Hans Jørn Kolmos - Academia.edu (original) (raw)

Papers by Hans Jørn Kolmos

Clinical Microbiology and Infection, 2018

Clinical Chemistry and Laboratory Medicine (CCLM), 2021

Objectives To develop a crude screening method for detecting biomarkers which frequently exhibit ... more Objectives To develop a crude screening method for detecting biomarkers which frequently exhibit a rise (or fall) in level prior to a serious event (e.g. a stroke) in patients with a chronic disease, signalling that the biomarker may have an alarm-raising or prognostic potential. The subsequent assessment of the marker’s clinical utility requires costly, difficult longitudinal studies. Therefore, initial screening of candidate-biomarkers is desirable. Methods The method exploits a cohort of patients with biomarkers measured at entry and with recording of first serious event during follow-up. Copying those individual records onto a common timeline where a specific event occurs on the same day (Day 0) for all patients, the baseline biomarker level, when plotted against the patient’s entry time on the revised timeline, will have a positive (negative) regression slope if biomarker levels generally rise (decline) the closer one gets to the event. As an example, we study 1,958 placebo-tre...

Atherosclerosis, 2019

Background and aim: Raised levels of serum endostatin, a biologically active fragment of collagen... more Background and aim: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but associations with incident cardiovascular events in patients with stable coronary heart disease is uncertain. Methods: The CLARICOR-trial is a randomised, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or allcause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as a discovery sample (1204 events, n=1998) and the clarithromycin-treated group as replication sample (1220 events, n=1979). Results: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03-1.19, p=0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95 % CI 1.00-1.14, p=0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1%). Conclusion: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.

Atherosclerosis, 2018

Background and aims: The lysosomal cysteine proteases cathepsin B and S have been implicated in t... more Background and aims: The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and cardiovascular events and mortality in patients with stable coronary heart disease. Methods: The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycin group as replication sample: n=1998, n=1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomes n=1204, n=1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs. Results: Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05-1.19, p<0.001, replication; HR 1.14, 95% CI 1.07-1.21, p<0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events. Conclusions: Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established.

Journal of the American Heart Association, Jan 23, 2018

We aimed to assess the associations and predictive powers between the soluble receptors for tumor... more We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease. CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) is a randomized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease. The primary outcome was a composite of nonfatal acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. Patients were followed up for 10 years; discovery sample, those assigned placebo (1204 events in n=1998); and replication sample, those assigned clarithromycin (1220 events in n=1979). We used Cox regression adjusted for C-reactive protein level, established cardiovascular risk factors, kidney function, and cardiovascular drugs. After adjustments, higher serum levels of TNFR1 and TNFR2 were associated wit...

Diagnostic and Prognostic Research, 2017

Background: The purpose of the predictors for major cardiovascular outcomes in stable ischaemic h... more Background: The purpose of the predictors for major cardiovascular outcomes in stable ischaemic heart disease (PREMAC) study is exploratory and hypothesis generating. We want to identify biochemical quantities which-conditionally on the values of available standard demographic, anamnestic, and biochemical data-may improve the prediction of cardiovascular outcomes and/or death in patients suffering from stable ischaemic heart disease. The candidate biochemical quantities include N-terminal pro-B-type natriuretic peptide, YKL-40, osteoprotegerin, high-sensitive assay cardiac troponin T (hs-cTnT), pregnancy-associated plasma protein-A (PAPP-A), cathepsin B, cathepsin S, soluble TNF receptor 1 and 2, neutrophil gelatinase-associated lipocalin, endostatin, and calprotectin. As an extra objective, we also want to assess if skewness in these predictors may explain why the clarithromycin for patients with stable coronary heart disease (CLARICOR) trial found increased all-cause and cardiovascular (CV) mortality on a brief clarithromycin regimen compared with placebo. Methods: Baseline data were obtained from the hospital files at five cardiology clinics covering the Copenhagen area. The CLARICOR trial included data from 4372 stable coronary artery disease patients recruited among such patients alive and diagnosed with acute myocardial infarction or unstable angina pectoris during 1993 to 1999 in Copenhagen and randomised during October 1999 to April 2000 to the CLARICOR trial of 14 days clarithromycin versus placebo. Initial follow-up lasted for 2.6 years, during which outcomes were collected through hospital and death registries and assessed by an adjudication committee. Corresponding register data later showed to produce similar results. The adjudicated outcomes were therefore replaced and augmented by register data on outcomes to cover 10 years of follow-up. Biochemical marker data were obtained from analysis of serum from the CLARICOR bio-bank collected at randomisation and stored at −80°C. Using Cox proportional hazard method, we will identify among the candidate biochemical quantities those which are significant predictors when used alone and in combination with the standard predictors as defined in the present study.

