Biomarkers predictive of atrial fibrillation in patients with cryptogenic stroke. Insights from the Nordic Atrial Fibrillation and Stroke (NOR-FIB) study.

BACKGROUND AND PURPOSE: There are currently no biomarkers to select cryptogenic stroke (CS) patients for monitoring with insertable cardiac monitors (ICMs), the most effective tool for diagnosing atrial fibrillation (AF) in CS. The purpose of this study was to assess clinically available biomarkers as predictors of AF. METHODS: Eligible CS and cryptogenic transient ischaemic attack patients underwent 12-month monitoring with ICMs, clinical follow-up and biomarker sampling. Levels of cardiac and thromboembolic biomarkers, taken within 14 days from symptom onset, were compared between patients diagnosed with AF (n = 74) during monitoring and those without AF (n = 185). Receiver operating characteristic curves were created. Biomarkers reaching area under the receiver operating characteristic curve ≥ 0.7 were dichotomized by finding optimal cut-off values and were used in logistic regression establishing their predictive value for increased risk of AF in unadjusted and adjusted models. RESULTS: B-type natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase, D-dimer and high-sensitivity cardiac troponin I and T were significantly higher in the AF than non-AF group. BNP and NT-proBNP reached the predefined area under the curve level, 0.755 and 0.725 respectively. Optimal cut-off values were 33.5 ng/l for BNP and 87 ng/l for NT-proBNP. Regression analysis showed that NT-proBNP was a predictor of AF in both unadjusted (odds ratio 7.72, 95% confidence interval 3.16-18.87) and age- and sex-adjusted models (odds ratio 4.82, 95% confidence interval 1.79-12.96). CONCLUSION: Several clinically established biomarkers were associated with AF. NT-proBNP performed best as AF predictor and could be used for selecting patients for long-term monitoring with ICMs.

De-labelling penicillin allergy in acutely hospitalized patients: a pilot study.

BACKGROUND: Penicillin allergy prevalence is internationally reported to be around 10%. However, the majority of patients who report a penicillin allergy do not have a clinically significant hypersensitivity. Few patients undergo evaluation, which leads to overuse of broad-spectrum antibiotics. The objective of this study was to monitor prevalence and implement screening and testing of hospitalized patients. METHODS: All patients admitted to the medical department in a local hospital in Oslo, Norway, with a self-reported penicillin allergy were screened using an interview algorithm to categorize the reported allergy as high-risk or low-risk. Patients with a history of low-risk allergy underwent a direct graded oral amoxicillin challenge to verify absence of a true IgE-type allergy. RESULTS: 257 of 5529 inpatients (4.6%) reported a penicillin allergy. 191 (74%) of these patients underwent screening, of which 86 (45%) had an allergy categorized as low-risk. 54 (63%) of the low-risk patients consented to an oral test. 98% of these did not have an immediate reaction to the amoxicillin challenge, and their penicillin allergy label could thus be removed. 42% of the patients under treatment with antibiotics during inclusion could switch to treatment with penicillins immediately after testing, in line with the national recommendations for antibiotic use. CONCLUSIONS: The prevalence of self-reported penicillin allergy was lower in this Norwegian population, than reported in other studies. Screening and testing of hospitalized patients with self-reported penicillin allergy is a feasible and easy measure to de-label a large proportion of patients, resulting in immediate clinical and environmental benefit. Our findings suggest that non-allergist physicians can safely undertake clinically impactful allergy evaluations.

Atrial fibrillation in cryptogenic stroke and transient ischaemic attack - The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study: Rationale and design.

PURPOSE: Paroxysmal atrial fibrillation is often suspected as a probable cause of cryptogenic stroke. Continuous long-term ECG monitoring using insertable cardiac monitors is a clinically effective technique to screen for atrial fibrillation and superior to conventional follow-up in cryptogenic stroke. However, more studies are needed to identify factors which can help selecting patients with the highest possibility of detecting atrial fibrillation with prolonged rhythm monitoring. The clinical relevance of short-term atrial fibrillation, the need for medical intervention and the evaluation as to whether intervention results in improved clinical outcomes should be assessed. METHOD: The Nordic Atrial Fibrillation and Stroke Study is an international, multicentre, prospective, observational trial evaluating the occurrence of occult atrial fibrillation in cryptogenic stroke and transient ischaemic attack. Patients with cryptogenic stroke or transient ischaemic attack from the Nordic countries are included and will have the Reveal LINQ® Insertable cardiac monitor system implanted for 12 months for atrial fibrillation detection. Biomarkers which can be used as predictors for atrial fibrillation and may identify patients, who could derive the most clinical benefit from the detection of atrial fibrillation by prolonged monitoring, are being studied. CONCLUSION: The primary endpoint is atrial fibrillation burden within 12 months of continuous rhythm monitoring. Secondary endpoints are atrial fibrillation burden within six months, levels of biomarkers predicting atrial fibrillation, CHA2DS2-VASc score, incidence of recurrent stroke or transient ischaemic attack, use of anticoagulation and antiarrhythmic drugs, and quality of life measurements. The clinical follow-up period is 12 months. The study started in 2017 and the completion is expected at the end of 2020.

