Proteomic prediction of incident heart failure and its main subtypes.

AIM: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables. METHODS AND RESULTS: In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with non-parametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on N-terminal pro-B-type natriuretic peptide and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study. CONCLUSION: A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to 8 years, with predictor performance significantly improving for events occurring less than 1 year ahead, a finding replicated in an external cohort study.

[Involuntary medication in psychiatric units at Landspitali University Hospital in the years 2014-2018].

INTRODUCTION: Coercion is considered controversial and is criticized around the world. Involuntary medication is one type of coercion, but the extent of its use in Iceland is not well known. The aim of this study is to shed light on the extent and time of involuntary medication in Landspitali University Hospital in Iceland, when it is most often used and whether there is a difference between patients who receive involuntary medication and those who do not receive such treatment. MATERIAL AND METHODS: This study is a quantitative descriptive retrospective study using data obtained from medical records. The sample consisted of all patients admitted to the psychiatric inpatient wards at Landspitali University Hospital in Iceland in the years 2014-2018 (N=4053). The sample was divided into two groups, group 1 with patients who received involuntary medication n=400 (9.9%) and group 2 with patients who did not receive such treatment n=3653 (90.1%). RESULTS: The total number of involuntary medications was 2438 and about 1% of the total sample received about half of all involuntary medication. Involuntary medications were most frequent during the daytime during weekdays and late at night, but no notable difference was seen between months of the year. When comparing the groups, it appears that proportionally more men and patients with foreign citizenship are in group 1 than in group 2, but no notable difference is seen in age between groups. Patients in group 1 had more visits to the emergency services at Landspitali, more admissions, and patient days per patient at psychiatric wards in Landspitali than those in group 2. The most common medical diagnosis in group 1 were within the schizophrenia spectrum (F20-F29) and mood disorders (F30-39) but in group 2 the most common medical diagnosis were mental and behavioral disorders due to psychoactive substance use (F10-19) and mood disorders (F30-F39). CONCLUSION: Findings indicate certain risk factors for involuntary medication regarding demographic, medical diagnosis, use of services as well as external factors such as timing of involuntary medication. A more detailed analysis could be used to reduce the use of coercive treatment. Further research is needed on the use of coercion in psychiatric wards in Iceland.

A proteogenomic signature of age-related macular degeneration in blood.

Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the elderly, with a complex and still poorly understood etiology. Whole-genome association studies have discovered 34 genomic regions associated with AMD. However, the genes and cognate proteins that mediate the risk, are largely unknown. In the current study, we integrate levels of 4782 human serum proteins with all genetic risk loci for AMD in a large population-based study of the elderly, revealing many proteins and pathways linked to the disease. Serum proteins are also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study identifies several proteins that are causally related to the disease and are directionally consistent with the observational estimates. In this work, we present a robust and unique framework for elucidating the pathobiology of AMD.

Medication use in populations exposed to the 2010 Eyjafjallajökull eruption: an interrupted time series analysis.

OBJECTIVES: To assess the trends in medication use indicative of physical and psychological morbidity following the 2010 volcanic eruption in Eyjafjallajökull immediately after and during a 3-year period following the eruption. DESIGN: Population-based register study. SETTING: Eyjafjallajökull eruption in Iceland, 2007-2013. PARTICIPANTS: All residents in Iceland who received at least one medication dispensing were identified. Residents of exposed areas were classified into exposure groups (individual-level data) and residents in other parts of Iceland were included as a non-exposed group (aggregated data). INTERVENTION/EXPOSURE: Eyjafjallajökull erupted on 14 April 2010 and continued for 39 days, producing heavy ash fall in South Iceland. MAIN OUTCOME MEASURES: Using interrupted time series analysis, we examined annual and quarterly changes in medicine use, measured as number of dispensed defined daily dose (DDD) per 1000 individuals. We calculated the level shift (immediate change) and change in slope from pre-eruption to post-eruption (long-term change) in medication dispensing. RESULTS: Among exposed residents, there was a 6% decrease (95% CI -7% to -4%) in the annual number of dispensed DDDs 1-year post-eruption in the overall medication class, including analgesics (-5%, 95% CI -6% to -3%), hypnotics and sedatives (-9%, 95% CI -11% to -7%) and respiratory medications (-7%, 95% CI -9% to -5%; -8%, 95% CI -11% to -4%). Simultaneously, there was a 9% decrease (95% CI -14% to -4%) in the overall medication class among non-exposed residents. Moreover, among exposed residents, we observed change in slope of -4% (95% CI -7% to -1%) in the overall medication class, including for analgesics (-6%, 95% CI -8% to -3%) and other respiratory drugs (-10%, 95% CI -16% to -4%). CONCLUSION: Our findings indicate that the eruption did not lead to increases in medication dispensing among residents of exposed areas, rather decreases for some medicine classes. The results should be interpreted with caution since the content of each eruption differs.

