Differential levels of circulating RNAs prior to endometrial cancer diagnosis.

Endometrial cancer (EC) is one of the most common female cancers and there is currently no routine screening strategy for early detection. An altered abundance of circulating microRNAs (miRNAs) and other RNA classes have the potential as early cancer biomarkers. We analyzed circulating RNA levels using small RNA sequencing, targeting RNAs in the size range of 17-47 nucleotides, in EC patients with samples collected prior to diagnosis compared to cancer-free controls. The analysis included 316 cases with samples collected 1-11 years prior to EC diagnosis, and 316 matched controls, both from the Janus Serum Bank cohort in Norway. We identified differentially abundant (DA) miRNAs, isomiRs, and small nuclear RNAs between EC cases and controls. The top EC DA miRNAs were miR-155-5p, miR-200b-3p, miR-589-5p, miR-151a-5p, miR-543, miR-485-5p, miR-625-p, and miR-671-3p. miR-200b-3p was previously reported to be among one of the top miRNAs with higher abundance in EC cases. We observed 47, 41, and 32 DA miRNAs for EC interacting with BMI, smoking status, and physical activity, respectively, including two miRNAs (miR-223-3p and miR-29b-3p) interacting with all three factors. The circulating RNAs are altered and show temporal dynamics prior to EC diagnosis. Notably, DA miRNAs for EC had the lowest q-value 4.39-6.66 years before diagnosis. Enrichment analysis of miRNAs showed that signaling pathways Fc epsilon RI, prolactin, toll-like receptor, and VEGF had the strongest associations.

Changes in life expectancy and disease burden in Norway, 1990-2019: an analysis of the Global Burden of Disease Study 2019.

BACKGROUND: Geographical differences in health outcomes are reported in many countries. Norway has led an active policy aiming for regional balance since the 1970s. Using data from the Global Burden of Disease Study (GBD) 2019, we examined regional differences in development and current state of health across Norwegian counties. METHODS: Data for life expectancy, healthy life expectancy (HALE), years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) in Norway and its 11 counties from 1990 to 2019 were extracted from GBD 2019. County-specific contributors to changes in life expectancy were compared. Inequality in disease burden was examined by use of the Gini coefficient. FINDINGS: Life expectancy and HALE improved in all Norwegian counties from 1990 to 2019. Improvements in life expectancy and HALE were greatest in the two counties with the lowest values in 1990: Oslo, in which life expectancy and HALE increased from 71·9 years (95% uncertainty interval 71·4-72·4) and 63·0 years (60·5-65·4) in 1990 to 81·3 years (80·0-82·7) and 70·6 years (67·4-73·6) in 2019, respectively; and Troms og Finnmark, in which life expectancy and HALE increased from 71·9 years (71·5-72·4) and 63·5 years (60·9-65·6) in 1990 to 80·3 years (79·4-81·2) and 70·0 years (66·8-72·2) in 2019, respectively. Increased life expectancy was mainly due to reductions in cardiovascular disease, neoplasms, and respiratory infections. No significant differences between the national YLD or DALY rates and the corresponding age-standardised rates were reported in any of the counties in 2019; however, Troms og Finnmark had a higher age-standardised YLL rate than the national rate (8394 per 100 000 [95% UI 7801-8944] vs 7536 per 100 000 [7391-7691]). Low inequality between counties was shown for life expectancy, HALE, all level-1 causes of DALYs, and exposure to level-1 risk factors. INTERPRETATION: Over the past 30 years, Norway has reduced inequality in disease burden between counties. However, inequalities still exist at a within-county level and along other sociodemographic gradients. Because of insufficient Norwegian primary data, there remains substantial uncertainty associated with regional estimates for non-fatal disease burden and exposure to risk factors. FUNDING: Bill & Melinda Gates Foundation, Research Council of Norway, and Norwegian Institute of Public Health.

Appraising Drugs Based on Cost-effectiveness and Severity of Disease in Norwegian Drug Coverage Decisions.