Journal of the American College of Cardiology, 2012

Background: Stable coronary artery disease (CAD) is the most frequent cause of death in western c... more Background: Stable coronary artery disease (CAD) is the most frequent cause of death in western country. Elevated serum YKL-40 is a shortterm risk factor for myocardial infarction (MI), cardiovascular and all-cause mortality in patients with stable CAD.We investigated whether the inflammatory biomarker YKL-40, corrected for high-sensitivity C-reactive protein (hs-CRP) and N-terminal-pro-B natriuretic peptide (NT-proBNP), could be used as an independent long-term predictor of all-cause death in patients with stable CAD. Methods: Serum YKL-40, hs-CRP and NT-proBNP were measured in 4372 patients with stable CAD included in the Claricor trial and death was registered in a 6-years follow-up period. Results: 4265 (96.8% out of the 4372) patients had blood samples available for serum YKL-40, hs-CRP and NT-proBNP determination leaving 107 with one or more missing. Difference between these two groups was not significant. Serum YKL-40 (transformed as ln(max(83, YKL-40/μg/L)) was significantly associated with all-cause mortality [hazard ratio (HR) =1.55, 95% confidence interval (CI)=1.39-1.73, p<0.001] after multivariable adjustment for treatment with Clarithromycin, age, sex, hypertension, diabetes, smoking status, previous MI, diuretics, digoxin, statin. After additional adjustment for ln(hs-CRP) and ln(NT-proBNP) serum YKL-40 still contributed significantly to prediction of all-cause mortality [HR=1.38, 95%CI=1.21-1.53, p<0.001]. Conclusions: Increased serum YKL-40 is an independent predictor of long-term mortality in patients with stable CAD. Serum YKL-40 can potentially be used to monitor outcome in patients with CAD and maybe also for monitoring clinical treatment.

The new microbiologica, 2017

We have previously shown that the phenothiazine, thioridazine, acts in synergy with the beta-lact... more We have previously shown that the phenothiazine, thioridazine, acts in synergy with the beta-lactam antibiotic, dicloxacillin, to kill methicillin-resistant Staphylococcus aureus. In this study, we investigated whether synergy by combining these two drugs could also be observed in vancomycin intermediate susceptible S. aureus (VISA) and methicillin-resistant Staphylococcus epidermidis (MRSE). Synergy was observed in three of four tested VISA strains, suggesting that the thickening of cell wall does not interfere with the effects of thioridazine. In S. epidermidis, no synergy was observed in all tested strains, suggesting that synergy by combining thioridazine and dicloxacillin is isolated to S. aureus species.

PloS one, 2015

The rise in antimicrobial resistance is a major global concern and requires new treatment strateg... more The rise in antimicrobial resistance is a major global concern and requires new treatment strategies. The use of helper compounds, such as thioridazine (TDZ), an antipsychotic drug, in combination with traditional antibiotics must be investigated. The aim of this study was to investigate the efficacy of TDZ as a helper compound for dicloxacillin (DCX) against methicillin-resistant Staphylococcus aureus (MRSA) in vivo, and compare the combination treatment of DCX+TDZ with vancomycin (VAN). Mice were inoculated with an intraperitoneal (IP) injection of MRSA (108 CFU) and treated in a 12-hour cycle for 48 hours. By termination, bacterial quantities in a peritoneal flush, spleen and kidneys were obtained. In the main trial the drugs were administered subcutaneously in five treatment groups: 1) DCX, 2) TDZ, 3) DCX+TDZ, 4) VAN, 5) SALINE. Additional smaller studies with IP administration and higher subcutaneous dosages (×1.5 and ×4) of the drugs were subsequently performed. In the main tr...

