Abstract Background Increasing attention has been given to patients with blood stream infection (BSI) and the concurrent prevalence of infective endocarditis (IE). However, there exist a gap in knowledge on the prevalence of IE among patients with a left-sided heart valve prosthesis and BSI. Purpose To examine the prevalence between different BSI and IE in patients with a left-sided heart valve prosthesis. Methods By linking Danish nationwide registries, we were able to identify patients with a left-sided prosthetic heart valve and first-time BSI of interest (Enterococcus faecalis, Staphylococcsus aureus, streptococci species (spp.), and coagulase negative staphylococci [CoNS]) in the period of 2010–2016. Concurrent admission for IE was identified from the Danish National Patient Registry in a period of up to 14 days after the BSI. Results A total of 1,465 patients with BSI were included (1,319 patients with an aortic valve prosthesis [82.6% bioprosthetic] and 146 patients with a mitral valve prosthesis [48.6% bioprosthetic]). Among the included patients, 244 had E. faecalis (median age: 78.3 years, 77.0% male), 301 had S. aureus (median age: 76.9 years, 69.1% male), 401 had streptococci spp. (median age: 78.0 years, 69.1% male) and 519 had CoNS (median age: 76.4 years, 64.2% male). The percentage of patients with a diagnosis of IE in relation to the BSI was 44.3%, 33.6%, 34.4%, and 7.9% for E. faecalis, S. aureus, streptococci spp., and CoNS, respectively. No difference in the overall results was seen by type of valve prosthesis, sex, or age group. Percentage of patients with endocarditis Conclusion In patients with a left-sided heart valve prosthesis, IE was diagnosed in almost half of the patients with E. faecalis, in 1/3 with S. aureus or streptococci spp. and in 1 in 12 with CoNS BSI. Future studies may try to explain why some microbes are more likely to cause prosthetic heart valve endocarditis, than others are.

BACKGROUND:Denmark has a high incidence rate of candidaemia. A Nordic study suggested a higher Danish prevalence of haematological malignancies as an underlying reason. This nationwide study ascertained clinical characteristics of Danish candidaemia patients and investigated potential factors contributing to the high incidence and mortality.METHODS:Microbiological and clinical data for candidaemia patients in 2010-2011 were retrieved. 30-day mortality was estimated by hazard ratios (HR) with 95% confidence intervals (CI, Cox regression).RESULTS:Data were available for 912/973 candidaemia episodes (93.7%). Intensive care unit (ICU) held the largest share of patients (43.2%). Prevalent host factors were multi-morbidity (≥2 underlying diseases, 74.2%) and gastrointestinal disease (52.5%). Haematological disease was infrequent (7.8%). Risk factors included antibiotic exposure (90.5%), CVC (71.9%) and Candida colonisation (66.7%). 30-day mortality was 43.4%, and 53.6% in ICU. Mortality was lower for patients with recent abdominal surgery (HR 0.70, 95% CI: 0.54-0.92).CONCLUSION:A substantial prevalence of multi-morbidity and a high 30-day mortality was found. We hypothesise, that an increasing population of severely ill patients with prolonged supportive treatment and microbiological testing may in part explain the high candidaemia incidence in Denmark. Nationwide studies are warranted to clarify this issue.

ABSTRACT New data from the years 2012 to 2015 from the Danish National Fungemia Surveillance are reported, and epidemiological trends are investigated in a 12-year perspective (2004 to 2015). During 2012 to 2015, 1,900 of 1,939 (98%) fungal bloodstream isolates were included. The average incidence was 8.4/100,000 inhabitants, and this appears to represent a stabilizing trend after the increase to 10.1/100,000 in 2011. The incidence was higher in males than females (10.0 versus 6.8) and in patients above 50 years, and those changes were mainly driven by an increasing incidence among 80-to-89-year-old males (65.3/100,000 in 2014 to 2015). The proportion of Candida albicans isolates decreased from 2004 to 2015 (64.4% to 42.4%) in parallel with a doubling of the proportion of Candida glabrata isolates (16.5% to 34.6%, P < 0.0001). C. glabrata was more common among females (34.0% versus 30.4% in males). Following an increase in 2004 to 2011, the annual drug use stabilized during the last 2 to 3 years of that time period but remained higher than in other Nordic countries. This was particularly true for the fluconazole and itraconazole use in the primary health care sector, which exceeded the combined national levels of use of these compounds in each of the other Nordic countries. Fluconazole susceptibility decreased (68.5%, 65.2%, and 60.6% in 2004 to 2007, 2008 to 2011, and 2012 to 2015, respectively, P < 0.0001), and echinocandin resistance emerged in Candida (0%, 0.6%, and 1.7%, respectively, P < 0.001). Amphotericin B susceptibility remained high (98.7%). Among 16 (2.7%) echinocandin-resistant C. glabrata isolates (2012 to 2015), 13 harbored FKS mutations and 5 (31%) were multidrug resistant. The epidemiological changes and the increased incidence of intrinsic and acquired resistance emphasize the importance of continued surveillance and of strengthened focus on antifungal stewardship.

