Jørgen Vildershøj Bjørnholt

Changes in physical fitness and changes in mortality

BACKGROUND Point estimates of physical fitness give important information on the risk of death in healthy people, but there is little information available on effects of sequential changes in physical fitness on mortality. We studied this latter aspect in healthy middle-aged men over a total follow-up period of 22 years. METHODS 2014 healthy men aged 40-60 years had a bicycle exercise test and clinical examination, and completed a questionnaire in 1972-75 (survey 1). This was repeated for 1756 (91%) of 1932 men still alive by Dec 31, 1982 (survey 2). The exercise scores were adjusted for age. The change in exercise scores between surveys was divided into quartiles (Q1=least fit, Q4=fittest). An adjusted Coxs proportional hazards model was used to study the association between changes in physical fitness and mortality, with the Q1 men used as controls. FINDINGS By Dec 31, 1994, 238 (17%) of the 1428 men had died, 120 from cardiovascular causes. There were 37 deaths in the Q4 group (19 cardiovascular); their relative risks of death were 0.45 (95% CI 0.29-0.69) for any cause and 0.47 (0.26-0.86) for cardiovascular causes. There was a graded, inverse relation between changes in physical fitness and mortality irrespective of physical fitness status at survey 1. INTERPRETATION Change in physical fitness in healthy middle-aged men is a strong predictor of mortality. Even small improvements in physical fitness are associated with a significantly lowered risk of death. If confirmed, these findings should be used to influence public health policy.

Lung function, smoking and mortality in a 26-year follow-up of healthy middle-aged males

Lung function has been associated with mortality after adjusting for other risk factors; however, few studies have adjusted for physical fitness and reported separate analyses according to smoking status. In 1972–1975, spirometry, clinical and physiological parameters were recorded in 1,623 apparently healthy males aged 40–59 yrs. After 26 yrs of follow-up, the current authors investigated the association between baseline lung function and mortality, adjusting for smoking, physical fitness and other potential factors. By 2000, 615 individuals (38%) had died, with 308 (50%) of these deaths from cardiovascular (CV) causes. Forced expiratory volume in one second was a predictor of all-cause mortality (risk ratio (RR) 1.10 per reduction of 10%) after adjusting for smoking, physical fitness, age, systolic blood pressure, body mass index and serum cholesterol. The corresponding multivariate RR was 1.07 for CV causes and 1.34 for respiratory death. In conclusion, in stratified analyses among current and former smokers, forced expiratory volume in one second % predicted was a strong independent predictor of all-cause mortality and respiratory death among current smokers. Forced expiratory volume in one second % predicted was not associated with mortality among never-smokers.

Novel Developmental Analyses Identify Longitudinal Patterns of Early Gut Microbiota that Affect Infant Growth

It is acknowledged that some obesity trajectories are set early in life, and that rapid weight gain in infancy is a risk factor for later development of obesity. Identifying modifiable factors associated with early rapid weight gain is a prerequisite for curtailing the growing worldwide obesity epidemic. Recently, much attention has been given to findings indicating that gut microbiota may play a role in obesity development. We aim at identifying how the development of early gut microbiota is associated with expected infant growth. We developed a novel procedure that allows for the identification of longitudinal gut microbiota patterns (corresponding to the gut ecosystem developing), which are associated with an outcome of interest, while appropriately controlling for the false discovery rate. Our method identified developmental pathways of Staphylococcus species and Escherichia coli that were associated with expected growth, and traditional methods indicated that the detection of Bacteroides species at day 30 was associated with growth. Our method should have wide future applicability for studying gut microbiota, and is particularly important for translational considerations, as it is critical to understand the timing of microbiome transitions prior to attempting to manipulate gut microbiota in early life.

Possible angina detected by the WHO angina questionnaire in apparently healthy men with a normal exercise ECG: coronary heart disease or not? A 26 year follow up study.

Objective: To determine whether men with possible angina (from their responses to the World Health Organization angina questionnaire) but a normal exercise ECG differ in long term rates of coronary heart disease events from men with no symptoms of angina. Design: During 1972–75, 2014 apparently healthy men aged 40–59 years underwent an examination programme including case history, clinical examination, exercise ECG to exhaustion, and various other tests. All men completed the WHO angina questionnaire. Subjects: Of 2014 men, 68 had possible angina, 1831 had no symptoms of angina, and 115 were excluded because they had definite angina or pathological exercise ECGs. All 68+1831 had normal exercise ECGs and none developed chest pain during the exercise test. Results: At 26 years, men with possible angina had a coronary heart disease mortality of 25.0% (17/68) v 13.8% (252/1831) among men with no symptoms of angina (p < 0.013). They also had a higher incidence of coronary artery bypass grafting (CABG) (p < 0.0004) and acute myocardial infarction (p < 0.026). The excess coronary heart disease mortality among men with possible angina only started after 15 years, whereas differences in CABG/acute myocardial infarction started early. Multivariate analysis including well recognised coronary heart disease risk factors showed that possible angina was an independent risk factor (relative risk 1.79, 95% confidence interval 1.26 to 2.10). Conclusions: Men with possible angina, even with a normal exercise test, have a greater risk of dying from coronary heart disease, having an acute myocardial infarct, or needing a CABG than age matched counterparts with no symptoms of angina.