Importance: Rising health care costs are a major health policy challenge globally. Norway has implemented a priority-setting system intended to balance cost-effectiveness and concerns for fair distribution, but little is known about this strategy and whether it works in practice. Objective: To present and evaluate a systematic drug appraisal method that uses the severity of disease to account for a fair distribution of health in cost-effectiveness analysis, forming the basis for price negotiations and coverage decisions. Design, Setting, and Participants: This cross-sectional study uses confidential drug price information and publicly available data from health technology assessments and logistic and linear regression analyses to evaluate drug coverage decisions for the Norwegian specialized health care sector from 2014 to 2019. Main Outcomes and Measures: Drug coverage decisions by Norwegian authorities and incremental cost-effectiveness and severity of disease measured as absolute shortfall of quality adjusted life years. Results: Between 2014 and 2019, a total of 188 drugs were appraised, of which 113 were cancer drugs. The overall coverage rate was 73% (138 of 188). The number of annual appraisals increased during the observation period. Based on 83 chosen decisions, regression analysis showed that incremental cost-effectiveness ratios (ICER) based on negotiated drug prices, adjusted for severity-differentiated cost-effectiveness thresholds, was the variable that best projected drug approvals (OR, 0.60; 95% CI, 0.42-0.86). An increase in the ICER by $10 000 was associated with a reduction in the odds for approval of 40% for drugs assessed from 2018 to 2019. Conclusions and Relevance: This cross-sectional study demonstrated how concerns for efficiency and fair distribution of health can be implemented systematically into drug appraisals and reimbursement decisions. New, expensive drugs are expected to escalate health care costs in the years to come, and it may be feasible to control costs by negotiating the prices of new drugs while appraising both their cost-effectiveness and how their health benefits are distributed.

Estimating Health Adjusted Age at Death (HAAD).

OBJECTIVES: At any point in time, a person's lifetime health is the number of healthy life years they are expected to experience during their lifetime. In this article we propose an equity-relevant health metric, Health Adjusted Age at Death (HAAD), that facilitates comparison of lifetime health for individuals at the onset of different medical conditions, and allows for the assessment of which patient groups are worse off. A method for estimating HAAD is presented, and we use this method to rank four conditions in six countries according to several criteria of "worse off" as a proof of concept. METHODS: For individuals with specific conditions HAAD consists of two components: past health (before disease onset) and future expected health (after disease onset). Four conditions (acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), schizophrenia, and epilepsy) are analysed in six countries (Ethiopia, Haiti, China, Mexico, United States and Japan). Data from 2017 for all countries and for all diseases were obtained from the Global Burden of Disease Study database. In order to assess who are the worse off, we focus on four measures: the proportion of affected individuals who are expected to have HAAD<20 (T20), the 25th and 75th percentiles of HAAD for affected individuals (Q1 and Q3, respectively), and the average HAAD (aHAAD) across all affected individuals. RESULTS: Even in settings where aHAAD is similar for two conditions, other measures may vary. One example is AML (aHAAD = 59.3, T20 = 2.0%, Q3-Q1 = 14.8) and ALL (58.4, T20 = 4.6%, Q3-Q1 = 21.8) in the US. Many illnesses, such as epilepsy, are associated with more lifetime health in high-income settings (Q1 in Japan = 59.2) than in low-income settings (Q1 in Ethiopia = 26.3). CONCLUSION: Using HAAD we may estimate the distribution of lifetime health of all individuals in a population, and this distribution can be incorporated as an equity consideration in setting priorities for health interventions.

A genome-wide scan of cleft lip triads identifies parent-of-origin interaction effects between ANK3 and maternal smoking, and between ARHGEF10 and alcohol consumption.