This national population-based study was conducted as part of the development of a national automated surveillance system for hospital-acquired bacteraemia and ascertains the utilization of blood cultures (BCs). A primary objective was to understand how local differences may affect interpretation of nationwide surveillance for bacteraemia. From the Danish Microbiology Database, we retrieved all BCs taken between 2010 and 2013 and linked these to admission data from the National Patient Registry. In total, 4 587 295 admissions were registered, and in 11%, at least one BC was taken. Almost 50% of BCs were taken at admission. The chance of having a BC taken declined over the next days but increased after 4 days of admission. Data linkage identified 876 290 days on which at least one BC was taken; 6.4% yielded positive results. Ten species, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Enterococcus faecium, Enterococcus faecalis, Pseudomonas aeruginosa, Candida albicans, Enterobacter cloacae and Klebsiella oxytoca, accounted for 74.7% of agents for this purpose classified as pathogenic. An increase in BCs and positive BCs was observed over time, particularly among older patients. BCs showed a seasonal pattern overall and for S. pneumoniae particularly. A predominance of male patients was seen for bacteraemias due to S. aureus, E. faecium and K. pneumoniae. Minor differences in BCs and positive BCs between departments of clinical microbiology underpin the rationale of a future automated surveillance for bacteraemia. The study also provides important knowledge for interpretation of surveillance of invasive infections more generally.

This national population-based study was conducted as part of the development of a national automated surveillance system for hospital-acquired bacteraemia and ascertains the utilization of blood cultures (BCs). A primary objective was to understand how local differences may affect interpretation of nationwide surveillance for bacteraemia. From the Danish Microbiology Database, we retrieved all BCs taken between 2010 and 2013 and linked these to admission data from the National Patient Registry. In total, 4 587 295 admissions were registered, and in 11%, at least one BC was taken. Almost 50% of BCs were taken at admission. The chance of having a BC taken declined over the next days but increased after 4 days of admission. Data linkage identified 876 290 days on which at least one BC was taken; 6.4% yielded positive results. Ten species, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Enterococcus faecium, Enterococcus faecalis, Pseudomonas aeruginosa, Candida albicans, Enterobacter cloacae and Klebsiella oxytoca, accounted for 74.7% of agents for this purpose classified as pathogenic. An increase in BCs and positive BCs was observed over time, particularly among older patients. BCs showed a seasonal pattern overall and for S. pneumoniae particularly. A predominance of male patients was seen for bacteraemias due to S. aureus, E. faecium and K. pneumoniae. Minor differences in BCs and positive BCs between departments of clinical microbiology underpin the rationale of a future automated surveillance for bacteraemia. The study also provides important knowledge for interpretation of surveillance of invasive infections more generally.

Bactec Plus blood culture bottles were preincubated at 35degreesC or at room temperature before entry into the Bactec 9240 instrument to determine the influence of preincubation temperature and time. Of 463 positive blood culture sets, 956 bottles were positive, of which the instrument detected 92.1%. Of 76 positive bottles undetected by the instrument, 68 were preincubated at 35degreesC and eight at room temperature. The median entry delay and instrument detection times were 17.9 and 7.2 h for preincubated bottles, and 16.4 and 13.4 h for bottles held at room temperature. Short entry delay and inspection before entry into the instrument are necessary if preincubation at 35degreesC is used.

Brucellosis is a rarely encountered infection in northern Europe. We report 4 cases of Brucella abortus bacteremia occurring in Denmark during 1999-2000. The clinical presentation was characteristically vague and brucellosis was not suspected by the attending physicians, partly because incomplete patient histories were obtained as a result of language barriers. The diagnosis was finally established by means of blood cultures, which were performed because of fever of unknown origin.