Infectious Diseases, 2021

Background: The Nordic countries have comparable nationwide antibiotic resistance surveillance sy... more Background: The Nordic countries have comparable nationwide antibiotic resistance surveillance systems and individual antibiotic stewardship programmes. The aim of this study was to assess antibiotic resistance among major pathogens in relation to practice guidelines for hospital antibiotic treatment and antibiotic use in Nordic countries 2010-2018. Methods: Antibiotic resistance among invasive isolates from 2010-2018 and aggregated antibiotic use were obtained from the European Centre for Disease Prevention and Control. Hospital practice guidelines were obtained from national or regional guidelines. Results: Antibiotic resistance levels among Escherichia coli and Klebsiella pneumoniae were similar in all Nordic countries in 2018 and low compared to the European mean. Guidelines for acute pyelonephritis varied; 2nd generation cephalosporin (Finland), 3rd generation cephalosporins (Sweden, Norway), ampicillin with an aminoglycoside or aminoglycoside monotherapy (Denmark, Iceland and Norway). Corresponding guidelines for sepsis of unknown origin were 2nd (Finland) or 3rd (Sweden, Norway, Iceland) generation cephalosporins, carbapenems, (Sweden) combinations of penicillin with an aminoglycoside (Norway, Denmark), or piperacillin-tazobactam (all Nordic countries). Methicillin-resistant Staphylococcus aureus rates were 0-2% and empirical treatment with anti-MRSA antibiotics was not recommended in any country. Rates of penicillin non-susceptibility among Streptococcus pneumoniae were low (<10%) except in Finland and Iceland (<15%), but benzylpenicillin was recommended for community-acquired pneumonia in all countries. Conclusion: Despite similar resistance rates among Enterobacteriaceae there were differences in practice guidelines for pyelonephritis and sepsis. National surveillance of antibiotic resistance can be used for comparison and optimization of guidelines and stewardship interventions to preserve the low levels of antibiotic resistance in Nordic countries.

BMJ Open, 2020

ObjectiveTo assess if 12 novel circulating biomarkers, when added to ‘standard predictors’ availa... more ObjectiveTo assess if 12 novel circulating biomarkers, when added to ‘standard predictors’ available in general practice, could improve the 10-year prediction of cardiovascular events and mortality in patients with stable coronary heart disease.DesignThe patients participated as placebo receiving patients in the randomised clarithromycin for patients with stable coronary artery disease (CLARICOR) trial at a random time in their disease trajectory.SettingFive Copenhagen University cardiology departments and a coordinating centre.Participants1998 participants with stable coronary artery disease.OutcomesDeath and composite of myocardial infarction, unstable angina pectoris, cerebrovascular disease and death.ResultsWhen only ‘standard predictors’ were included, 83.4% of all-cause death predictions and 68.4% of composite outcome predictions were correct. Log(calprotectin) and log(cathepsin-S) were not associated (p≥0.01) with the outcomes, not even as single predictors. Adding the remain...

Emerging Infectious Diseases, 2016

We describe 2 fatal cases of methicillin-resistant Staphylococcus aureus (MRSA) clonal complex 39... more We describe 2 fatal cases of methicillin-resistant Staphylococcus aureus (MRSA) clonal complex 398 septicemia in persons who had no contact with livestock. Whole-genome sequencing of the isolated MRSA strains strongly suggest that both were of animal origin and that the patients had been infected through 2 independent person-to-person transmission chains.

Journal of Clinical Medicine, 2020

Elevated pregnancy-associated plasma protein A (PAPP-A) is associated with mortality in acute cor... more Elevated pregnancy-associated plasma protein A (PAPP-A) is associated with mortality in acute coronary syndromes. Few studies have assessed PAPP-A in stable coronary artery disease (CAD) and results are conflicting. We assessed the 10-year prognostic relevance of PAPP-A levels in stable CAD. The CLARICOR trial was a randomized controlled clinical trial including outpatients with stable CAD, randomized to clarithromycin versus placebo. The placebo group constituted our discovery cohort (n = 1.996) and the clarithromycin group the replication cohort (n = 1.975). The composite primary outcome was first occurrence of cardiovascular event or death. In the discovery cohort, incidence rates (IR) for the composite outcome were higher in those with elevated PAPP-A (IR 12.72, 95% Confidence Interval (CI) 11.0–14.7 events/100 years) compared to lower PAPP-A (IR 8.78, 8.25–9.34), with comparable results in the replication cohort. Elevated PAPP-A was associated with increased risk of the composi...

Open Heart, 2018

ObjectiveTo characterise the long-term prognosis of patients with stable coronary artery heart di... more ObjectiveTo characterise the long-term prognosis of patients with stable coronary artery heart disease by means of ‘standard predictors’ defined as demographic, clinical and biochemical quantities routinely available in general practices and ascertained at an interview not prompted by renewed cardiac complaints.MethodsThis is an observational study based on data from 2199 Copenhagen placebo patients from the ‘clarithromycin for patients with stable coronary heart disease’ trial of patients with stable coronary heart disease. In the trial, we compared the effects of 14 days of clarithromycin treatment versus placebo. The predictors were based on the interview forms and blood samples collected at entry, along with demographic information from hospital files.We studied ‘standard predictors’ of a composite outcome (myocardial infarction, unstable angina, cerebrovascular disease or all-cause death) and of all-cause death. Using Cox regression, we compared predictions of status at 3, 6 an...

