surveys were explored to investigate period effects. Linear mixed-effects models of FEV1 and FVC z-scores on birth cohort, with survey as random effect, were used to investigate cohort effects, both in subjects of the total population and in healthy ones. Results Relatively higher FEV1 and FVC z-scores in healthy subjects were found in the first survey (1965–1970) compared to the more recent ones (1988–1999), suggesting period effects. FEV1 and FVC z-scores increased significantly with birth cohort from 1894 to 1935, after adjustment for covariates. A more stable trend of FEV1 and FVC z-scores with birth cohort was evidenced for subjects born more recently (1945–1969). Conclusions An increase of lung function with year of birth was observed in Norwegian subjects during the first half of the 20th century. The impact of period effects on lung function decreased from 1965 to 1999.

ObjectiveTo assess the trajectory of symptoms and symptom-defined post-traumatic stress disorder (PTSD) from 1.5 to 12 months after hospitalization for COVID-19 and determine risk factors for persistent symptoms and PTSD.MethodsThis was a prospective cohort study of consecutive patients discharged after hospitalization for COVID-19 before 1 June 2020 in six hospitals in Southern Norway. Symptom-defined PTSD was assessed by the post-traumatic stress disorder (PTSD) checklist for DSM-5 (PCL-5) at 1.5, 3 and/or 12 months after hospitalization, using DSM-5 criteria. Changes in PCL-5 symptom score and the prevalence of PTSD were analyzed with multivariable mixed models.ResultsIn total, 388 patients were discharged alive, and 251 (65%) participated. Respondents had a mean (SD) age of 58.4 (14.2) years, and 142 (57%) were males. The prevalence of symptom-defined PTSD was 14, 8, and 9% at 1.5, 3, and 12 months, respectively. WHO disease severity for COVID-19 was not associated with PCL-5 scores. Female sex, lower age and non-Norwegian origin were associated with higher PCL-5 scores. The odds ratio (OR) (95%CI) for PTSD was 0.32 (0.12 to 0.83, p = 0.019) at 3 months and 0.38 (0.15 to 0.95, p = 0.039) at 12 months compared to 1.5 months. There was no association between PTSD and WHO severity rating.ConclusionsThe level of PTSD symptoms decreased from 1.5 to 3 months after hospitalization, but did not decrease further to 12 months, and there was no association between PTSD symptoms and COVID-19 disease severity.

Abstract Background Recently, a large group of patients with persistent dyspnea, poor physical capacity, and reduced health-related quality of life (HRQoL) following pulmonary embolism (PE) has been identified and clustered under the name “post pulmonary embolism syndrome” (PPS). These patients seem good candidates for pulmonary rehabilitation. The aim of the study is to explore whether a pulmonary rehabilitation program can improve physical capacity, dyspnea, and HRQoL in PPS patients. Methods A two-center randomized controlled trial (RCT) is being performed at Østfold Hospital and Akershus University Hospital in Norway. Patients with PPS are 1:1 randomized into an intervention or a control group. The intervention consists of a supervised, outpatient rehabilitation program twice weekly (1 h) for 8 weeks provided by experienced physiotherapists. The intervention involves individually adapted exercises based on existing pulmonary rehabilitation programs (relaxation, interval, and resistance training), and an educational session including topics such as normal anatomy and physiology of the respiratory and circulatory system, information on PE/PPS, breathing strategies, and benefits of exercise/physical activity. Patients randomized to the control group receive usual care without specific instructions to exercise. Participants in the intervention and control groups will be compared based on assessments conducted at baseline, 12 weeks, and 36 weeks after inclusion using the incremental shuttle walk test (primary outcome) and endurance shuttle walk test (exercise capacity), Sensewear activity monitor (daily physical activity), the modified Medical Research Council scale, the Shortness of Breath Questionnaire (dyspnea), and EQ-5D-5L and the Pulmonary Embolism Quality of Life Questionnaire (HRQoL). Recruitment of 190 patients is currently ongoing. Discussion Results from this study may provide a currently untreated group of PPS patients with an effective treatment resulting in reduced symptoms of dyspnea, improved exercise capacity, and better HRQoL following PE. Trial registration Clinical Trials NCT03405480 . Registered prospectively on September 2017. Protocol version 1 (from original protocol September 2017). The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 1).

