Publikasjoner

Abstract

IMPORTANCE The prevalence and baseline risk factors of post–COVID-19 condition (PCC) remain unresolved among the large number of young people who experienced mild COVID-19.

OBJECTIVES To determine the point prevalence of PCC 6 months after the acute infection, to determine the risk of development of PCC adjusted for possible confounders, and to explore a broad range of potential risk factors.

DESIGN, SETTING, AND PARTICIPANTS This cohort study included nonhospitalized individuals from 2 counties in Norway between ages 12 and 25 years who underwent reverse transcription–polymerase chain reaction (RT-PCR) testing. At the early convalescent stage and at 6-month follow-up, participants underwent a clinical examination; pulmonary, cardiac, and cognitive functional testing; immunological and organ injury biomarker analyses; and completion of a questionnaire. Participants were classified according to theWorld Health Organization case definition of PCC at follow-up. Association analyses of 78 potential risk factors were performed.

EXPOSURES SARS-CoV-2 infection.

MAIN OUTCOMES AND MEASURES The point prevalence of PCC 6 months after RT-PCR testing in the SARS-CoV-2–positive and SARS-CoV-2–negative groups, and the risk difference with corresponding 95%CIs.

RESULTS A total of 404 individuals testing positive for SARS-CoV-2 and 105 individuals testing negative were enrolled (194 male [38.1%]; 102 non-European [20.0%] ethnicity). A total of 22 of the SARS-CoV-2–positive and 4 of the SARS-CoV-2–negative individuals were lost to follow-up, and 16 SARS-CoV-2–negative individuals were excluded due to SARS-CoV-2 infection in the observational period. Hence, 382 SARS-CoV-2–positive participants (mean [SD] age, 18.0 [3.7] years; 152 male [39.8%]) and 85 SARS-CoV-2–negative participants (mean [SD] age, 17.7 [3.2] years; 31 male [36.5%]) could be evaluated. The point prevalence of PCC at 6 months was 48.5%in the SARS-CoV-2– positive group and 47.1%in the control group (risk difference, 1.5%; 95%CI, −10.2%to 13.1%). SARSCoV- 2 positivity was not associated with the development of PCC (relative risk [RR], 1.06; 95%CI, 0.83 to 1.37; final multivariable model utilizing modified Poisson regression). The main risk factor for PCC was symptom severity at baseline (RR, 1.41; 95%CI, 1.27-1.56). Low physical activity (RR, 0.96; 95%CI, 0.92-1.00) and loneliness (RR, 1.01; 95%CI, 1.00-1.02) were also associated, while biological markers were not. Symptom severity correlated with personality traits.

CONCLUSIONS AND RELEVANCE The persistent symptoms and disability that characterize PCC are associated with factors other than SARS-CoV-2 infection, including psychosocial factors. This finding raises questions about the utility of theWorld Health Organization case definition and has implications for the planning of health care services as well as for further research on PCC.

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It is, so to say, not a prerogative authority assigned to SLE classification criteria that allow them to declare something definitively important about SLE. This is particularly true as criteria-based classification processes overrule the highly needed evolution of concise diagnostic criteria. It is classification criteria that allocate SLE patients into cohorts intended to describe the nature of their disease. Therefore, all major SLE classification criteria since the 1971 preliminary criteria usurp the role of diagnostic criteria. Today´s practice silently accept that the SLE classification process “diagnose” SLE patients despite the fact that classification criteria are not accepted as diagnostic criteria! This is a central paradox in contemporary SLE research strategies. Contemporary SLE cohorts are designed to investigate SLE´s etiological features. However, each cohort that is categorized by classification criteria has one central inherent problem. From theoretical and practical arguments, they embody multiple distinct clinical phenotypes. This raises the critical and principal question if phenotypically heterogenic SLE cohorts are useful to identify basic SLE-specific etiology(ies) and disease process(es). In times to come, we must prioritize development of firm diagnostic criteria for SLE, as the classification criteria have not contributed to reduce the enigmatic character of the syndrome. No radical improvements are visible in the horizon that may lead to concise investigations of SLE in well-defined homogenous SLE cohorts. We must develop new strategies where studies of phenotypically standardized cohorts of SLE must be central elements. Problems related to contemporary SLE classification criteria are contemplated, analyzed, and critically discussed in this study.

A multidrug-resistant (MDR) strain of Haemophilus influenzae, Hi-228, with phenotypic resistance toward ampicillin, cefotaxime, chloramphenicol, gentamicin, and azithromycin, was isolated in Oslo, Norway. The strain was part of a clonal outbreak (2016–2017) comprising five ST143 strains with identical resistotypes. Hi-228 carries a novel integrative and conjugative element (ICE), Tn7100, contributing to this remarkable and previously unreported MDR profile. Tn7100 contains the following resistance genes: blaTEM−1B, catA2, aac(6′)-Im, aph(2″)-Ib, mef (E), and mel. The latter four are previously unreported or rarely reported in H. influenzae. In this study, we investigated the genetic environment, mechanisms of transfer, impact on phenotypic susceptibility, and fitness cost of this ICE. We found that Tn7100 has an overall structure similar to the previously described ICE Tn6686, with blaTEM−1B and catA2 carried by Tn3 and Tn10, respectively. The major difference between Tn7100 and Tn6686 is that Tn7100 lacks tet(B) but carries the resistance gene pairs aac(6′)-Im and aph(2″)-Ib and mef (E) and mel. The gene pairs are located on the novel transposable elements Tn7470 and Tn7471, which have high sequence identities to a plasmid in Enterobacterales and an ICE in streptococcal species, respectively. Tn7100 does circularize and is transferable, however, at a low frequency. Head-to-head competition experiments showed that uptake of Tn7100 reduces bacterial fitness. Our study shows that MDR strains are capable of clonal spread and that the H. influenzae supragenome comprises an increasingly wide range of transferable resistance genes, with evidence of transfer from unrelated genera. The findings offer a glimpse into the genome dynamics of H. influenzae, highlighting the importance of rational antibiotic usage to contain antimicrobial resistance and the emergence of MDR strains in this important pathogen.