Background: Lipoprotein (a) (Lp(a)) is a risk marker for the development of atherosclerotic coronary heart disease. Growth hormone (GH) administration to GH-deficient (GHD) adults increases serum Lp(a) concentrations, and the levels of Lp(a) and GH are correlated in patients with acromegaly. Studies in rats have demonstrated differential effects of constant and intermittent GH patterns on levels of certain lipoproteins. The aim of the present studies was to describe the impact of intermittent and continuous patterns of GH delivery to GHD patients on serum levels of Lp(a) and other lipoproteins. Methods: In one study (A) 10 GHD patients received in random order a fixed GH dose intravenously as: (1) continuous infusion; (2) eight bolus injections, and (3) a combination of 1 and 2. Each study lasted 36 h and was preceded by at least 4 weeks without GH. In another study (B) 13 GHD patients received GH in random order as: (1) continuous subcutaneous (s.c.) infusion, and (2) daily s.c. injections in the evening for 1 month each. The patients were studied during steady-state conditions at the end of each treatment period. Results: In study A Lp(a) levels increased significantly following continuous (p < 0.05) and combined patterns (p < 0.02) of GH administration to GH-deprived GHD patients, whereas the increase after GH bolus injections alone was not significant (p = 0.14). In study B significantly higher (p < 0.05) serum levels of Lp(a) were obtained after continuous s.c. infusion as compared with daily s.c. injections of GH. Concentrations of the high-density lipoprotein (HDL) cholesterol were significantly lower (p < 0.02) after the continuous GH pattern. Similarly, the HDL fraction Apo A-1 tended to be lower with constant GH delivery (p = 0.052). Serum levels of total cholesterol, triglyceride and Apo B were similar on the two occasions. Conclusion: Short-term GH administration to GH-deprived GHD patients increased serum Lp(a), but only significantly with continuous delivery. During more prolonged GH exposure, constant s.c. infusion of GH resulted in slightly raised Lp(a) levels and reduced HDL and Apo A1 levels as compared with intermittently administered GH. The findings are consistent with the more effective induction of serum IGF-I levels after continuous patterns of GH delivery previously reported in GHD patients. Longer-term data are needed before conclusions with respect to the impact of the pattern of GH administration on, e.g., the risk of developing coronary heart disease can be drawn.

The objective of the present study was to examine the possible associations between low molecular weight (LMW) apolipoprotein(a) (apo(a)) isoforms (F,B,S1,S2) and coronary heart disease (CHD). We conducted a nested case-control (prospective) study of five cohorts of white men: The 1936 cohort (baseline 1976, n=548) and four cohorts from MONICA I born in 1923 (n=463), 1933 (n=491), 1943 (n=504) and 1953 (n=448) studied at baseline in 1983. At follow up in 1991, 52 subjects had developed a first myocardial infarction and 22 had been hospitalized with angina pectoris. Plasma samples obtained at baseline were stored frozen until 1993–94, when case samples (n=74) were analyzed together with samples from matched (disease free) controls (n=190). In a statistical model (conditional logistic regression) including all age groups, cholesterol (or apo B) level (P<0.01), systolic blood pressure (P=0.05) and smoking (P=0.02) predicted CHD. In the statistical model Lp(a) interacted significantly with age (OR=5.7; 95% CI: 1.4–23.6; P=0.016), and high Lp(a) (over 45 mg/dl) was associated with significantly increased risk in subjects under 60 years (OR=3.82; 95% CI: 1.47–9.96), but not in older men (OR=0.67; 95% CI: 0.235–1.89). Therefore, we studied the impact of Lp(a)/apo(a) and other variables in subjects who had been under 60 years when they became cases. Among the younger subjects the presence of LMW apo(a) isoforms significantly predicted the development of CHD (OR=3.83; 95% CI: 1.18–12.4). The increased risk pertained to high Lp(a) (above versus below 45 mg/dl: OR=3.68; 95% CI: 1.03–13.10), and to Lp(a) concentrations when entered into the model as a continuous variable (P=0.04). Cholesterol or apo B (P<0.01), smoking (P=0.02), systolic blood pressure (P=0.05) and low alcohol consumption (under nine drinks/week) (P=0.04) were also significant predictors of CHD. We conclude that LMW apo(a) isoforms are significantly associated with increased risk of CHD in men under 60 years.