Abstract Background Central nervous system depressant medications (CNSDs) such as opioid analgesics and sedative-hypnotics are commonly prescribed to older patients for the treatment of chronic pain, anxiety and insomnia. Yet, while many studies reported potential harms, it remains unknown whether persistent use of these medications is beneficial for older patients’ self-reported health-related quality of life (HRQoL). The present study clarified this knowledge gap through comparing HRQoL of hospitalized older patients with versus without using CNSD drugs for ≥4 weeks. Moreover, we explored the relationship between such use and HRQoL, adjusting for the effects of polypharmacy, comorbidity burden and other clinically relevant covariates. Methods The study was cross-sectional and included 246 older patients recruited consecutively from somatic departments of a large regional university hospital in Norway. We defined prolonged CNSD use as using opioids, benzodiazepines and/or z-hypnotics for ≥4 weeks. Patients’ self-reported HRQoL were measured with scales of the EuroQol EQ-5D-3L instrument. Data analyses were mainly descriptive statistics and regression models. Results Patients with prolonged use of CNSDs reported lower scores on both EQ-5D index and EQ VAS compared with those without such use (p

Background. National valuation studies are costly, with ∼1000 face-to-face interviews recommended, and some countries may deem such studies infeasible. Building on previous studies exploring sample size, we determined the effect of sample size and alternative model specifications on prediction accuracy of modeled coefficients in EQ-5D-5L value set generating regression analyses. Methods. Data sets ( n = 50 to ∼1000) were simulated from 3 valuation studies, resampled at the respondent level and randomly drawn 1000 times with replacement. We estimated utilities for each subsample with leave-one-out at the block level using regression models (8 or 20 parameter; with or without a random intercept; time tradeoff [TTO] data only or TTO + discrete choice experiment [DCE] data). Prediction accuracy, root mean square error (RMSE), was calculated by comparing to censored mean predicted values to the left-out block in the full data set. Linear regression was used to estimate the relative effect of changes in sample size and each model specification. Results. Results showed that doubling the sample size decreased RMSE by on average 0.012. Effects of other model specifications were smaller but can when combined compensate for loss in prediction accuracy from a small sample size. For models using TTO data only, 8-parameter models clearly outperformed 20-parameter models. Adding a random intercept, or including DCE responses, also improved mean RMSE, most prominently for variants of the 20-parameter models. Conclusions. The prediction accuracy impact of further increases in sample size after 300 to 500 were smaller than the impact of combining alternative modeling choices. Hybrid modeling, use of constrained models, and inclusion of random intercepts all substantially improve the expected prediction accuracy. Beyond a minimum of 300 to 500 respondents, the sample size may be better informed by other considerations, such as legitimacy and representativeness, than by the technical prediction accuracy achievable. Highlights Increases in sample size beyond a minimum in the range of 300 to 500 respondents provide smaller gains in expected prediction accuracy than alternative modeling approaches. Constrained, nonlinear models; time tradeoff + discrete choice experiment hybrid modeling; and including a random intercept all improved the prediction accuracy of models estimating values for the EQ-5D-5L based on data from 3 different valuation studies. The tested modeling choices can compensate for smaller sample sizes.