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Objectives

Internal quality control (IQC) plays an important role in quality assurance in laboratory medicine. However, there is no universal consensus or guideline on when and how IQC should be analyzed on point-of-care testing (POCT) devices. The aim of this study was to develop a scoring system to determine how often IQC should be analyzed in primary healthcare on the various POCT devices.

Methods

Based on a systematic literature review and a thorough process involving the whole Noklus, a nationwide POC organization, a scoring system for when to analyze IQC was developed. Four factors were considered to significantly impact IQC frequency: The importance of the analyte in diagnosing and monitoring patients, type of POCT device, user-friendliness, and number of patient samples. For each POCT device, the first three factors were given a score, and the sum of the scores determined the general recommended IQC frequency. The number of patient samples determined whether and how to adjust these frequencies in each individual general practice.

Results

The scoring system was applied to 17 analytes and 134 different POCT devices (153 analyte-device combinations). Most of the devices analyzing high-risk analytes (71 out of 74) obtained daily or weekly IQC frequency. For example, all blood-cell counters and all glucose meters should undergo IQC daily and weekly, respectively.

Conclusions

This study presents a consensus-based scoring system for differentiated and device-specific recommendations for IQC frequency on POCT devices in primary healthcare. The scoring system can easily be adopted to other local environments and is easy to use. 

Summary: Mild, subacute COVID-19 in young people show inflammatory enhancement, but normal pulmonary function. Inflammatory markers are associated with age and male sex, whereas clinical symptoms are associated with age and female sex, but not with objective disease markers.

Background: Coronavirus Disease 2019 (COVID-19) is widespread among adolescents and young adults across the globe. The present study aimed to compare inflammatory markers, pulmonary function and clinical symptoms across non-hospitalized, 12 – 25 years old COVID-19 cases and non-COVID-19 controls, and to investigate associations between inflammatory markers, clinical symptoms, pulmonary function and background variables in the COVID-19 group.

Methods: The present paper presents baseline data from an ongoing longitudinal observational cohort study (Long-Term Effects of COVID-19 in Adolescents, LoTECA, ClinicalTrials ID: NCT04686734). A total of 31 plasma cytokines and complement activation products were assayed by multiplex and ELISA methodologies. Pulmonary function and clinical symptoms were investigated by spirometry and questionnaires, respectively.

Results: A total of 405 COVID-19 cases and 111 non-COVID-19 controls were included. The COVID-19 group had significantly higher plasma levels of IL-1β, IL-4, IL-7, IL-8, IL-12, TNF, IP-10, eotaxin, GM-CSF, bFGF, complement TCC and C3bc, and significantly lower levels of IL-13 and MIP-1α, as compared to controls. Spirometry did not detect any significant differences across the groups. IL-4, IL-7, TNF and eotaxin were negatively associated with female sex; eotaxin and IL-4 were positively associated with age. Clinical symptoms were positively associated with female sex and age, but not with objective disease markers.

Conclusions: Among non-hospitalized adolescents and young adults with COVID-19 there was significant alterations of plasma inflammatory markers in the subacute stage of the infection. Still, pulmonary function was normal. Clinical symptoms were independent of inflammatory and pulmonary function markers, but positively associated with age and female sex.

Abstract

Keywords: Candida; antifungal; biofilm; chito-oligosaccharides; chitosan; yeast.

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Atherosclerosis and its consequences cause considerable morbidity and mortality world-wide. We have previously shown that expression of the DNA glycosylase NEIL3 is regulated in human atherosclerotic plaques, and that NEIL3-deficiency enhances atherogenesis in Apoe-/- mice. Herein, we identified a time point prior to quantifiable differences in atherosclerosis between Apoe-/-Neil3-/- mice and Apoe-/- mice. Mice at this age were selected to explore the metabolic and pathophysiological processes preceding extensive atherogenesis in NEIL3-deficient mice. Untargeted metabolomic analysis of young Apoe-/-Neil3-/- mice revealed significant metabolic disturbances as compared to mice expressing NEIL3, particularly in metabolites dependent on the gut microbiota. 16S rRNA gene sequencing of fecal bacterial DNA indeed confirmed that the NEIL3-deficient mice had altered gut microbiota, as well as increased circulating levels of the bacterially derived molecule LPS. The mice were challenged with a FITC-conjugated dextran to explore gut permeability, which was significantly increased in the NEIL3-deficient mice. Further, immunohistochemistry showed increased levels of the proliferation marker Ki67 in the colonic epithelium of NEIL3-deficient mice, suggesting increased proliferation of intestinal cells and gut leakage. We suggest that these metabolic alterations serve as drivers of atherosclerosis in NEIL3-deficient mice.

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Background

We evaluated if flowcytometry, using Sysmex UF-5000, could improve diagnosis of urinary tract infections by rapid identification of culture negative and contaminated samples prior to culture plating, thus reducing culture plating workload and response time. We also evaluated if it is possible to reduce the response time for antibiotic susceptibility profiles using the bacteria information flag on Sysmex UF-5000 to differentiate between Gram positive and negative bacteria, followed by direct Antibiotic Susceptibility Testing (dAST) on the positive urine samples.