Background and Aim: We have studied the distribution of apo(a) KpnI alleles and their relationship to Lp(a) concentrations and apo(a) protein phenotypes in 455 forty-year-old Danish men. Methods and Results: The distribution of apo(a) alleles was similar to that described in a Tyrolean population, and the size of the apo(a) alleles was inversely correlated to Lp(a) concentrations. When comparing results of apo(a) KpnI genotyping and apo(a) protein phenotyping by SDS-PAGE the major differences were that subjects with single-banded protein isoform detected by Western blotting, had an allele coding for S4, too. In agreement with these findings the majority of the 0 (null) isoforms had two apo(a) alleles that coded for S4 protein isoforms. Even though most of the apo(a) alleles associated with no detectable apo(a) protein were relatively large, they were distributed over the entire apo(a) allele size range. Conclusions: When comparing the distribution of apo(a) protein phenotypes and apo(a) KpnI alleles in two groups according to protein size and allele size, respectively, we found no difference between the distributions and the median Lp(a) concentrations in the groups, suggesting that the use of apo(a) KpnI genotyping would not have changed the results of previous studies comparing apo(a) allele distributions by SDS-polyacrylamide gel electrophoresis. (C) 1997, Medikal Press.

The role of growth hormone (GH) and thyroid hormone in the regulation of lipid and lipoprotein metabolism is not fully established. Furthermore, the possible linkage between the well-known GH-induced increase in peripheral thyroxine (T4) to triiodothyronine (T3) generation and the effects of GH on lipid and lipoprotein metabolism has not been elucidated. In this double-blind placebo-controlled study, we compared the effects of GH and T3 administration alone and in combination on lipid and lipoprotein metabolism in a group of healthy young adults. The dose of T3 was selected to mimic the T2 increase seen during exogenous GH exposure. Eight normal male subjects (aged 21 to 27 years; body mass index, 21.11 to 27.17 kg/m2) were randomly studied during four 10-day treatment periods with (1) daily subcutaneous placebo injections and placebo injections and placebo tablets, (2) daily subcutaneous GH injections (0.1 IU/kg.d) and placebo tablets, (3) daily T3 administration (40 micrograms on even dates or 20 micrograms on uneven dates) plus placebo injections, and (4) daily GH injections plus T3 administration. GH administration increased free T3 (FT3) to the same level as during T3 administration. GH caused decreased levels of total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol and increased levels of triglycerides (TG) and lipoprotein(a) (Lp(a)), but no changes in high-density lipoprotein (HDL) cholesterol and apolipoprotein B (apo B). T3 administration caused no alteration in these parameters, except for decreased levels of TC comparable to those seen after GH administration. Combined GH and T3 administration caused changes identical to those seen after GH administration, in addition to decreased apo B levels and a further decrease of TC levels. We conclude that GH and iodothyronines in the physiologic range exert distinct but disparate effects on lipids and lipoproteins, and do not support the hypothesis that the effects observed during GH administration are exclusively secondary to changes in peripheral T3 levels.

Polymorphisms in the genes for the low-density lipoprotein (LDL) receptor ligands, apolipoprotein E (apoE), and apolipoprotein B (apoB) are associated with variation in plasma levels of LDL cholesterol. Lp(a) lipoprotein(a) [Lp(a)] is LDL in which apoB is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined isoforms differing in molecular weight, which are inversely correlated with Lp(a) concentrations in blood. The interaction of apo(a) with triglyceride-rich lipoproteins differs with the size of apo(a), and therefore the effects of apoE gene polymorphism on Lp(a) levels could also depend on apo(a) size. We have investigated the possible effect of genetic variation in the apoE and apoB genes on plasma Lp(a) concentrations in 466 white men with different apo(a) phenotypes. Overall there was no significant association between the common apoE polymorphism and Lp(a), but in the subgroup with apo(a)-S4, concentrations of Lp(a) differed significantly among the apoE genotypes (P=0.05). Lp(a) was highest in the apoE genotypes epsilon(2) epsilon(3) and epsilon(3) epsilon(3) and lowest in genotype epsilon(3) epsilon(4), and the apoE polymorphism was estimated to account for about 2.4% of the variation in Lp(a). In contrast, in the subgroup with apo(a)-S2 Lp(a) was significantly lower (P=0.04) in apoE genotype epsilon(2) epsilon(3) than in genotype epsilon(3) epsilon(3). Lp(a) concentrations did not differ among the XbaI (P=0.65) or SP 24/27 (P=0.26) polymorphisms of the apoB gene. The expected effects of both apoE and apoB polymorphism on LDL levels were significant in the whole population sample and in subjects with large-sized apo(a) isoforms (P<0.01), whereas no effect was seen in those with low molecular weight apo(a) isoforms. We conclude that the influence of apoE genotypes on Lp(a) concentrations depends on the size of the apo(a) molecule in Lp(a), possibly because both apo(a)-S4 and apoE4 have high affinity for triglyceride-rich lipoproteins and may be taken up and degraded rapidly by remnant receptors.