A genome-wide association study of serum proteins reveals shared loci with common diseases.

With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein's genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.

Coding and regulatory variants are associated with serum protein levels and disease.

Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases.

Validation of the Modified Checklist for Autism in Toddlers, Revised with Follow-up in a Population Sample of 30-Month-Old Children in Iceland: A Prospective Approach.

The Modified Checklist for Autism in Toddlers, Revised with Follow-up was validated on a population sample in Reykjavik, Iceland. The participants (N = 1585) were screened in well-child care at age 30 months and followed up for at least 2 years to identify autism cases. The sensitivity, specificity, positive and negative predictive values were 0.62, 0.99, 0.72, and 0.99, respectively. True-positive children were diagnosed 10 months earlier than false-negative children. Autism symptom severity and the proportions of children with verbal and performance IQs/DQs < 70 were similar between groups. Although the sensitivity was suboptimal, the screening contributed to lowering the age at diagnosis for many children. Adding autism-specific screening to the well-child care program should be considered.

Outpatient physical therapy population has been aging faster than the general population: a total population register-based study.

BACKGROUND: The Icelandic population is aging like other populations in the world, the life expectancy is high, and the national focus is to help people to age in their own homes. The objectives of this research was to describe 17 years of demographic changes among outpatient physical therapy (OPT) clients and to determine if these changes reflect aging in the total population. METHODS: Data was obtained from a national registry with information on all OPT clients reimbursed by Icelandic Health Insurance from 1999 to 2015, and general population data from the Statistics Iceland registry covering the same 17 years. Simple counts, proportions, Rate Ratios (RR) and 95 % Confidence Intervals (CI) were used to describe and compare the two time-points (1999 and 2015) in both populations, and regression analyses were used to estimate linear changes for each of these 17 years. RESULTS: Comparing the endpoints of the 17-year period, the proportion of older adults within the total OPT clientele increased by 23 % (from 18.3 % to 1999 to 23.5 % in 2015; RR 1.23; 95 %CI 1.19-1.27).) while in the general Icelandic population, the proportion of older adults increased by 15 % (from 11.6 % to 1999 to 13.5 % in 2015; RR 1.15; 95 % CI 1.1-1.21). For each of these 17 years, there was an overall 5 % yearly increase in the rate of older adults from the general older Icelandic population who used an OPT (accounting for population aging), and an overall 3.5 % yearly increase in the proportional contribution of older adults to the total OPT clientele. Adjusting for sex and older age group revealed that this increase in rate and proportion was most pronounced among ≥ 85-year-old men. CONCLUSIONS: This case of Iceland is an example of how health-related and population-based registers may potentially be used to routinely inform and facilitate optimal planning of future health care services for older adults.

Serum levels of ACE2 are higher in patients with obesity and diabetes.

OBJECTIVE: As severity of outcome in COVID-19 is disproportionately higher among individuals with obesity, smokers, patients with hypertension, kidney disease, chronic pulmonary disease, coronary heart disease (CHD), and/or type 2 diabetes (T2D), serum levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2, were examined in these high-risk groups. METHODS: Associations of ACE2 levels to smokers and patients with hypertension, T2D, obesity, CHD, or COPD were investigated in a single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavík Study (AGES-RS) of the elderly (mean age 75 ± 6 years), using multiple linear regression analysis. RESULTS: Serum levels of ACE2 were higher in smokers and individuals with T2D and/or obesity while they were unaffected in the other patient groups. CONCLUSION: ACE2 levels are higher in some patient groups with comorbidities linked to COVID-19 including obesity and T2D and as such may have an emerging role as a circulating biomarker for severity of outcome in the disease.

Antihypertensive medication uses and serum ACE2 levels: ACEIs/ARBs treatment does not raise serum levels of ACE2.

Importance: Recent reports have shown that hypertension is the most common comorbidity associated with mortality in the current coronavirus disease 2019 (COVID-19). This has been related to the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) as animal studies indicate that these medications increase levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2. This has prompted clinicians to recommend discontinuing ACEIs and ARBs. Objective: To examine the effect of ACEIs or ARBs treatment on serum levels of ACE2 and other key enzymes in the renin-angiotensin system (RAS). Design Setting and Participants: A single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75±6 years) stratified by ACEIs (N = 699) or ARBs (N = 753) treatment. Main Outcomes and Measures: The AGES-RS study population was stratified by ACEIs and ARBs medication use and compared for age, body mass index (BMI) (kg/m2), hypertension and type 2 diabetes (T2D) as well as serum levels of renin, ACE and ACE2. Results: While renin and ACE levels were significantly raised in serum of individuals on ACEIs or ARBs treatments, the ACE2 levels remained unaffected. Conclusions and Relevance: Treatment with ACEIs or ARBs does not raise ACE2 levels in serum. Therefore, the present study does not support the proposed discontinuation of these medications among patients affected with COVID-19.