Methods

One thousand urine samples were analyzed for bacteria, white blood cells and squamous cells by flowcytometry before culture plating. Results from flowcytometric analysis at different cut-off values were compared to results of culture plating. We evaluated dAST on 100 urine samples that were analyzed as positive by flowcytometry, containing either Gram positive or Gram negative bacteria.

Results

Using a cut-off value with bacterial count ≥100.000/mL and WBCs ≥10/μL, flowcytometry predicted 42,1% of samples with non-significant growth. We found that most contaminated samples contain few squamous cells. For 52/56 positive samples containing Gram negative bacteria dAST was identical to routine testing. Overall, there was concordance in 555/560 tested antibiotic combinations.

Conclusion

Flowcytometry offers advantages for diagnosis of urinary tract infections. Screening for negative urine samples on the day of arrival reduces culture plating and workload, and results in shorter response time for the negative samples. The bacteria information flag predicts positive samples containing Gram negative bacteria for dAST with high accuracy, thus Antibiotic Susceptibility Profile can be reported the day after arrival. For the positive samples containing Gram negative bacteria the concordance was very good between dAST and Antibiotic Susceptibility Testing in routine. For positive samples containing Gram positive bacteria the results were not convincing. We did not find any correlation between epithelial cells and contamination.

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This study assessed the prevalence and determinants of fatigue in a population-based cohort of non-hospitalized subjects 1.5–6 months after COVID-19. It was a mixed postal/web survey of all non-hospitalized patients ≥18 years with a positive PCR for SARS-CoV-2 until 1 June 2020 in a geographically defined area. In total, 938 subjects received a questionnaire including the Chalder fatigue scale (CFQ-11) and the energy/fatigue scale of the RAND-36 questionnaire. We estimated z scores for comparison with general population norms. Determinants were analyzed using multivariable logistic and linear regression analysis. In total, 458 subjects (49%) responded to the survey at median 117.5 days after COVID-19 onset, and 46% reported fatigue. The mean z scores of the CFQ-11 total was 0.70 (95% CI 0.58 to 0.82), CFQ-11 physical 0.66 (0.55 to 0.78), CFQ-11 mental 0.47 (0.35 to 0.59) and RAND-36 energy/fatigue −0.20 (−0.31 to −0.1); all CFQ-11 scores differed from those of the norm population (p < 0.001). Female sex, single/divorced/widowed, short time since symptom debut, high symptom load, and confusion during acute COVID-19 were associated with higher multivariable odds of fatigue. In conclusion, the burden of post-viral fatigue following COVID-19 was high, and higher than in a general norm population. Symptoms of fatigue were most prevalent among women, those having a high symptom load, or confusion during the acute phase.

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Invasive pulmonary aspergillosis (IPA) optimal duration of antifungal treatment is not known. In a joint effort, four international scientific societies/groups performed a survey to capture current practices in European haematology centres regarding management of IPA. We conducted a cross-sectional internet-based questionnaire survey in 2017 to assess practices in sixteen European countries concerning IPA management in haematology patients including tools to evaluate treatment response, duration and discontinuation. The following four groups/societies were involved in the project: European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG), Infectious Diseases Working Party-European Society for Blood and Bone Marrow Transplantation (IDWP-EBMT), European Organisation for Research and Treatment-Infectious Disease group (EORTC-IDG) and Sorveglianza Epidemiologica Infezioni nelle Emopatie (SEIFEM). A total of 112 physicians from 14/16 countries answered the survey. Galactomannan antigen was available in serum and bronchoalveolar lavage in most centres (106/112 [95%] and 97/112 [87%], respectively), quantitative Aspergillus PCR in 27/112 (24%) centres, β-D-glucan in 24/112 (21%) and positron emission tomography in 50/112 (45%). Treatment duration differed between haematological malignancies, with a median duration of 6 weeks [IQR 3-12] for patients with AML, 11 [4-12] for patients with allogenic stem cell transplantation and GvHD and 6 [3-12] for patients with lymphoproliferative disease. Treatment duration significantly differed according to country. Essential IPA biomarkers are not available in all European countries, and treatment duration is highly variable according to country. It will be important to provide guidelines to help with IPA treatment cessation with algorithms according to biomarker availability.

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Background

INTRODUCTION:

Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to explore clinical symptoms as well as markers of disease mechanisms in fatigued and non-fatigued adolescents 6 months after EBV-infection, and in healthy controls.

MATERIALS AND METHODS:

A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed 6 months after the initial infectious event and divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of 70 healthy controls with similar distribution of sex and age was included. Symptoms were mapped with a questionnaire. Laboratory assays included EBV PCR and serology; detailed blood leukocyte phenotyping and serum high-sensitive C-reactive protein; and plasma and urine cortisol and catecholamines. Assessment of autonomic activity was performed with continuous, non-invasive monitoring of cardiovascular variables during supine rest, controlled breathing and upright standing. Differences between EBV CF+ and EBV CF- were assessed by simple and multiple linear regression adjusting for sex as well as symptoms of depression and anxiety. A p-value ≤ 0.05 was considered statistically significant. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents).