Introduction: The incidence of thromboembolism during COVID-19 and the use of thromboprophylaxis vary greatly between studies. Only a few studies have investigated the rate of thromboembolism post-discharge. This study determined the 90-day incidence of venous and arterial thromboembolic complications, risk factors for venous thromboembolic events and characterized the use of thromboprophylaxis during and after hospitalization. Materials and methods: We retrospectively reviewed medical records for adult patients hospitalized for >24 h for COVID-19 before May 15, 2020, in ten Norwegian hospitals. We extracted data on demographics, thromboembolic complications, thromboembolic risk factors, and the use of thromboprophylaxis. Cox proportional hazards regression was used to determine risk factors for VTE. Results: 550 patients were included. The 90-day incidence of arterial and venous thromboembolism in hospitalized patients was 6.9% (95% CI: 5.1–9.3) overall and 13.8% in the ICU. Male sex (hazard ratio (HR) 7.44, 95% CI 1.73–32.02, p = 0.007) and previous VTE (HR 6.11, 95% CI: 1.74–21.39, p = 0.005) were associated with risk of VTE in multivariable analysis. Thromboprophylaxis was started in 334 patients (61%) with a median duration of 7 days (25th–75th percentile 3–13); in the VTE population 10/23 (43%) started thromboprophylaxis prior to diagnosis. After discharge 20/223 patients received extended thromboprophylaxis and 2/223 (0.7%, 95% CI: 0.3–1.9) had a thromboembolism. Conclusions: The 90-day incidence of thromboembolism in COVID-19 patients was 7%, but

Background The extent of cardiac dysfunction post‐COVID‐19 varies, and there is a lack of data on arrhythmic burden. Methods and Results This was a combined multicenter prospective cohort study and cross‐sectional case‐control study. Cardiac function assessed by echocardiography in patients with COVID‐19 3 to 4 months after hospital discharge was compared with matched controls. The 24‐hour ECGs were recorded in patients with COVID‐19. A total of 204 patients with COVID‐19 consented to participate (mean age, 58.5 years; 44% women), and 204 controls were included (mean age, 58.4 years; 44% women). Patients with COVID‐19 had worse right ventricle free wall longitudinal strain (adjusted estimated mean difference, 1.5 percentage points; 95% CI, −2.6 to −0.5; P=0.005) and lower tricuspid annular plane systolic excursion (−0.10 cm; 95% CI, −0.14 to −0.05; P

Studies have reported reduced cognitive function following COVID-19 illness, mostly from hospital settings with short follow-up times. This study recruited non-hospitalized COVID-19 patients from a general population to study prevalence of late cognitive impairment and associations with initial symptoms. We invited patients with PCR-confirmed COVID-19. A postal questionnaire addressed basic demographics, initial COVID-19 symptoms and co-morbidity about 4 months after diagnosis. About 7 months later, we conducted cognitive tests using the Cambridge Neuropsychological Test Automated Battery, comprising four tests for short-term memory, attention and executive function. We present descriptive statistics using z-scores relative to UK population norms and defined impairment as z-score

This study determined the association between respiratory symptoms and death from cardiovascular (CV) diseases during 45 years in a pooled sample of four cohorts of random samples of the Norwegian population with 95,704 participants. Respiratory symptoms were assessed using a modification of the MRC questionnaire on chronic bronchitis. We analyzed the association between respiratory symptoms and specific cardiovascular deaths by using Cox regression analysis with age as the time variable, accounting for cluster-specific random effects using shared frailty for study cohort. Hazard ratios (HR) for death were adjusted for sex, highest attained education, smoking habits, occupational air pollution, and birth cohort. Overall, 12,491 (13%) of participants died from CV diseases: 4,123 (33%) acute myocardial infarction, 2,326 (18%) other ischemic heart disease, 2,246 (18%) other heart diseases, 2,553 (20%) cerebrovascular diseases, and 1,120 (9%) other vascular diseases. The adjusted HR (95% confidence interval) for CV deaths was 1.9 (1.7–2.1) in men and 1.5 (1.2–1.9) in women for “yes” to the question “Are you breathless when you walk on level ground at an ordinary pace?”. The same item response showed an adjusted HR for death from acute myocardial infarction of 1.8 (1.5–2.1), other ischemic heart disease 2.2 (1.8–2.7), other heart diseases 1.5 (1.1–1.9), cerebrovascular disease 1.8 (1.5–2.3), and other circulatory diseases 1.7 (1.2–2.4). The adjusted HR for CV death was 1.3 (1.2–1.4) when answering positive to the question” Are you more breathless than people of your own age when walking uphill?”. However, positive answers to questions on cough, phlegm, wheezing and attacks of breathlessness were after adjustments not associated with early CV deaths. The associations between CV deaths and breathlessness were also present in never smokers. Self-reported breathlessness was associated with CV deaths and could be an early marker of CV deaths.