ACE2 levels are altered in comorbidities linked to severe outcome in COVID-19.

AIMS: Severity of outcome in COVID-19 is disproportionately higher among the obese, males, smokers, those suffering from hypertension, kidney disease, coronary heart disease (CHD) and/or type 2 diabetes (T2D). We examined if serum levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2, were altered in these high-risk groups. METHODS: Associations of serum ACE2 levels to hypertension, T2D, obesity, CHD, smokers and males in a single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75+/-6 years). RESULTS: Smokers, males, and individuals with T2D or obesity have altered serum levels of ACE2 that may influence productive infection of SARS-CoV-2 in these high-risk groups. CONCLUSION: ACE2 levels are upregulated in some patient groups with comorbidities linked to COVID-19 and as such may have an emerging role as a circulating biomarker for severity of outcome in COVID-19.

[Effects of cardiac rehabilitation on the physical capacity of individuals with heart failure].

PURPOSE: Limited information is available on the effects of cardiac rehabilitation (CR) on individuals with heart failure (HF) in Iceland. The aim of this study was to analyze whether CR yielded increased physical capacity (PC) (w/kg) as measured by maximum exercise test at the end of the training period. MATERIALS AND METHODS: This is a retrospective data study from January 2010 to June 2018. Participants were patients with HF and also patients with ejection fraction (EF) 45% or less. Age and other diagnoses did not limit participation. Information about EF and exercise test at the beginning and end of the training period had to be recorded. Relative change in PC on these tests was evaluated by general linear models for repeated measurements. During the study period, 112 participants were enrolled, 27 did not finish the training period and 9 had incomplete data. Data from 76 participants aged 36-83 were analyzed. RESULTS: Participants' PC increased on average by 16% (p<0.001; confidence interval 13-18%). On average, those who attended training more than twice a week improved their PC by 18% which is -significantly more than those who trained twice or less who improved by 6%. The age group 65-83 improved by 19%, which is significantly more compared to the age group 36-64, which added 12%. No significant difference was in improvement between groups with EF under 40% or 40% and more. CONCLUSION: Focused CR for individuals with HF and individuals with impaired EF resulted in increased PC.

[Review of epidemiology of fractures in the Icelandic Heart Association cohort].

IIn recent years, scientific papers have been published in Osteoporosis International on the epidemiology of fractures in Iceland based on the Icelandic Heart Association cohort. We report the main results with emphasis on the major osteoporotic fractures (MOF), distal forearm, upper arm, clinical vertebral and hip. Those four types of fractures have been reported to cause about 90% of the total burden of all osteoporotic fractures. The incidence of those four fractures in the Icelandic Heart Association cohort have been used as the basis for the international fracture risk calculator "FRAX "in Iceland. "FRAX" assesses the risk of those fractures for the next 10 years in both sexes in the age group 40-90 years. FRAX Iceland was opened on the internet in the year 2013. We emphasize the importance of previous fracture history as almost 40% of all major osteoporotic fractures occur after first MOF according to our cohort. The results demonstrate the importance of time from the first fracture as the risk of the second fracture is greater in the first two years although increased risk remains during the next 20 years. This indicates the importance of secondary prevention early after the first fracture especially amongst elderly people. These results give a good overall view about the epidemiology of fractures in Iceland in comparison with foreign studies and shows that age standardized incidence of the most important osteoporotic fracture, the hip fracture, reached a maximum around the millennium but has decreased among women until 2008 similar to what has been observed in Sweden and Denmark.

Fracture risk assessment in older adults using a combination of selected quantitative computed tomography bone measures: a subanalysis of the Age, Gene/Environment Susceptibility-Reykjavik Study.

Bone mineral density (BMD) and geometric bone measures are individually associated with prevalent osteoporotic fractures. Whether an aggregate of these measures would better associate with fractures has not been examined. We examined relationships between self-reported fractures and selected bone measures acquired by quantitative computerized tomography (QCT), a composite bone score, and QCT-acquired dual-energy X-ray absorptiometry-like total femur BMD in 2110 men and 2682 women in the Age, Gene/Environment Susceptibility-Reykjavik Study. The combined bone score was generated by summing gender-specific Z-scores for 4 QCT measures: vertebral trabecular BMD, femur neck cortical thickness, femur neck trabecular BMD, and femur neck minimal cross-sectional area. Except for the latter measure, lower scores for QCT measures, singly and combined, showed positive (p < 0.05) associations with fractures. Results remained the same in stratified models for participants not taking bone-promoting medication. In women on bone-promoting medication, greater femur neck cortical thickness and trabecular BMD were significantly associated with fracture status. However, the association between fracture and combined bone score was not stronger than the associations between fracture and individual measures or total femur BMD. Thus, the selected measures did not all similarly associate with fracture status and did not appear to have an additive effect on fracture status.