RESULTS:

The EBV CF+ group had significantly higher scores for all clinical symptoms. All markers of infection and most immune, neuroendocrine and autonomic markers were similar across the EBV CF+ and EBV CF- group. However, the EBV CF+ group had slightly higher serum C-reactive protein (0.48 vs 0.43 mg/L, p=0.031, high-sensitive assay), total T cell (CD3+) count (median 1573 vs 1481 x 106cells/L, p=0.012), plasma norepinephrine (1420 vs 1113 pmol/L, p=0.01) and plasma epinephrine (363 vs 237 nmol/L, p=0.032); lower low-frequency:high frequency (LF/HF) ratio of heart rate variability at supine rest (0.63 vs 0.76, p=0.008); and an attenuated decline in LF/HF ratio during controlled breathing (-0.11 vs -0.25, p=0.002). Subgrouping according to different CFS diagnostic criteria did not significantly alter the results. Within the EBV CF+ group, there were no strong correlations between clinical symptoms and markers of disease mechanisms. In a multiple regression analysis, serum CRP levels were independently associated with serum cortisol (B= 4.5 x 10-4, p<0.001), urine norepinephrine (B=9.6 x 10-2, p=0.044) and high-frequency power of heart rate variability (B= -3.7 x 10-2, p=0.024).

CONCLUSIONS:

Abstract

Introduction

BACKGROUND:

Human Chorionic Gonadotropin (hCG) is produced by germ cell tumors, but can also be elevated in benign conditions such as primary hypogonadism, where hCG is produced by the pituitary gland. In our experience, the reference limits for hCG (Elecsys hCG+β-assay, Roche Diagnostics), were unnecessarily high and did not reflect levels encountered in clinical practice. We wanted to establish new reference limits to increase the clinical utility of the hCG-assay.

METHODS:

We analysed hCG in serum samples from a healthy adult population and in a cohort of testicular cancer survivors. The gonadotropins LH and FSH were measured in the cohort and in a selection of the reference population to assess gonadal function.

RESULTS:

We found low hCG levels for all men and women <45years (97.5 percentiles 0.1 and 0.2IU/L, respectively) from the healthy population (n=795) having normal FSH and LH. Due to assay limitations, we suggest a common reference limit of <0.3IU/L. For the age group ≥45, the 97.5 percentiles in the healthy population were 0.5IU/L for men and 6.0IU/L for women. In all subjects from both the reference population and the cohort (n=732), hCG levels exceeding the reference limit could be fully explained by reduced gonadal function indicated by elevated LH and FSH levels.

CONCLUSION:

The Elecsys hCG+β-assay should have lower reference limits than recommended by the manufacturer, with important implications for tumor follow-up. Elevated hCG is rare with intact gonadal function, both in a normal population and among survivors of testicular cancer, and should lead to further investigations when encountered in clinical practice.

Background: 

The concentration of vitamin K1 in serum or plasma is the most common index for assessing vitamin K status. The aim of this study was to develop and validate a rapid and reliable routine method for quantifying vitamin K1 above 0.1 ng/mL. Semi-automation of a simple sample preparation with fast analysis by supercritical fluid chromatography–tandem mass spectrometry (SFC-MS/MS) was exploited.

Methods: 

Vitamin K1 was extracted from 250-μL serum samples by the use of protein precipitation and reversed-phase solid-phase extraction (SPE) in 96-well plates and quantified by SFC on a 2.1 × 100 mm Torus 1-Aminoanthracene (1-AA) column in 3.8 min with electrospray ionization—tandem mass spectrometry (MS/MS) detection.

This method shows good linearity in the concentration range of 0.1–50 ng/mL with a correlation coefficient of R2 >0.999. Imprecision was satisfactory, with repeatability and reproducibility <10% CV. The lower limit of the measuring interval was 0.1 ng/mL, and no systematic bias was observed for the method, which used vitamin K1-d7 as internal standard. Recovery of vitamin K1 in external quality controls was satisfactory compared to other laboratories participating in the external quality assurance scheme. The method is currently in routine use for analysis of serum samples.

Conclusions: 

The method allows high-throughput reliable determination of vitamin K1 in serum in the range 0.1–50 ng/mL.

BACKGROUND:

The mortality rate in patients with severe community-acquired pneumonia (SCAP) is high. We investigated the 5-year mortality rate and causes of death in a patient population treated for SCAP in our intensive care unit (ICU), and compared the mortality rate in patients with or without chronic obstructive pulmonary disease (COPD) as comorbidity.

METHODS:

This retrospective study, which covers a period of 10 years, included patients aged > 18 years admitted to our ICU with SCAP as primary diagnosis and in need of mechanical ventilation for more than 24 h. Data were collected from the ICU internal database and the patients' medical records. The times of death were collected from the Norwegian National Registry, and the causes of death from the Norwegian Cause of Death Registry.

RESULTS:

Hundred and seventy three patients were included in the study. The 5-year mortality rate for the total study population was 57.2%. There were no significant differences in the mortality rate between the group with COPD and the group without COPD (61.2% vs. 54.7%, P = 0.43). There was a wide range of comorbidities. The most common were COPD, myocardial infarction and diabetes mellitus. The two main causes of death after discharge were COPD (17 deaths) and cardiovascular diseases (seven deaths).

CONCLUSIONS:

The 5-year mortality rate of the study population was high (57.2%). COPD did not seem to be a risk factor for mortality compared to non-COPD patients. The most common causes of death after discharge were COPD and cardiovascular diseases.

Background: The microscopical diagnosis of male urethritis was recentlyquestioned by Rietmeijer and Mettenbrink, lowering the diagnosticcriteria of the diagnosis to ≥2 polymorphonuclear leucocytes (PMNL)per high power field (HPF), and adopted by Centers for Disease Controland Prevention in their 2015 STD Treatment Guidelines. The EuropeanNon-Gonococcal Urethritis Guideline advocates a limit of ≥5 PMNL/HPF.

Objective: To determine if syndromic treatment of urethritis should beconsidered with a cutoff value of ≥2 PMNL/HPF in urethral smear.