Methicillin-Resistant Staphylococcus aureus CC398 in Humans and Pigs in Norway: A “One Health” Perspective on Introduction and Transmission

This study provides strong, novel evidence that humans may introduce methicillin-resistant Staphylococcus aureus CC398 into closed pig populations; it also demonstrates that stringent control and eradication measures were effective and prevented dissemination from pig farms to the general human population.

Nosocomial candidemia; risk factors and prognosis revisited; 11 years experience from a Norwegian secondary hospital.

The aim of the study was to review the epidemiology and prognosis of candidemia in a secondary hospital, and to examine the intra-hospital distribution of candidemia patients. Study design is a retrospective cohort study. Trough 2002–2012, 110 cases of candidemia were diagnosed, giving an incidence of 2, 6/100000 citizens/year. Overall prognosis of candidemia was dismal, with a 30 days case fatality rate of 49% and one year case fatality rate of 64%. Candidemia was a terminal event in 55% of 30 days non-survivors, defined as Candida blood cultures reported positive on the day of death or thereafter (39%), or treatment refrained due to hopeless short-term prognosis (16%). In terminal event candidemias, advanced or incurable cancer was present in 29%. Non-survivors at 30 days were 9 years (median) older than survivors. In 30 days survivors, candidemia was not recognised before discharge in 13% of cases. No treatment were given and no deaths or complications were observed in this group. Candidemia patients were grouped into 8 patient categories: Abdominal surgery (35%), urology (13%), other surgery (11%), pneumonia (13%), haematological malignancy (7%), intravenous drug abuse (4%), other medical (15%), and new-borns (3%). Candidemia was diagnosed while admitted in the ICU in 46% of patients. Urology related cases were all diagnosed in the general ward. Multiple surgical procedures were done in 60% of abdominal surgery patients. Antibiotics were administered prior to candidemia in 87% of patients, with median duration 17 (1–108) days. Neutropenia was less common than expected in patients with candidemia (8/105) and closely associated to haematological malignancy (6/8). Compared with previous national figures the epidemiology of invasive candidiasis seems not to have changed over the last decade.

Symptom-limited exercise testing, ST depressions and long-term coronary heart disease mortality in apparently healthy middle-aged men

Background Previous studies have shown that ST depressions ≤ 1.0 mm during or post-exercise increase long-term risk of dying from coronary heart disease (CHD), the need for coronary artery bypass grafting (CABG) or the development of acute myocardial infarction (AMI) in healthy men. In the present prospective cohort study we investigate whether less marked ST depressions may influence CHD mortality, incidence of AMI, the need for a CABG or having a non-fatal stroke. Methods During 1972–75, 2014 men aged 40–59 years, free from somatic diseases and not using any drugs, underwent an examination programme including case history, clinical examination, various blood tests and a symptom-limited exercise ECG-test. ECG was registered during exercise and at 30 s, 1, 2, 3 and 5 min post-exercise. The possible prognostic impact of ST-changes of 0.50–0.99 mm and ≤ 1.00 mm compared with normal ST-segments were studied separately and combined. Horizontal, down-sloping and slowly up-sloping ST-segment patterns were combined. Results After adjustment for age, smoking, blood pressure, cholesterol, maximal heart rate, left ventricular hypertrophy and physical fitness ST depressions ≤ 0.50 mm - during and/or post-exercise - were associated with a 1.47-fold [95% confidence interval (CI) 1.10–1.95], and 1.54-fold (95% CI of 1.17–2.04) increased 26 years risk of CHD-mortality, respectively. The same ST-changes also increased 22 years risk of developing non-fatal AMI or needing CABG but not developing non-fatal stroke. Conclusions Even an ST depression ≤ 0.50 mm during and/or after exercise increases the long-term risk of CHD-death, developing an AMI or needing CABG. No association was found between ST-changes and incidence of non-fatal strokes.

Molecular and epidemiological characterization of carbapenemase-producing Enterobacteriaceae in Norway, 2007 to 2014