Background: Although both genetic and environmental factors have been reported to influence the risk of isolated cleft lip with or without cleft palate (CL/P), the exact mechanisms behind CL/P are still largely unaccounted for. We recently developed new methods to identify parent-of-origin (PoO) interactions with environmental exposures (PoOxE) and applied them to families with children born with isolated cleft palate only. Here, we used the same genome-wide association study (GWAS) dataset and methodology to screen for PoOxE effects in the larger sample of CL/P triads. Methods: Genotypes from 1594 complete triads and 314 dyads (1908 nuclear families in total) with CL/P were available for the current analyses. Of these families, 1024 were Asian, 825 were European and 59 had other ancestries. After quality control, 341,191 SNPs remained from the original 569,244. The exposures were maternal cigarette smoking, use of alcohol, and use of vitamin supplements in the periconceptional period. The methodology applied in the analyses is implemented in the R-package Haplin. Results: Among Europeans, there was evidence of a PoOxSmoke effect for ANK3 with three SNPs (rs3793861, q=0.20, p=2.6e-6; rs7087489, q=0.20, p=3.1e-6; rs4310561, q=0.67, p=4.0e-5) and a PoOxAlcohol effect for ARHGEF10 with two SNPs (rs2294035, q=0.32, p=2.9e-6; rs4876274, q=0.76, p=1.3e-5). Conclusion: Our results indicate that the detected PoOxE effects have a plausible biological basis, and thus warrant replication in other independent cleft samples. Our demonstration of the feasibility of identifying complex interactions between relevant environmental exposures and PoO effects offers new avenues for future research aimed at unravelling  the complex etiology of cleft lip defects.

Novel protein signatures suggest progression to muscular invasiveness in bladder cancer.

Patients with bladder cancer need frequent controls over long follow-up time due to high recurrence rate and risk of conversion to muscle invasive cancer with poor prognosis. We identified cancer-related molecular signatures in apparently healthy bladder in patients with subsequent muscular invasiveness during follow-up. Global proteomics of the normal tissue biopsies revealed specific proteome fingerprints in these patients prior to subsequent muscular invasiveness. In these presumed normal samples, we detected modulations of proteins previously associated with different cancer types. This study indicates that analyzing apparently healthy tissue of a cancer-invaded organ may suggest disease progression.

Cerebrovascular reactivity after treatment of unruptured intracranial aneurysms--A transcranial Doppler sonography and acetazolamide study.

BACKGROUND: Cerebrovascular reactivity (CVR) is defined as the change in cerebral blood flow, or blood velocity, in response to a vasoactive stimulus. There is a possible association between impaired CVR and vasospasm after aneurysmal subarachnoid hemorrhage. Most studies on CVR and vasospasm have used healthy subjects as reference. However, due to potential different vascular features, CVR in persons with intracranial aneurysms may differ from CVR in healthy subjects. Therefore, our aim was to examine CVR in patients with unruptured intracranial aneurysms (UIA). METHODS: CVR was examined in 37 patients in the first postoperative week after treatment for UIA, using acetazolamide (AZ) test with transcranial Doppler monitoring of blood flow velocities. RESULTS: Mean blood flow velocity in the middle cerebral arteries was 58.5 (SD 12.8) cm/s at baseline, and 94.3 (SD 19.5) cm/s after stimulation with AZ. Mean CVR was 62.6 (SD 16.8) %. There was no significant difference when comparing right and left sides, and treated and untreated sides. A simple regression analysis suggested that CVR increased with 0.7% points for each year a patient aged (p=0.004). However, the significance disappeared in a multiple analysis (increase of 0.6% points per year, p=0.055). Other possible influencing factors (gender, smoking, hypertension, body mass index, aneurysm location and treatment modality) were not significantly associated with CVR. CONCLUSIONS: CVR in patients with UIA is not different from normal values reported in healthy subjects, and does not indicate a systemically impaired vascular system in patients with UIA. We suggest that CVR in age and gender matched healthy controls can be used as reference for persons with intracranial aneurysms.

Targeted program for provision of mother's own milk to very low birth weight infants.