Methods: The design was a cross-sectional study investigating the presenceand degree of urethritis relative to specific infections in men attendingan STI clinic as drop-in patients.

Results: The material included 2 cohorts: a retrospective study of 13,295men and a prospective controlled study including 356 men.We observed amean chlamydia prevalence of 2.3% in the 0–9 stratum, and a 12-foldhigher prevalence (27.3%) in the strata above 9. Of the chlamydia cases,89.8% were diagnosed in strata above 9. For Mycoplasma genitalium, theprevalence was 1.4% in the 0–9 stratum and 11.2% in the stratum ≥10,and 83.6% were diagnosed in strata above 9. For gonorrhea, a significantincrease in the prevalence occurred between the 0–30 strata and >30 stratafrom 0.2% to 20.7%. The results of the prospective study were similar.

Conclusions: Our data do not support lowering the cutoff to ≥2 PMNL/HPF. However, a standardization of urethral smear microscopy seems to beimpossible. The cutoff value should discriminate between low and highprevalence of chlamydia, mycoplasma, and gonorrhea to include as manyas possible with a specific infection in syndromic treatment, withoutovertreating thosewith few PMNL/HPFand high possibility of having nonspecificor no urethritis.

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BACKGROUND:

Public health nurses report on effects of fresh human milk as treatment for conjunctivitis, rhinitis and atopic eczema (AE), the latter being highly prevalent in early childhood. Emollients and topical corticosteroids are first line treatment of AE. As many caregivers have steroid phobia, alternative treatment options for mild AE are of interest. The aim of this small pilot study was to assess the potential effects and risks of applying fresh human milk locally on eczema spots in children with AE.

METHODS:

This was a split body, controlled, randomized and physician blinded pilot study, of children with AE with two similar contralateral eczema spots having a mother breastfeeding the child or a sibling. Fresh expressed milk and emollient was applied on the intervention spot and emollient alone on the control area, three times a day for four weeks. The severity and area of the eczema spots was evaluated weekly, and samples from milk and the spots were analysed weekly with respect to bacterial colonisation.

RESULTS:

Of nine patients included, six completed the study. Mean age at inclusion was 18.5 months. The spots examined were localized on the arms, legs or cheeks. The spots were similar in severity, but differed in area. In one patient the eczema ceased after inclusion. In four patients both control and intervention areas increased during the intervention. The relative change in eczema area compared to baseline showed less increase in the intervention spots in two patients, whereas the opposite was observed in three. In four children Staphylococcus aureus was found in their eczema once or more. In three of the 28 human milk samples, Staphylococcus aureus, alfa haemolytic streptococci or coagulase negative staphylococci were detected. Staphylococcus aureus was found once both in human milk and in the eczema spots, no clinical signs of infection were however observed. No secondary infection due to milk application was detected.

CONCLUSION:

In this small pilot study, no effect was found on eczema spots treated with topical application of fresh human milk. (ClinicalTrials.gov Identifier, NCT02381028 ).

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Vi har gode metoder for å forebygge, påvise og behandle infeksjonssykdommer. Likevel er disse sykdommene et stort helseproblem; de er svært vanlige, og de er smittsomme. I 4. utgave av Medisinsk mikrobiologi og infeksjonssykdommer blir kunnskap om infeksjonssykdommer knyttet til mikroorganismene som forårsaker dem.

Medisinsk mikrobiologi og infeksjonssykdommer er egnet for studenter og yrkesaktive innenfor alle helseprofesjonene.

Purpose: To assess longitudinal long-term alterations of testosterone (T), LH, and FSH intesticular cancer survivors (TCSs).

Methods: In all, 307 TCSs treated from 1980-1994 provided blood samples after orchiectomybut before further treatment, at Survey I (SI) (1998-2002), and Survey II (SII) (2007-2008).Levels of sex hormones were categorized according to quartiles and reference range (2.5- and 97.5 percentiles) of 599 controls for each decadal age group. TCSs were categorizedaccording to treatment; surgery (S), radiotherapy (RT) or chemotherapy (CT). The risk ofhigher (LH) or lower (T) levels was assessed with Chi-square test (FSH) or ordinal logisticregression analysis, and expressed as odds ratios (ORs) with 95% Confidence Interval (CI).

Results: Risk of lower T and higher LH and FSH levels was significantly increased for TCSsat all time points after RT or CT. At SII, ORs for lower T categories were 3.3 (95%CI; 2.3–4.7) and 5.2 (95%CI; 3.5– 7.9) for RT and CT respectively. ORs for increased LH and FSHwere: 4.4 (95%CI; 3.1-6.5) and 18.9 (95%CI; 11.0-32.6), respectively (RT), and 3.6 (95%CI;2.4-5.3) and 14.2 (95%CI; 8.3-24.4), respectively (CT). The cumulative platinum dose wassignificantly associated with risk of higher LH levels at both surveys and FSH at SI. In total,half of TCSs had at least one out of three sex hormone levels outside the reference range atSII.

Conclusion: Long-term TCSs are at risk of premature hormonal ageing. Our findings maypertain to cancer survivors in general, underlining the importance of extended follow-up.

BACKGROUND: Mounting evidence suggests that deficiency of vitamin D may be associated with major health problems, including alcohol-use disorders (AUD) and major depression (MD). This study aimed to identify the vitamin D status of Nepalese inpatients with an AUD. We explored socio-demographic and alcohol-use related correlates and the relationship between vitamin D deficiency and comorbid MD.

METHODS: A cross-sectional study was conducted on AUD inpatients (N=174) at eight alcohol/drug treatment centres around Kathmandu. Structured questionnaires were administered to assess the socio-demographic and alcohol-use parameters and to establish DSM-IV diagnoses of AUD and MD. Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D (25(OH)D) concentration of <50nmol/L.