The prevalence of carbapenemase-producing Enterobacteriaceae (CPE) is increasing worldwide. Here we present associated patient data and molecular, epidemiological and phenotypic characteristics of all CPE isolates in Norway from 2007 to 2014 confirmed at the Norwegian National Advisory Unit on Detection of Antimicrobial Resistance. All confirmed CPE isolates were characterized pheno- and genotypically, including by whole genome sequencing (WGS). Patient data were reviewed retrospectively. In total 59 CPE isolates were identified from 53 patients. Urine was the dominant clinical sample source (37%) and only 15% of the isolates were obtained from faecal screening. The majority of cases (62%) were directly associated with travel or hospitalization abroad, but both intra-hospital transmission and one inter-hospital outbreak were observed. The number of CPE cases/year was low (2–14 cases/year), but an increasing trend was observed. Klebsiella spp. (n = 38) and E. coli (n = 14) were the dominant species and blaKPC (n = 20), blaNDM (n = 19), blaOXA-48-like (n = 12) and blaVIM (n = 7) were the dominant carbapenemase gene families. The CPE isolates were genetically diverse except for K. pneumoniae where clonal group 258 associated with blaKPC dominated. All isolates were multidrug-resistant and a significant proportion (21%) were resistant to colistin. Interestingly, all blaOXA-48-like, and a large proportion of blaNDM-positive Klebsiella spp. (89%) and E. coli (83%) isolates were susceptible in vitro to mecillinam. Thus, mecillinam could have a role in the treatment of uncomplicated urinary tract infections caused by OXA-48- or NDM-producing E. coli or K. pneumoniae. In conclusion, the impact of CPE in Norway is still limited and mainly associated with travel abroad, reflected in the diversity of clones and carbapenemase genes.

DNA microarray analysis of Staphylococcus aureus causing bloodstream infection: bacterial genes associated with mortality?

Providing evidence for microbial genetic determinants’ impact on outcome in Staphylococcus aureus bloodstream infections (SABSI) is challenging due to the complex and dynamic microbe–host interaction. Our recent population-based prospective study reported an association between the S. aureus clonal complex (CC) 30 genotype and mortality in SABSI patients. This follow-up investigation aimed to examine the genetic profiles of the SABSI isolates and test the hypothesis that specific genetic characteristics in S. aureus are associated with mortality. SABSI isolates (n = 305) and S. aureus CC30 isolates from asymptomatic nasal carriers (n = 38) were characterised by DNA microarray analysis and spa typing. Fisher’s exact test, least absolute shrinkage and selection operator (LASSO) and elastic net regressions were performed to discern within four groups defined by patient outcome and characteristics. No specific S. aureus genetic determinants were found to be associated with mortality in SABSI patients. By applying LASSO and elastic net regressions, we found evidence suggesting that agrIII and cna were positively and setC (=selX) and seh were negatively associated with S. aureus CC30 versus non-CC30 isolates. The genes chp and sak, encoding immune evasion molecules, were found in higher frequencies in CC30 SABSI isolates compared to CC30 carrier isolates, indicating a higher virulence potential. In conclusion, no specific S. aureus genes were found to be associated with mortality by DNA microarray analysis and state-of-the-art statistical analyses. The next natural step is to test the hypothesis in larger samples with higher resolution methods, like whole genome sequencing.

Hypothesis: The recent decline in coronary heart disease mortality - Mainly a shift from fatal to non-fatal events?

OBJECTIVES A marked, sequential decline in coronary heart disease (CHD) mortality is established, but not its causes. Does it reflect modern treatment effects or a spinoff of primary prevention? The aim of this study was to explore this issue using a prospective cohort follow-up design. DESIGN In 1972-1975 and 1980-1982 Cohorts 1 (n = 613) and 2 (n = 667) of identical age (males, mean 56 years) were examined, and thereafter followed closely for 14 years. CHD risk- and treatment patterns, incidence of non-fatal myocardial infarctions (MIs) and total-, cardiovascular and CHD mortality rates were studied. RESULTS CHD risk factors were more favourable, medical treatment more aggressive and 14-years CHD mortality, as expected, lower in Cohort 2 (7.7%/4.8%, p = 0.032). However, hospital- and prospective ECG data revealed opposite trends in non-fatal cohort CHD incidence, and aggregated numbers of CHD deaths and non-fatal MI cases were 16.7%/16.0% in Cohort 1/2 (p = 0.90). CONCLUSIONS A marked, sequential reduction in CHD mortality was followed by a reciprocal increase in non-fatal MIs. This phenomenon may prevail in low CHD-endemic areas, and may call for altered primary preventive measures for reduction in total CHD incidence.Objectives- A marked, sequential decline in coronary heart disease (CHD) mortality is established, but not its causes. Does it reflect modern treatment effects or a spinoff of primary prevention? The aim of this study was to explore this issue using a prospective cohort follow-up design. Design- In 1972-1975 and 1980-1982 Cohorts 1 (n = 613) and 2 (n = 667) of identical age (males, mean 56 years) were examined, and thereafter followed closely for 14 years. CHD risk- and treatment patterns, incidence of non-fatal myocardial infarctions (MIs) and total-, cardiovascular and CHD mortality rates were studied. Results- CHD risk factors were more favourable, medical treatment more aggressive and 14-years CHD mortality, as expected, lower in Cohort 2 (7.7%/4.8%, p = 0.032). However, hospital- and prospective ECG data revealed opposite trends in non-fatal cohort CHD incidence, and aggregated numbers of CHD deaths and non-fatal MI cases were 16.7%/16.0% in Cohort 1/2 (p = 0.90). Conclusions- A marked, sequential reduction in CHD mortality was followed by a reciprocal increase in non-fatal MIs. This phenomenon may prevail in low CHD-endemic areas, and may call for altered primary preventive measures for reduction in total CHD incidence.