OBJECTIVE: Evaluate the effect of an evolving targeted program to encourage mothers to provide own milk (MM) to their very low birth weight (VLBW) infants in a traditional open-bay NICU. METHODS: Retrospective review of medical records on all VLBW infants (birth weight <1500 g) born in a geographical region of Norway in 1986/1987, 1996, and 2007/2008 (n = 203). Types of nutrition and data on maternal and infant health were prospectively and similarly recorded during all time periods. Between each period, targeted programs were initiated to encourage provision of MM. RESULTS: The rates of providing MM (exclusively MM in parenthesis) for the 3 periods were 55% (33%), 85% (60%), and 89% (62%) when achieving full enteral feeds; 48% (11%), 76% (39%), and 92% (60%) at discharge; 15%, 42%, and 62% at 2 to 4 months' corrected age; and 10%, 40%, and 53% at 6 to 8 months' corrected age (P < .001 at all end points). Neither maternal or pregnancy disorders nor neonatal morbidity had significant effects on provision of MM, but smoking was associated with a lower rate after discharge. CONCLUSIONS: Both early and long-term provision of MM for their VLBW infants were strongly associated with targeted programs to encourage provision. We suggest that almost all mothers are able to provide their own milk if given targeted encouragement and guidance, even in crowded open-bay NICUs.

Risk factors and their impact on carotid intima-media thickness in young and middle-aged ischemic stroke patients and controls: the Norwegian Stroke in the Young Study.

BACKGROUND: Vascular morbidity and mortality due to cardiovascular disease (CVD) are high after ischemic stroke at a young age. Data on carotid intima-media thickness (cIMT) as marker of atherosclerosis are scarce for young stroke populations. In this prospective case-control study, we examined cIMT, the burden of vascular risk factors (RF) and their associations among young and middle-aged ischemic stroke patients and controls. We aimed to detect clinical and sub-clinical arterial disease. METHODS: This study was conducted in 150 patients aged 15-60 years and 84 controls free of CVD. We related RF to ultrasonographic B-mode cIMT-measurements obtained from 12 standardized multiangle measurements in the common carotid artery (CCA), carotid bifurcation (BIF) and internal carotid artery (ICA). RESULTS: RF burden was higher among patients than among controls (p < 0.001). In multivariate analyses of all 234 participants, increased cIMT was associated with age in each carotid segment. Incident stroke was associated with increased ICA-IMT. ICA-IMT increase was associated with a family history of CVD among patients aged 15-44 years, and with RF at mid-age. The overall cIMT difference between patients and controls was 12% for CCA, 17% for BIF and 29% for ICA. Further, increased CCA-IMT was associated with male sex and hypertension. Increased BIF-IMT was associated with dyslipidemia, coronary heart disease and smoking. Increased ICA-IMT was associated with dyslipidemia and stroke. CONCLUSIONS: Ischemic stroke is associated with increased ICA-IMT, related to a family history of CVD among patients aged <45 years, and to increasing RF burden with increasing age. Preventive strategies and aggressive RF treatment are indicated to avoid future cardiovascular events. TRIAL REGISTRATION: NOR-SYS is registered in ClinicalTrials.gov (NCT01597453).

Carotid intima-media thickness--a potential predictor for rupture risk of intracranial aneurysms.