RESULTS: The prevalence of vitamin D deficiency was 64%. Higher age, having a stable job or business, shorter time since last alcohol intake and winter serum samples were related to having lower 25(OH)D levels. Several features of AUD severity were associated with low vitamin D levels: guilt about drinking, using alcohol as eye-opener, and history of relapse after alcohol treatment (p≤0.03). Patients with a comorbid major depression, in particular secondarily depressed cases, were less likely to have vitamin D deficiency (X(2)=6.8; p=0.01).

CONCLUSIONS: This study confirms high rates of vitamin D deficiency in alcohol treatment sample and shows a positive association between vitamin D deficiency and severity of alcohol-use disorders. Competing risk and other confounders may help explain the vitamin D status among patients with alcohol-use disorders and comorbid major depression.

BAKGRUNN: Når laboratoriet påviser analyseresultater som kan medføre alvorlig helsefare for pasienten, skal behandlingsansvarlig lege varsles. Det er per i dag ingen enighet om når et prøvesvar er så avvikende at varsling bør gjøres.

MATERIALE OG METODE: En arbeidsgruppe i regi av Norsk selskap for medisinsk biokjemi innhentet oversikt over hvilke varslingsgrenser som blir brukt ved norske laboratorier samt i internasjonal litteratur, og foretok en spørreundersøkelse blant allmennpraktikere som rekvirerte analyser fra seks norske laboratorier. Det ble utført litteratursøk for å innhente kunnskapsbasert informasjon om når et analyseresultat medfører akutt livsfare. Konsekvenser for ressursbruk ved bruk av ulike grenser ble estimert på bakgrunn av analyseresultater fra en 6 måneders periode fra et større norsk sykehuslaboratorium.

RESULTATER: Hvilke grenser som brukes nasjonalt og internasjonalt varierer, men medianverdiene for disse er relativt sammenfallende. Allmennpraktikerne ønsket at en del analyser skulle varsles, hovedsakelig elektrolytter og hematologiske parametre. De varslingsgrensene allmennpraktikerne foreslo var gjennomgående mindre avvikende sammenlignet med de som ble brukt av laboratoriene (medianverdier). Hvilke grenser som brukes har stor betydning for hvor mye ressurser laboratoriene vil bruke på varsling av laboratorieresultater.

FORTOLKING: Laboratorier og allmennleger har ulike oppfatninger av hva som bør være varslingsgrenser for medisinsk biokjemiske analyseresultater hos voksne. Anbefalingen fra arbeidsgruppen må oppfattes som veiledende.

BACKGROUND: Atorvastatin is commonly used to reduce cholesterol. Atorvastatin acid is converted to its corresponding lactone form spontaneously or via glucuronidation mediated by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A3. Atorvastatin lactone is pharmacologically inactive, but is suspected to be muscle toxic and cause statin-induced myopathy (SIM). A several fold increase in systemic exposure of atorvastatin lactone has previously been observed in patients with SIM compared with healthy control subjects. In this study we aimed to investigate the association between polymorphisms in the UGT1A gene locus and plasma atorvastatin lactone levels.

METHODS: DNA was extracted from whole blood obtained from a previous pharmacokinetic study of patients carefully diagnosed as having true SIM (n = 13) and healthy control subjects (n = 15). The UGT1A1*28(TA) 7 , UGT1A3*2, UGT1A3*3, and UGT1A3*6 polymorphisms were detected by pyrosequencing.

RESULTS: Carriers of the low-expression allele UGT1A1*28(TA) 7 tended to have lower levels of atorvastatin lactone (p < 0.05) than carriers with the normal-activity allele (TA) 6.

CONCLUSION: The low-expression UGT1A1*28(TA) 7 allele seems to be associated with decreased systemic exposure of the suspected muscle-toxic metabolite atorvastatin lactone.

BACKGROUND: New cases of gonorrhoea (Neisseria gonorrhoeae) and chlamydia (Chlamydia trachomatis) infections have been steadily increasing in Scandinavian countries over the last decade. There is a particular urgency in reducing new infections as isolation of multiple drug resistant strains of gonorrhoea is becoming more frequent. The aim of this study was to determine the prevalence and sites of infection of common sexually transmissible infections (STIs) in men who have sex with men (MSM).

METHODS: We have performed a retrospective analysis of the three major STIs, gonorrhoea, chlamydia and Mycoplasma genitalium in urogenital, anorectal and oropharyngeal samples from MSM that attended two STI clinics in Oslo.

RESULTS: One hundred and thirty-six men (6.0%) out of 2289 MSM tested were found to be positive for gonorrhoea using a porA gene targeted nucleic acid amplification test (NAAT). Of these, 106 (77.9%) would not have been identified through testing first-void urine alone. Two hundred and twenty eight (10.0%) patients from 2289 tested were found to be positive for chlamydia, 164 (71.9%) of which were identified through anorectal specimens. Ninety-one (5.1%) patients from 1778 tested were found to be positive for M. genitalium, with 65 (71.4%) identified through testing of anorectal specimens.

CONCLUSIONS: Our results supports the European findings that the MSM population carries a high burden of STIs and that testing the anorectum and oropharynx will identify a significantly higher percentage of infected patients and reservoirs of STIs.