Antimicrobial Agents and Chemotherapy, 1996

Wound infections frequently originate from the subcutaneous tissue. The effect of gentamicin in s... more Wound infections frequently originate from the subcutaneous tissue. The effect of gentamicin in subcutaneous tissue has, however, normally been evaluated from concentrations in blood or wound fluid. The aim of the present study was to investigate the pharmacokinetic properties of gentamicin in human subcutaneous adipose tissue by a microdialysis technique. Seven healthy young volunteers each had four microdialysis probes placed in the fat (subcutaneous) layer of the abdominal skin. After the administration of a 240-mg gentamicin intravenous bolus, consecutive measurements of the drug concentrations in serum and subcutaneous interstitial fluid were obtained simultaneously for 6 h. The tissue gentamicin concentration peaked after 10 to 30 min. The peak concentration in the tissue was 6.7 +/- 2.0 mg.liter-1 (standard deviation), equivalent to 39.1% of the peak concentration in serum. The area under the concentration-versus-time curve for the first 6 h in the tissue was 1,281 +/- 390.0)...

Frontiers in cellular and infection microbiology, 2018

Most bacterial infections initiate at the mucosal epithelium lining the gastrointestinal, respira... more Most bacterial infections initiate at the mucosal epithelium lining the gastrointestinal, respiratory, and urogenital tracts. At these sites, bacterial pathogens must adhere and increase in numbers to effectively breach the outer barrier and invade the host. If the bacterium succeeds in reaching the bloodstream, effective dissemination again requires that bacteria in the blood, reestablish contact to distant endothelium sites and form secondary site foci. The infectious potential of bacteria is therefore closely linked to their ability to adhere to, colonize, and invade epithelial and endothelial surfaces. Measurement of bacterial adhesion to epithelial cells is therefore standard procedure in studies of bacterial virulence. Traditionally, such measurements have been conducted with microtiter plate cell cultures to which bacteria are added, followed by washing procedures and final quantification of retained bacteria by agar plating. This approach is fast and straightforward, but yie...

PLOS ONE, 2016

We sought to investigate whether hypoalbuminaemia was mainly caused by acute or chronic factors i... more We sought to investigate whether hypoalbuminaemia was mainly caused by acute or chronic factors in patients with community-acquired bacteraemia. In this population-based study, we considered 1844 adult cases of community-acquired bacteraemia that occurred in Funen, Denmark between 2000 and 2008. We used a stepwise prognostic predisposition-insult-response-organ dysfunction (PIRO) logistic regression model by initially including age and comorbidity, then added bacterial species, and finally sepsis severity. The models were furthermoreanalysed using receiver operating characteristic (ROC) curves. Outcomes comprised mortality incidence on days 0-30 and 31-365 after the bacteraemia episode. Each step was performed with and without baseline albumin level measured on the date of bacteraemia. In 422 patients, their latest albumin measurement taken 8-30 days before the date of bacteraemia was also used in the analysis together with the baseline albumin level. For each decrease of 1g/L in plasma albumin level, the odds ratios (95% confidence intervals) of mortality in the period of 0-30 days after bacteraemia were 0.86 (0.84-0.88) in both predisposition (P) and predisposition-insult (PI) models and 0.87 (0.85-0.89) in the full PIRO-model. The AUC values were 0.78 and 0.66 for mortality in the period of 0-30 days in the model comprising only predisposition factors with and without albumin levels added as a factor, respectively. The AUC values in the full PIRO-model were 0.81 and 0.73 with and without consideration of albumin levels, respectively. A higher proportion of patients died within 30 days if there was a decrease in the albumin level between days 8 and 30 before bacteraemia and the actual bacteraemia date. A single plasma albumin PLOS ONE |

Health, 2012

Anti-viral chemotherapy plays an important part in treating and preventing influenza illness. How... more Anti-viral chemotherapy plays an important part in treating and preventing influenza illness. However, its effectiveness in severe infections can be debated and a reoccurring problem is the emergence of resistant virus. Passive immunisation has for a long time been and is still used for prophylaxis and treatment of a number of infectious diseases. In this experimental study anti-influenza antibodies were passively administrated to mice, subsequently they were infected with influenza virus and treated with oseltamivir. The aim was to investigate, if anti-influenza antibodies influenced the out come of oseltamivir treatment and development of resistance towards oseltamivir. We show, that oseltamivir alone was not able to effectively prevent a fatal outcome, but that oseltamivir administered together with a limited amount of antibodies, resulted in improvement of the clinical condition of the mice. The results also showed that a higher dosage of antibodies alone were able to protect the mice from a lethal dose of virus. These findings suggest that the effectiveness of oseltamivir depends on the host's immune response to the influenza virus, and that that passive immunization is an option that should be considered in the in control of influenza.