Purpose The Oslo Ischaemia Study was designed to investigate the prevalence and predictors of silent coronary disease in Norwegian middle-aged men, specifically validating exercise electrocardiography (ECG) findings compared with angiography. The study has been important in investigating long-term predictors of cardiovascular morbidity and mortality, as well as investigating a broad spectrum of epidemiological and public health perspectives.Participants In 1972–1975, 2014 healthy men, 40–59 years old, were enrolled in the study. Comprehensive clinical examination included an ECG-monitored exercise test at baseline and follow-ups. The cohort has been re-examined four times during 20 years. Linkage to health records and national health registries has ensured complete endpoint registration of morbidity until the end of 2006, and cancer and mortality until the end of 2017.Findings to date The early study results provided new evidence, as many participants with a positive exercise ECG, but no chest pain (‘silent ischaemia’), did not have significant coronary artery stenosis after all. Still, they were over-represented with coronary disease after years of follow-up. Furthermore, participants with the highest physical fitness had lower risk of cardiovascular disease, and the magnitude of blood pressure responses to moderate exercise was shown to influence the risk of cardiovascular disease and mortality. With time, follow-up data allowed the scope of research to expand into other fields of medicine, with the aim of investigating predictors and the importance of lifestyle and risk factors.Future plans Recently, the Oslo Ischaemia Study has been found worthy, as the first scientific study, to be preserved by The National Archives of Norway. All the study material will be digitised, free to use and accessible for all. In 2030, the Oslo Ischaemia Study will be linked to the Norwegian Cause of Death Registry to obtain complete follow-up to death. Thus, a broad spectrum of additional opportunities opens.

Background Female athletes might develop reduced bone mineral density (BMD) and amenorrhoea due to low energy intake.Objective To systematically review the literature of randomised controlled trials (RCTs) assessing the effect of oestrogen oral contraceptives (OCP), conjugated oestrogens (CE) and transdermal estradiol (TE) on BMD in premenopausal women with functional hypothalamic amenorrhoea (FHA) due to weight loss, vigorous exercise and/or stress.Methods A comprehensive literature search in PubMed, MEDLINE, Cochrane Library, Ovid and CINAHL from inception to 1 October 2020.Data extraction and synthesis Two authors independently extracted data. When possible, the data were pooled in a random-effects meta-analysis.Main outcomes Difference in BMD (g/cm2) at the lumbar spine.Results Nine RCTs comprising 770 participants met the inclusion criteria; five studies applied OCP, two CE and two TE. Four RCTs (two OCP, two TE) found an increased BMD in premenopausal women with FHA, and five (three OCP, two CE) found a decreased BMD compared with controls. A meta-analysis showed no difference in BMD between the treatment and control groups, (standardised mean difference (SMD) 0.30, 95% CI −0.12 to 0.73). A secondary analysis for change scores from baseline to first assessment point, showed a similar overall result (SMD 0.17, 95% CI −0.16 to 0.51). No serious adverse events were reported.Conclusion The literature suggests that TE might increase lumbar BMD in premenopausal women with FHA, but pooled results revealed no effect of the intervention. The findings do not support oestrogen therapy to improve BMD in these patient groups.