In a Danish family highly susceptible to ischemic heart disease, hyperlipidemia did not simply cosegregate with a previously undescribed 10 bp deletion in the LDL receptor gene causing heterozygous familial hypercholesterolemia (FH). This mutation, designated as FH DK-4, deletes 10 nucleotides from exon 4 coding for the third cysteine-rich repeat of the ligand-binding domain. The resulting translational frameshift and stop codon corresponding to amino acid position 181 in the LDL receptor cDNA is predicted to result in a truncated LDL receptor protein. Several family members had hyperlipidemia and early onset of ischemic heart disease not due to the 10 bp deletion, and several family members had unexpectedly high serum lipoprotein(a) contributing to high concentrations of serum LDL cholesterol. The study illustrates important limitations and possibilities of molecular genetic diagnosis.

Eskimos of the east coast of Greenland very rarely had contacts with Caucasians until late in the 19th century. Their genes are therefore likely to be similar to those in the original Eskimo gene pool. We have compared serum concentrations of Lp(a) and apo(a) phenotypes in 78 East Greenland Eskimos (EGE) with those in Eskimos from Western Greenland (WGE) (n = 100) and Caucasian Danes (n = 466). Lp(a) levels were higher in EGE (median: 11.9 mg/dl [95% CI: 9.1-16.4]) than in Danes (p < 0.01), (median: 6.3 mg/dl [95% CI: 5.5-7.3]) and WGE (p < 0.01), (median: 7.8 mg/dl [95% CI: 5.7-10.2]). Lp(a) concentrations above 30 mg/dl were (p < 0.05) more common in EGE (19%) than in WGE (9%) and similar (p = 0.89) to those in Danes (20%). Apo(a) molecules as small as S2 or smaller (S1, B and F) were present in 26% of Danes and in 3% of WGE but were absent in EGE (p < 0.01). In contrast, a large apo(a) variant (VS4) was present in 54% of EGE and 62% of WGE, whereas it was very rare in Danes (2%). Lp(a) concentrations were inversely associated with apo(a) size in EGE (p < 0.05), WGE (p < 0.01) and Danes (p < 0.01), but EGE with S3 or S4 had significantly higher Lp(a) levels than Danes (p < 0.05) with the same phenotypes.

We have compared lipoprotein(a) (Lp(a)) concentrations and apoliprotein (a) (apo(a)) phenotypes in 101 Danish patients with ischemic heart disease (IHD) with those in 466 Danish reference subjects. The median Lp(a) concentration was significantly higher in IHD patients (19.0 mg/dl; 95% CI 14.4-26.4) than in reference men (6.33 mg/dl; 95% CI 5.5-7.3). The phenotype distribution in IHD patients and reference men was significantly different (p=0.00811) with higher frequencies of the apo(a) low molecular weight isoforms in IHD patients. This indicated that Lp(a) is a risk factor for IHD in a Danish population and supports the concept that alleles at the apo(a) gene locus predict the risk of IHD.

The enormous interindividual variation in the plasma concentrations of the atherogenic lipoprotein(a) [Lp(a)] is almost entirely controlled by the apo(a) locus on chromosome 6q26-q27. A variable number of transcribed kringle4 repeats (K4-VNTR) in the gene explains a large fraction of this variation, whereas the rest is presently unexplained. We here have analyzed the effect of the K4-VNTR and of a pentanucleotide repeat polymorphism (TTTTA)n (n = 6-11) in the 5' control region of the apo(a) gene on plasma Lp(a) levels in unrelated healthy Tyroleans (n = 130), Danes (n = 154), and Black South Africans (n = 112). The K4-VNTR had a significant effect on plasma Lp(a) levels in Caucasians and explained 41 and 45% of the variation in Lp(a) plasma concentration in Tyroleans and Danes, respectively. Both, the pentanucleotide repeat (PNR) allele frequencies and their effects on Lp(a) concentrations were heterogeneous among populations. A significant negative correlation between the number of pentanucleotide repeats and the plasma Lp(a) concentration was observed in Tyroleans and Danes. The effect of the 5' PNRP on plasma Lp(a) concentrations was independent from the K4-VNTR and explained from 10 to 14% of the variation in Lp(a) concentrations in Caucasians. No significant effect of the PNRP was present in Black Africans. This suggests allelic association between PNR alleles and sequences affecting Lp(a) levels in Caucasians. Thus, in Caucasians but not in Blacks, concentrations of the atherogenic Lp(a) particle are strongly associated with two repeat polymorphisms in the apo(a) gene.