Lower bone mineral density in older female endurance skiers - a cross-sectional, observational study.

BACKGROUND: Physical activity (PA) is generally beneficial for bone health, but the effect of high levels of PA over many years, in older women, is unknown. METHODS: T-score from Dual-energy X-ray absorptiometry (DXA), and self-reported baseline characteristics were recorded for 24 female, cross-country-skiing-competitors, aged 68-76 years, from the Birkebeiner Ageing Study. Data from 647 women in the same age range from the Tromso-6 population study, with recorded DXA findings, were used for comparison. RESULTS: The athletes reported a median(range) of 9(1-34) participations in the 54 km, yearly ski-race, indicating long-term PA. They also reported more moderate and high levels of PA than women in the general population (52% vs. 12 and 30% vs. 0%, respectively). The athletes had lower body mass index (BMI) than the controls (mean BMI 21.7 vs 26.9 kg/m2, p < 0.001). As many as 22/24(92%) of the athletes and 477/647(74%) of the controls had a low bone mineral density (BMD) (T-score < - 1), p 0.048, Pearson chi square test. Odds ratio (OR) of low BMD was 3.9 in athletes vs. controls (p 0.048, logistic regression), but adjusting for BMI largely diminished the effect estimate, which was no longer statistically significant (aOR 1.81, p 0.432). The proportion of self-reported fractures was the same in the two groups. CONCLUSIONS: This pilot study suggests that long-term, high levels of PA are associated with low bone mineral density in older women, and the finding might be due to differences in BMI. Despite the lower bone mineral density the athletes did not report more fractures.

Validity of the European short list of respiratory diseases: a 40-year autopsy study.

The predictors of autopsy and the accuracy of European short list (E) codes of respiratory diseases lack recent knowledge. A 10% random sample (n=6811) of inhabitants of Bergen, Norway, aged 20-70 years, was invited to participate in a survey in 1965-1971 (participation rate 83%). By December 31, 2005, 4387 (64%) participants had died and 1163 (27% of the deceased) had been given an autopsy. Causes of death were tuberculosis (E02, 0.2%), lung malignancy (E15, 3.5%), influenza (E38, 0.2%), pneumonia (E39, 6.5%) and chronic lower respiratory diseases (E40, 3.2%). Male sex, early deaths in the surveillance period and E15 were positive predictors of an autopsy examination, whereas old age and E39 were strong negative predictors. Among those referred for a post mortem examination, the cause of death was verified as tuberculosis in 0.3%, lung cancer in 8.1%, acute pneumonia in 2.0% and chronic obstructive lung diseases in 4.9%. Cohen's kappa coefficients (E codes versus autopsy) were 0.91 (95% CI 0.86-0.96) for E15, 0.37 (95% CI 0.20-0.54) for E39 and 0.65 (95% CI 0.54-0.76) for E40. These findings matter when deaths from respiratory diseases are used as end-points in epidemiological association studies and clinical trials.

The association between lung function and fatal stroke in a community followed for 4 decades.

BACKGROUND: Previous studies, all of <20 years of follow-up, have suggested an association between lung function and the risk of fatal stroke. This study investigates the stability of this association in a cohort followed for 4 decades. METHODS: The Bergen Clinical Blood Pressure Survey was conducted in Norway in 1964-1971. The risk of fatal stroke associated with forced expiratory volume after one second (FEV(1)) was estimated with Cox proportional hazards regression, making progressive adjustment for potential confounders. RESULTS: Of 5617 (84%) participants with recorded baseline FEV(1), 462 died from stroke over 152 786 subsequent person-years of follow-up according to mortality statistics of 2005; mean (SD) follow-up was 27 (12) years. An association between baseline FEV(1) (L) and fatal stroke was observed; HR=1.38 (95% CI 1.11 to 1.71) and HR=1.62 (95% CI 1.22 to 2.15) for men and women, respectively (adjusted for age and height). The findings were not explained by smoking, hypertension, diabetes, atherosclerosis, socioeconomic status, obstructive lung disease, physical inactivity, cholesterol or body mass index and persisted in subgroups of never-smokers, subgroups without respiratory symptoms and survivors of the first 20 years of follow-up. For male survivors with a valid FEV(1) at follow-up (1988-1990) (n=953), baseline FEV(1) (L) indicated a possible strong and independent association to the risk of fatal stroke after adjustments for individual changes in FEV(1) (ml/year) (HR 1.95 (95% CI 0.98 to 3.86)). CONCLUSION: There is a consistent, independent and long-lasting association between lung function and fatal stroke, probably irrespective of changes during adult life.

Ageing, physical activity and mortality--a 42-year follow-up study.