Objectives: Use of inferior vena cava (IVC) filters in patients following severe trauma without recent history of venous thromboembolism (VTE) is controversial. Our objective was to determine if IVC filter placement in the setting of severe trauma effects the hazard of in-hospital pulmonary embolism (PE), deep venous thrombosis (DVT) and mortality. Methods: This retrospective study recruited patients from a single Level I Trauma Center between 1/2008 and 12/2013. Inclusion criteria were age>15 years, Injury Severity Score (ISS)>15 and survival>24 h after hospital admission. Patients with VTE diagnosed prior to IVC filter placement were excluded. A Cox proportional hazards regression model was used, adjusting for immortal time bias with landmark analysis at predefined time after injury. Differences between IVC filter and non-IVC filter groups were adjusted using propensity score. Results: In total 1451 patients were reviewed; 282 patients received an IVC filter and 1169 patients had no IVC filter placed. The mean age was 45.9 vs. 56.9 years and the mean ISS was 29.8 vs. 22.6 in the IVC filter and the non-IVC filter group, respectively. IVC filter placement was not associated with the hazard of PE (HR = 0.46; 95 % CI, 0.12,1.70; P = 0.24) or mortality (HR = 1.02; 95 % CI 0.60,1.75; P = 0.93). However, IVC filter placement was associated with the hazard of DVT (HR = 2.73; 95 % CI, 1.28,5.85; P = 0.01). Conclusions: In patients with severe trauma, those with prophylactic IVC filter placement did not have a reduced hazard of PE or mortality, but an increased hazard of DVT was observed.

This study determined the association between respiratory symptoms and death from respiratory causes over a period of 45 years. In four cohorts of random samples of Norwegian populations with 103,881 participants, 43,731 persons had died per 31 December 2016. In total, 5,949 (14%) had died from respiratory diseases; 2,442 (41%) from lung cancer, 1,717 (29%) chronic obstructive pulmonary disease (COPD), 1,348 (23%) pneumonia, 119 (2%) asthma, 147 (2%) interstitial lung disease and 176 (3%) other pulmonary diseases. Compared with persons without respiratory symptoms the multivariable adjusted hazard ratio (HR) for lung cancer deaths increased with score of breathlessness on effort and cough and phlegm, being 2.6 (95% CI 2.1-3.2) for breathlessness score 3 and 2.1 (95% CI 1.7-2.5) for cough and phlegm score 5. The HR of COPD death was 6.4 (95% CI 5.4-7.7) for breathlessness score 3 and 3.0 (2.4-3.6) for cough and phlegm score 5. Attacks of breathlessness and wheeze score 2 had a HR of 1.6 (1.4-1.9) for COPD death. The risk of pneumonia deaths increased also with higher breathlessness on effort score, but not with higher cough and phlegm score, except for score 2 with HR 1.5 (1.2-1.8). In this study with >2.4 million person-years at risk, a positive association was observed between scores of respiratory symptoms and deaths due to COPD and lung cancer. Respiratory symptoms are thus important risk factors, which should be followed thoroughly by health care practitioners for the benefit of public health.

Background: The practice of non-medical switch (NMS) from a reference biological (originator) to a biosimilar is widely accepted in some countries. However, there is little documentation on the impact of NMS from one originator to another originator. Objectives: To assess the consequences for patients of NMS from one biological originator to another, based on existing literature. The focus was on efficacy and cost of treatment with TNF-α-inhibitors in three disease areas. Methods: A literature search was conducted in Ovid (PubMed, EMBASE) and abstracts from meetings in key therapeutic areas, to identify studies reporting efficacy, safety or costs by switching between originator biologics. Results: 167 references were identified and abstracts screened; 36 papers reviewed in full text, and 6 fulfilled the inclusion criteria. Three clinical studies of NMS had very small sample sizes, but suggested that NMS is beneficial. The remaining three studies used administrative data with little clinical information, indicating that NMS was disadvantageous and associated with increased health care utilization and costs. Conclusions: There is very limited documentation on NMS from one originator biological to another, and the literature suffers from methodological limitations. The results are mixed and preclude drawing an overriding conclusion. Future studies, are warranted.