Case report

SIR : A 51-year-old man from Northern Pakistan(parents from the Kashmir and Peshawar areas,respectively) with type 2 diabetes attended to hisgeneral practitioner for a routine visit. Previous laboratorytests had shown satisfactory HbA1c levels(5.0 – 5.9%, recommended  7%) analyzed with cation-exchange HPLC on a Tosoh G7 in standard mode.In contrast, simultaneously measured fasting glucoseconcentrations exhibited increased levels between 7.9and 11.4 mmol/L (142 and 205 mg/dL) [referenceinterval, 4.0 – 6.0 mmol/L (72 – 108 mg/dL)].

[...]

BACKGROUND: The major rate-limiting enzyme for de novo cholesterol synthesis is 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). HMGCR is sterically inhibited by statins, the most commonly prescribed drugs for the prevention of cardiovascular events. Alternative splicing of HMGCR has been implicated in the control of cholesterol homeostasis. The aim of this study was to identify novel alternatively spliced variants of HMGCR with potential physiological importance.

RESULTS: Bioinformatic analyses predicted three novel HMGCR transcripts containing an alternative exon 1 (HMGCR-1b, -1c, -1d) compared with the canonical transcript (HMGCR-1a). The open reading frame of the HMGCR-1b transcript potentially encodes 20 additional amino acids at the N-terminus, compared with HMGCR-1a. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to examine the mRNA levels of HMGCR in different tissues; HMGCR-1a was the most highly expressed variant in most tissues, with the exception of the skin, esophagus, and uterine cervix, in which HMGCR-1b was the most highly expressed transcript. Atorvastatin treatment of HepG2 cells resulted in increased HMGCR-1b mRNA levels, but unaltered proximal promoter activity compared to untreated cells. In contrast, HMGCR-1c showed a more restricted transcription pattern, but was also induced by atorvastatin treatment.

CONCLUSIONS: The gene encoding HMGCR uses alternative, mutually exclusive exon 1 sequences. This contributes to an increased complexity of HMGCR transcripts. Further studies are needed to investigate whether HMGCR splice variants identified in this study are physiologically functional.

OBJECTIVES: Two functional genetic variants in the inosine triphosphatase (ITPA) gene have been shown to be strongly associated with protection from ribavirin (RBV)-induced hemolysis. We aimed at evaluating this finding in a chronic hepatitis C genotype 2/3 cohort with a predominance of genotype 3 patients where available data are scarce. A second objective was to determine whether a protective association translated into the need for RBV reduction and hence a possible impact on treatment response.

METHODS: Overall, 457 patients were recruited from two trials of genotype 2/3 patients treated with pegylated interferon α-2b and weight-based RBV. rs1127354 and rs7270101 were genotyped and a composite ITPAase deficiency variable was graded according to the two single nucleotide polymorphisms. The primary endpoints were hemoglobin (Hb) decline from baseline and Hb decline of more than 3 g/dl at week 4.RESULTS: Both single nucleotide polymorphisms and the composite ITPAase deficiency variable were strongly and independently associated with protection from a decline in Hb at week 4 in multivariate linear regression models (Prs1127354=7.0×10, Prs7270101=0.0036, PITPase deficiency variable =6.3×10). Patients with any degree of reduced ITPAase activity were less likely to have their RBV dose reduced (odds ratio 0.39, 95% confidence interval 0.16-0.96, P=0.040), although this did not translate into increased rapid viral response or sustained viral response (Prvr=0.93, Psvr=0.22).

CONCLUSION: We have confirmed a strong association between functional ITPA variants and RBV-induced hemolysis and showed protection from RBV dose reduction, although this did not translate into increased rapid viral response or sustained viral response.

Background:

The ATP-binding cassette transporter ABCC6 gene is located on chromosome 16 between its two pseudogenes (ABCC6P1 and ABCC6P2). Previously, we have shown that ABCC6P1 is transcribed and affects ABCC6 at the transcriptional level. In this study we aimed to determine copy number variations of ABCC6, ABCC6P1 and ABCC6P2 in different populations. Moreover, we sought to study the transcription pattern of ABCC6 and ABCC6 pseudogenes in 39 different human tissues.

Findings:

Genomic DNA from healthy individuals from five populations, Chinese (n = 24), Middle East (n = 20), Mexicans (n = 24), Caucasians (n = 50) and Africans (n = 24), were examined for copy number variations of ABCC6 and its pseudogenes by pyrosequencing and quantitative PCR. Copy number variation of ABCC6 was very rare (2/142; 1.4%). However, one or three copies of ABCC6P1 were relatively common (3% and 8%, respectively). Only one person had a single copy of ABCC6P2 while none had three copies. In Chinese, deletions or duplications of ABCC6P1 were more frequent than in any other population (9/24; 37.5%). The transcription pattern of ABCC6P2 was highly similar to ABCC6 and ABCC6P1, with highest transcription in liver and kidney. Interestingly, the total transcription level of pseudogenes, ABCC6P1 + ABCC6P2, was higher than ABCC6 in most tissues, including liver and kidney.

Conclusions:

Copy number variations of the ABCC6 pseudogenes are quite common, especially in populations of Chinese ancestry. The expression pattern of ABCC6P2 in 39 human tissues was highly similar to that of ABCC6 and ABCC6P1 suggesting similar regulatory mechanisms for ABCC6 and its pseudogenes.

INTRODUCTION:

Thalassemia and iron deficiency may both result in hypochromic microcytic anemia. Hematological algorithms that differentiate the two are mainly established in adult selected diagnostic groups. We aimed at creating an algorithm applicable in the presence of children, hemoglobin variants, and iron deficiency.

METHODS:

Our study material constituted blood samples referred during 1 year for routine diagnostics of hemoglobinopathy. We included 443 samples, of which 37% were from children 3 months or older. We found β-thalassemia trait, α-thalassemia, combined α-/β-thalassemia hemoglobin variants, and no-hemoglobinopathy, of whom 107 had a ferritin at or below 20 μg/L. We included reticulocyte hemoglobin equivalent, ferritin, and erythrocyte count in our algorithm.