BACKGROUND: Individual assessment of rupture risk of cerebral aneurysms is challenging, and increased knowledge of predictors for aneurysm rupture is needed. Smoking and hypertension are shared risk factors for atherosclerotic disease and cerebral aneurysms, and patients with atherosclerosis have an increased prevalence of intracranial aneurysms. Carotid ultrasound with evaluation of intima-media thickness (IMT) is a non-invasive, safe, rapid, well-validated and reproducible technique for quantification of subclinical atherosclerosis and assessment of cardio- and cerebrovascular risk. Increased IMT is associated with elevated risk for ischemic stroke and myocardial infarction, but sparse data exist on carotid ultrasound findings in patients with intracranial aneurysms. AIMS: The purpose of this study was to investigate carotid IMT in patients with unruptured intracranial aneurysms (UIA) and aneurysmal subarachnoid hemorrhage (aSAH), and to assess if IMT might be associated with aneurysm rupture risk. METHODS: Patients treated for saccular aneurysms (UIA and aSAH) from February 2011 to August 2012 were included. Standardized high resolution B-mode ultrasound assessment of carotid arteries was done after aneurysm treatment, and traditional vascular risk factors were recorded. Healthy partners of young patients with ischemic stroke were used as controls. RESULTS: 69 patients treated for UIA (n=28) and aSAH (n=41) were compared with 80 controls. Mean IMT was higher in patients with aSAH (0·79 mm) than patients with UIA (0·65 mm) and controls (0·63 mm). Multiple multinomial regression analysis comparing aSAH, UIA and control groups demonstrated that IMT was the only variable predicative of aSAH compared to UIA. According to the multiple regression model, the probability of having aSAH compared to non-rupture increased by 62% for each 0·10 mm increment of mean IMT (RRR=1·62, P=0·017). Taking into account only patients harboring intracranial aneurysms, simple binary logistic regression was then applied to the UIA and aSAH groups. According to this model the risk of belonging to the aSAH group increased with higher mean IMT values (OR=1·40 per 0·10 mm increase of mean IMT, P=0·024). CONCLUSION: There is an association between IMT and intracranial aneurysm rupture status at the time of aneurysm treatment. Carotid IMT can be a potential predictor of aneurysm rupture. IMT may thus be a possible adjunct in the risk assessment of aneurysm rupture, and a helpful tool in patient risk stratification and counseling.

Quantitative proteomics comparison of arachnoid cyst fluid and cerebrospinal fluid collected perioperatively from arachnoid cyst patients.

BACKGROUND: There is little knowledge concerning the content and the mechanisms of filling of arachnoid cysts. The aim of this study was to compare the protein content of arachnoid cysts and cerebrospinal fluid by quantitative proteomics to increase the understanding of arachnoid cysts. METHODS: Arachnoid cyst fluid and cerebrospinal fluid from five patients were analyzed by quantitative proteomics in two separate experiments.In a label-free experiment arachnoid cyst fluid and cerebrospinal fluid samples from individual patients were trypsin digested and analyzed by Orbitrap mass spectrometry in a label-free manner followed by data analysis using the Progenesis software.In the second proteomics experiment, a patient sample pooling strategy was followed by MARS-14 immunodepletion of high abundant proteins, trypsin digestion, iTRAQ labelling, and peptide separation by mix-phase chromatography followed by Orbitrap mass spectrometry analysis. The results from these analyzes were compared to previously published mRNA microarray data obtained from arachnoid membranes. RESULTS: We quantified 348 proteins by the label-free individual patient approach and 1425 proteins in the iTRAQ experiment using a pool from five patients of arachnoid cyst fluid and cerebrospinal fluid. This is by far the largest number of arachnoid cyst fluid proteins ever identified, and the first large-scale quantitative comparison between the protein content of arachnoid cyst fluid and cerebrospinal fluid from the same patients at the same time. Consistently in both experiment, we found 22 proteins with significantly increased abundance in arachnoid cysts compared to cerebrospinal fluid and 24 proteins with significantly decreased abundance. We did not observe any molecular weight gradient over the arachnoid cyst membrane. Of the 46 proteins we identified as differentially abundant in our study, 45 were also detected from the mRNA expression level study. None of them were previously reported as differentially expressed. We did not quantify any of the proteins corresponding to gene products from the ten genes previously reported as differentially abundant between arachnoid cysts and control arachnoid membranes. CONCLUSIONS: From our experiments, the protein content of arachnoid cyst fluid and cerebrospinal fluid appears to be similar. There were, however, proteins that were significantly differentially abundant between arachnoid cyst fluid and cerebrospinal fluid. This could reflect the possibility that these proteins are affected by the filling mechanism of arachnoid cysts or are shed from the membranes into arachnoid cyst fluid. Our results do not support the proposed filling mechanisms of oncotic pressure or valves.