Introduction Norway is one of several European countries that lacks a national value set and scoring algorithm for the EuroQol five dimensions (EQ-5D). Recent studies have found differences between countries in terms of health values or preferences for health states described by instruments such as the EQ-5D. The project aims to model a national value set for the five level version of the EQ-5D based on values elicited from a representative sample of the Norwegian adult general population in terms of region, age, sex and level of education. Using a sampling strategy supporting the collection of values for both hypothetical and experienced health states, the study will have the additional aim of assessing the feasibility of collecting experience-based values in accordance with the latest EQ-5D valuation study protocol, and comparing values with those given for hypothetical health states.Methods and analysis Multistage random sampling and quota-sampling will contribute to representativeness. To increase the number of valuations of experienced health states, those with less than perfect health will be oversampled, increasing the total number of interviews from 1000 to 1300–1500. The most recent EQ-5D valuation protocol will be followed which includes computer assisted face-to-face, one-to-one interviews and use of composite time trade-off and discrete choice experiments.Ethics and dissemination The study has been reviewed and found to be outside of the scope of the ethics committee and thus not in need of ethical approval. The study findings will be disseminated through peer-reviewed publications, conference presentations and summaries for key stakeholders and partners in the field. The scoring algorithms will be available for widely used statistical software.

Abstract Background The EQ-5D-3 L instrument is a standardized questionnaire which was developed as a simple, generic measure of health for clinical and economic appraisal. To aid in the interpretation, scores are often compared with a normative group. The objectives of this study were 1) to provide population norms for the EQ-5D-3 L for Norway, and 2) to compare scores from postal and web surveys. Methods We conducted two surveys in samples that were aimed to be representative of the Norwegian general population: 1) a postal survey (n = 5000) and 2) a panel study with electronic data collection (n = 1936). For scoring the EQ-5D Index, we used the UK tariff. EQ-5D items were compared using multivariable ordinal logistic regression analysis and EQ-5D Index and EQ VAS scores using multivariable linear regression, adjusting for age, sex and education. Results In total 1131 (22.6%) responded to the postal survey and 977 (50.5%) to the web survey. The odds ratio (OR) for being in a higher score category on the Pain/Discomfort scale in the web survey was 1.25 (95%CI 1.04 to 1.50, p = 0.019) relative to the postal survey. The odds were similar in the other four dimensions. The EQ-5D Index and EQ VAS scores were similar in the postal and web surveys in the various strata according to age, sex and education, except for lower unadjusted and adjusted score for web respondents aged 41–50 years and for those with higher education (≥14 years) than postal respondents. Conclusions The distribution of scores for the EQ-5D descriptive system and its derived utility scores were rather similar in a postal survey and a panel web survey. Hence, these values were combined into a norm set for Norway.

Abstract Background It is widely accepted that exercise capacity in healthy individuals is limited by the cardiac function, while the respiratory system is considered oversized. Although there is physiological, age-related decline in both lung function and physical capacity, the association between decline in lung function and decline in exercise capacity is little studied. Therefore, we examined the longitudinal association between lung function indices and exercise capacity, assessed by the total amount of work performed on a standardized incremental test, in a cohort of middle-aged men. Methods A total of 745 men between 40 and 59 years were examined using spirometry and standardized bicycle exercise ECG test within “The Oslo Ischemia Study,” at two time points: once during 1972–1975, and again, approximately 16 years later, during 1989–1990. The subjects exercise capacity was assessed as physical fitness i.e. the total bicycle work (in Joules) at all workloads divided by bodyweight (in kg). Results Higher FEV1, FVC and PEF values related to higher physical fitness at both baseline and follow-up (all p values