Mid-thigh cortical bone structural parameters, muscle mass and strength, and association with lower limb fractures in older men and women (AGES-Reykjavik Study).

In a cross-sectional study we investigated the relationship between muscle and bone parameters in the mid-thigh in older people using data from a single axial computed tomographic section through the mid-thigh. Additionally, we studied the association of these variables with incident low-trauma lower limb fractures. A total of 3,762 older individuals (1,838 men and 1,924 women), aged 66-96 years, participants in the AGES-Reykjavik study, were studied. The total cross-sectional muscular area and knee extensor strength declined with age similarly in both sexes. Muscle parameters correlated most strongly with cortical area and total shaft area (adjusted for age, height, and weight) but explained <10 % of variability in those bone parameters. The increment in medullary area (MA) and buckling ratio (BR) with age was almost fourfold greater in women than men. The association between MA and muscle parameters was nonsignificant. During a median follow-up of 5.3 years, 113 women and 66 men sustained incident lower limb fractures. Small muscular area, low knee extensor strength, large MA, low cortical thickness, and high BR were significantly associated with fractures in both sexes. Our results show that bone and muscle loss proceed at different rates and with different gender patterns.

Effect of vertebral fractures on function, quality of life and hospitalisation the AGES-Reykjavik study.

BACKGROUND: understanding the determinants of health burden after a fracture in ageing populations is important. OBJECTIVE: assess the effect of clinical vertebral and other osteoporotic fractures on function and the subsequent risk of hospitalisation. DESIGN: individuals from the prospective population-based cohort study Age, Gene/Environment Susceptibility (AGES)-Reykjavik study were examined between 2002 and 2006 and followed up for 5.4 years. SUBJECTS: a total of 5,764 individuals, 57.7% women, born 1907-35, mean age 77. METHOD: four groups with a verified fracture status were used; vertebral fractures, other osteoporotic fractures excluding vertebral, non-osteoporotic fractures and not-fractured were compared and analysed for the effect on mobility, strength, QoL, ADL, co-morbidity and hospitalisation. RESULTS: worst performance on functional tests was in the vertebral fracture group for women (P < 0.0001) and the other osteoporotic fractures group for men (P < 0.05). Both vertebral and other osteoporotic fractures, showed an increased risk of hospitalisation, HR = 1.4 (95% CI: 1.3-1.7) and 1.2 (95% CI: 1.1-1.2) respectively (P < 0.0001). Individuals with vertebral fractures had 50% (P < 0.0001) longer hospitalisation than not-fractured and 33% (P < 0.002) longer than the other osteoporotic fractures group. CONCLUSION: individuals with a history of clinical vertebral fracture seem to carry the greatest health burden compared with other fracture groups, emphasising the attention which should be given to those individuals.

Distribution of cortical bone in the femoral neck and hip fracture: a prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study.

In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm², DXA-like), (p=0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n=143) from controls (n=298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture.

Surgical treatment of depression fractures of the lateral tibial plateau using porous titanium granules.

The clinical and radiological results were excellent in this pilot study of four cases of depression fracture of the lateral tibial plateau, where, in addition to internal fixation with screws or a buttress plate, porous titanium granules were used to support the elevated articular surface.

The Hansson Twin Hook is adequate for fixation of trochanteric fractures: 2 fixation failures in a series of 157 prospectively followed patients.

BACKGROUND AND PURPOSE: The Hansson Twin Hook (HTH) is an alternative to the lag screw in the treatment of trochanteric fractures. In osteoporotic bone, mechanical tests have indicated that the HTH has better fixation properties than the lag screw. We evaluated the fixation stability of the HTH in a large series of elderly patients with trochanteric fractures. Many surgeons were involved in assessment of whether the device was user-friendly. PATIENTS AND METHODS: In a prospective bicentric study, 55 surgeons used the HTH and a standard plate in 157 consecutive patients with trochanteric fractures, 83% of which were unstable. The mean age of the patients was 83 (43-98) years. They were followed regularly clinically and radiographically for at least 4 months, with a radiographic file search at 2 years. RESULTS: Technical errors occurred intraoperatively in 7 cases. The reduction of the fracture was inaccurate in these patients; thus, the HTH had not been placed centrally in the femoral head. One of these errors was immediately and easily corrected without interference with the standard plate, and caused no further problems. 2 of the remaining 6 intraoperative errors developed into failures of fixation during the 2-year period. INTERPRETATION: The HTH gives adequate fixation in the bone of elderly patients with trochanteric fractures and has a low failure rate. It is also easy to use.