BACKGROUND: Physical activity (PA) is inversely associated with mortality in the general population. We wanted to quantify the association of self-reported PA with mortality from all causes, ischaemic heart disease (IHD) and stroke, and compare it with other known risk factors in different age segments. METHODS: The Bergen Clinical Blood Pressure Survey examined a sample of 6811 Norwegian men and women in 1965-71 with follow-up until 2005-07. Cox proportional hazard regression ratio (HR) and population attributable fraction (PAF) were calculated for the old (>65), middle-aged (45-64) and young adults (22-44), respectively. We minimized confounding and bias by progressive comprehensive adjustments and subgroup-analyses (excluding early follow-up deaths, participants with self-reported disease and participants with changes in their PA-level prior baseline due to disease). RESULTS: The HR [95% confidence interval (CI)] associated with a high PA-level was 0.63(0.56-0.71), 0.66(0.52-0.83) and 0.66(0.47-0.93) for mortality from all causes, IHD and stroke, respectively (reference: no participation in any of the listed activities, adjusted for age and gender). PAF (95% CI) of no/low activity (reference: any activity) was consistent across all age groups, varying from 7.3% (3.4-11.4) in the young adults to 9.1% (3.6-15.3) in the old. PAF of smoking and high s-cholesterol declined with increasing age [smoking from 19.9% (15.3-24.7) to 1.5% (-1.3 to 6.2) and s-cholesterol from 11.5% (5.6-17.5) to -9.5% (-18.1 to -0.7)], whereas PAF of hypertension increased from 5.3% (2.1-9.1) to 18.9% (8.3-28.4). CONCLUSION: The relative importance of traditional risk factors varies between the age groups, but physical activity is a major health promoting factor across all age segments and should be encouraged particularly in an ageing population.

Diagnostic validity of fatal cerebral strokes and coronary deaths in mortality statistics: an autopsy study.

Mortality statistics represent important endpoints in epidemiological studies. The diagnostic validity of cerebral stroke and ischemic heart disease recorded as the underlying cause of death in Norwegian mortality statistics was assessed by using mortality data of participants in the Bergen Clinical Blood Pressure Study in Norway and autopsy records from the Gade Institute in Bergen. In the 41 years of the study (1965-2005) 4,387 subjects had died and 1,140 (26%) had undergone a post mortem examination; 548 (12%) died from cerebral stroke and 1,120 (24%) from ischemic heart disease according to the mortality statistics, compared to 113 (10%) strokes and 323 (28%) coronary events registered in the autopsy records. The sensitivity and positive predictive value of fatal cerebral strokes in the mortality statistics were 0.75, 95% confidence interval (CI) [0.66, 0.83] and 0.86 [0.77, 0.92], respectively, whereas those of coronary deaths were 0.87 [0.84, 0.91] and 0.85 [0.81, 0.89] respectively. Cohen's Kappa coefficients were 0.78 [0.72, 0.84] for stroke and 0.80 [0.76, 0.84] for coronary deaths. In addition to female gender and increasing age at death, cerebral stroke was a negative predictor of an autopsy being carried out (odds ratio (OR) 0.69, 95% CI [0.54, 0.87]), whereas death from coronary heart disease was not (OR 1.14, 95% CI [0.97, 1,33]), both adjusted for gender and age at death. There was substantial agreement between mortality statistics and autopsy findings for both fatal strokes and coronary deaths. Selection for post mortem examinations was associated with age, gender and cause of death.

Increased mortality in the slim elderly: a 42 years follow-up study in a general population.

The Bergen Clinical Blood Pressure Study in Norway was used to examine the relationship between body mass index (BMI (kg/m(2))) and total mortality in different age segments. Of 6,811 invited subjects, 5,653 (84%) participated in the study (1965-1971) and 4,520 (66%) died during 182,798 person-years of follow-up (1965-2007). Mean age at baseline was 47.5 years; range 22-75 years. BMI (kg/m(2)) was calculated from standardized measurements of body height and weight and divided into four groups (<22.0, 22.0-24.9, 25.0-27.9, > or =28.0). The 20 years cumulative risk of death related to baseline BMI was U-shaped in the elderly (aged 65-75 years), whereas the pattern was more linear in the youngest age group (20-44 years). In contrast to the younger age groups, the highest mortality in the elderly was in the lower BMI range (<22.0 kg/m(2)) (adjusted Cox proportional Hazard Ratio 1.39, 95% Confidence Interval 1.10, 1.75) compared to the BMI reference group (22.0-24.9 kg/m(2)). This pattern persisted after 72 months of early follow-up exclusion and it was robust to adjustments for a wide range of possible confounders including gender, history of cardiovascular disease, respiratory disease or hypertension, smoking habits, physical activity, socioeconomic status, physical appearance and other anthropometric measures. The study shows that a low BMI is an appreciable independent risk factor of total mortality in the elderly, and not a result of subclinical disease or confounding factors such as current or previous smoking. Awareness of this issue ought to be emphasized in advice, care and treatment of elderly subjects.