Abstract Background Several patient reported outcome measures (PROMs) are available for assessing the outcomes of ankle fracture but few have been compared for recommended measurement properties. This study compares the measurement properties of the Lower Extremity Function Scale (LEFS), Olerud Molander Ankle Score (OMAS) and Self-Reported Foot and Ankle Score (SEFAS) following ankle surgery. Methods The retrospective cohort study included 959 patients aged 18 years and over who underwent surgical treatment (ORIF) for unstable and closed ankle fractures in SE Norway. The PROMs were included in a postal questionnaire sent to patients’ homes in 2015, three years after surgery. Missing data, structural validity, internal consistency, test-retest reliability and validity were assessed. Results Confirmatory factor analysis results showed model fit for the SEFAS and a bi-dimensional LEFS with scales of easy and difficult items. The OMAS performed less satisfactorily. Cronbach’s alpha and test-retest correlations ranged from 0.82 to 0.96 and 0.91 to 0.93 respectively. The smallest detectable differences for group and individual comparisons were 14.1 to 20.6 and 0.93 to 1.55; SEFAS performed best. As hypothesised, instrument scores were highly correlated and with those for the EQ-5D and SF-36 physical functioning. Mean imputation where half or more items are completed increased usable scores by 1.4–15.7% without affecting measurement properties. Conclusions The three instruments largely performed satisfactorily in relation to important measurement properties but the LEFS had evidence for two dimensions relating to easier and more difficult aspects of function. Mean imputation where half or more items are completed increased the number of usable responses for all three instruments. The three instruments represent different approaches to measuring outcomes and their content should be considered carefully when choosing between them. The SEFAS is designed for a range of foot disorders including ankle fractures and has the best measurement properties in this population.

Abstract Background Excessive daytime sleepiness (EDS, defined as Epworth sleepiness scale score > 10) is a common symptom, with a prevalence of 10–20% in the general population. It is associated with headache and other chronic pain disorders. However, little is known about the prevalence of EDS among people with secondary chronic headaches. Findings A total of 30,000 persons aged 30–44 from the general population was screened for headache by a questionnaire. The 633 eligible participants with self-reported chronic headache were interviewed and examined by a headache specialist who applied the International Classification of Headache Disorders with supplementary definitions for chronic rhinosinusitis and cervicogenic headache. A total of 93 participants had secondary chronic headache and completed the ESS. A total of 47 participants had chronic post-traumatic headache (CPTH) and/or cervicogenic headache (CEH), 39 participants had headache attributed to chronic rhinosinusitis (HACRS), while 7 had other secondary headaches. 23.3% of those with CPTH, CEH or HACRS reported EDS. In multivariable logistic regression analysis the odds ratios of EDS were not significantly different in people with CPTH/CEH or HACRS. Conclusion Almost one out of four subjects with secondary chronic headache reported EDS with no differences between the various secondary chronic headaches.

Background and purpose — It has been suggested that preoperative posterior tilt of the femoral head may increase the risk of fixation failure in Garden-I and -II femoral neck fractures. To investigate this association, we studied a cohort of 322 such patients. Patients and methods — Patients treated with internal fixation between 2005 and 2012 were retrospectively identified using hospital records and the digital image bank. 2 raters measured the preoperative posterior tilt angle and categorized it into 3 groups: < 10°, 10–20°, and ≥ 20°. The inter-rater reliability (IRR) was determined. Patients were observed until September 2013 (with a minimum follow-up of 18 months) or until failure of fixation necessitating salvage arthroplasty. The risk of fixation failure was assessed using competing-risk regression analysis, adjusting for time to surgery. Results — Patients with a posterior tilt of ≥ 20° had a higher risk of fixation failure: 19% (8/43) as compared to 11% (14/127) in the 10–20° category and 6% (9/152) in the < 10° category (p = 0.03). Posterior tilt of ≥ 20° increased the risk of fixation failure, with an adjusted hazard ratio of 3.4 (95% CI: 1.3–8.9; p = 0.01). The interclass correlation coefficient for angular measurements of posterior tilt was 0.90 (95% CI: 0.87–0.92), and the IRR for the categorization of posterior tilt into 3 groups was 0.76 (95% CI: 0.69–0.81). Interpretation — Preoperative posterior tilt of ≥ 20° in Garden-I and -II femoral neck fractures increased the risk of fixation failure necessitating salvage arthroplasty. The reliability of the methods that we used to measure posterior tilt ranged from good to excellent.

Background:. The purposes of the present study were to identify the determinants of health status 3 to 6 years after open reduction and internal fixation (ORIF) for the treatment of closed ankle fracture and to compare the health status of patients who had undergone this procedure with that in the general population after adjusting for sociodemographic variables, body mass index (BMI), and smoking status. Methods:. The present study was a historical cohort study combined with a postal survey. In total, 1,149 patients who underwent ORIF for the treatment of closed ankle fractures at 2 hospitals were eligible for chart review; 959 with low-energy fractures were eligible for a postal survey, and 471 (49%) responded to the Short Form Health Survey-36 (SF-36) health status questionnaire and provided data on BMI. Determinants of the physical functioning (PF), physical component summary (PCS), and mental component summary (MCS) scores of the SF-36 were analyzed by means of multivariable linear regression analysis. The health status of patients with an ankle fracture (n = 471) was compared with that in a sample of the general population (n = 5,396) by means of multivariable regression. Results:. Age, American Society of Anesthesiologists (ASA) class III, and complications following surgery were associated with PF and PCS scores, and a BMI of ≥30 kg/m2 and current smoking status was associated with PF and MCS scores. However, the PF, PCS, and MCS scores of patients with ankle fractures did not differ from those of the general population, with unstandardized regression coefficients of 0.25 (95% confidence interval [CI], –1.67 to 2.16; p = 0.80), 0.67 (95% CI, –0.35 to 1.70; p = 0.199), and –0.57 (95% CI, –1.63 to 0.49; p = 0.29), respectively. Conclusions:. Age, ASA class III, and complications following surgery were associated with PF and PCS scores at 3 to 6 years after surgery for the treatment of closed ankle fractures. However, the health status of patients with ankle fractures did not differ from that in the general population after adjusting for differences in demographic variables, BMI, and smoking status. Level of Evidence:. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Few previous studies have investigated associations between clinical variables available after 24 hours in the intensive care unit (ICU), including the Charlson Comorbidity Index (CCI), and decisions to restrict life-sustaining treatment. The aim of this study was to identify factors associated with the life-sustaining treatment restriction and to explore if CCI contributes to explaining decisions to restrict life-sustaining treatment in the ICU at a university hospital in Norway from 2007 to 2009.Patients' Simplified Acute Physiology Score II (SAPS II), age, sex, type of admission, and length of hospital stay prior to being admitted to the unit were recorded. We retrospectively registered the CCI for all patients based on the medical records prior to the index stay. A multivariable logistic regression analysis was used to assess factors associated with treatment restriction during the ICU stay.We included 936 patients, comprising 685 (73%) medical, 204 (22%) unscheduled and 47 (5%) scheduled surgical patients. Treatment restriction was experienced by 241 (26%) patients during their ICU stay. The variables that were significantly associated with treatment restriction in multivariable analysis were older age (odds ratio [OR] = 1.48 per 10 years, 95% confidence interval [CI] = 1.28-1.72 per 10 years), higher SAPS II (OR = 1.05, 95% CI = 1.04-1.07) and CCI values relative to the reference of CCI = 0: CCI = 2 (OR = 2.08, 95% CI = 1.20-3.61) and CCI≥3 (OR = 2.72, 95% CI = 1.65-4.47).In multivariable analysis, older age, greater illness severity after 24 h in the ICU and greater comorbidity at hospital admission were independently associated with subsequent life-sustaining treatment restriction. The CCI score contributed additional information independent of the SAPS II illness severity rating.