RESULTS:

Our algorithm differentiated β-thalassemia from no-hemoglobinopathy with a sensitivity of 99% at 83% specificity. It performed better than other published algorithms when applied to all patient samples, while equally or moderately better in the 63% adult samples. Our algorithm also detected the clinically significant α-thalassemias, and most of the combined α-/β-thalassemias and thalassemic hemoglobin variants.

CONCLUSION:

Our algorithm efficiently differentiated thalassemia and thalassemic hemoglobin variants from iron deficiency in children and adults.

BACKGROUND: The prevalence of Mycoplasma genitalium and Ureaplasma genitalium in populations outside sexually transmitted infection clinics in Norway is unknown.

OBJECTIVE: To assess the prevalence of potential sexually transmitted organisms in a non-clinical setting, among college students in Northern Norway.

METHODS: In total 655 students, 449 men and 206 women, were tested for Chlamydia trachomatis, M. genitalium, and U. urealyticum by nucleic acid amplification testing of urine samples. All subjects completed questionnaires.

RESULTS: Among the included men, the prevalences of C. trachomatis, M. genitalium, and U. urealyticum were 4.2%, 1.1% and 8.9%, respectively. Prevalence among included women was 1.9%, 1% and 8.2%, respectively. In men, the number of sexual partners in the preceding 6 months was associated with prevalence of U. urealyticum and C. trachomatis.

CONCLUSIONS: U. urealyticum appeared more prevalent than C. trachomatis and increased number of sexual partners was associated with increased risk of a positive test. M. genitalium had a low prevalence.

BACKGROUND: The analytical quality of self-monitoring of blood glucose (SMBG) can be affected by environmental conditions such as temperature. The objective of this study was to determine the influence of (1) a shift in the ambient temperature immediately before measurement and (2) taking measurements in the lower and upper part of the operating temperature range.

METHODS: Nine different SMBG systems on the Norwegian market were tested with heparinized venous blood (4.8 and 19.0 mmol/L). To test the shift in ambient temperature effect, the glucometer and strips were equilibrated for 1 h at 5°C or 1 h at 30°C before the meter and strips were moved to room temperature, and measurements were performed after 0, 5, 10, 15, and 30 min. To test the lower and upper temperature range, measurements were performed at 10°C and at 39°C after 1 h for temperature equilibration of the glucometer and strips. All these measurements were compared with measurements performed simultaneously on a meter and strips kept at room temperature the whole time.

RESULTS: Six of nine SMBG systems overestimated and/or underestimated the results by more than 5% after moving meters and strips from 5°C or 30°C to room temperature immediately before the measurements. Two systems underestimated the results at 10°C. One system overestimated and another underestimated the results by more than 5% at 39°C.

CONCLUSIONS: The effect on analytical performance was most pronounced after a rapid shift in the ambient temperature. Therefore patients need to wait at least 15 min for temperature equilibration of affected meters and strips before measuring blood glucose.

BACKGROUND: Allergic sensitisation increases the risk for asthma development. In this prospective birth cohort (Environment and Childhood Asthma) study, we hypothesized that combining quantitative measures of IgE antibodies (Sigma-IgE) and Severity score of obstructive airways disease (OAD) at 2 years of age (Severity score) is superior to predict current asthma (CA) at 10 years than either measure alone. Secondarily, we assessed if gender modified the prediction of CA.

METHODS: A follow-up study at 10 years of age was performed in 371 2-year-old children with recurrent (n = 219) or no (n = 152) bronchial obstruction with available serum analysed for Sigma-IgE to common food and inhalant allergens through a panel test, Phadiatop Infant) (Phadia, Uppsala, Sweden). Clinical variables included allergic sensitisation and exercise testing to characterise children with CA vs not CA at 10 years and the Severity score (0-12, 0 indicating no OAD) was used to assess risk modification.

RESULTS: Severity score alone explained 24% (Nagelkerke R(2) = 0.24) of the variation in CA, whereas Sigma-IgE explained only 6% (R(2) = 0.06). Combining the two increased the explanatory capacity to R(2) = 0.30. Gender interacted significantly with Sigma-IgE; whereas Severity score predicted CA in both genders, the predictive capacity of Sigma-IgE for CA at 10 years was significant in boys only.

CONCLUSION: Combining Sigma-IgE to inhalant allergens and Severity score at 2 years was superior to predict asthma at 10 years than either alone. Severity score predicted CA in both genders, whereas Sigma-IgE significantly predicted CA in boys only.

”Når jeg går til min lege vil jeg at han skal gi meg den beste medisinen, ikke den beste medisinen som han forstår virkningen av.” Engelsk statistiker om leger og statistiske modeller .

I medisinsk biokjemi har vi ofte flere enn to variabler. Vi vet at gamma-GT er økt både for personer med høyt alkoholinntak og for personer med høy BMI. Hva med en person som har høy BMI, vil alkoholinntak føre til enda høyere gamma-GT eller ikke? Med lineær regresjon kan vi se sammenhenger mellom flere variabler

Bakgrunn. En variant av Chlamydia trachomatis (nvC trachomatis) har skapt problemer for chlamydiadiagnostikken i Sverige. Andelen nvC trachomatis i Sverige i 2006–07 var fylkesvis 25–80 % av dem som var smittet av C trachomatis. Vårt formål har vært å overvåke nvC trachomatis blant våre pasienter fra januar 2007 frem til juli 2008.

Materiale og metode. 1.1. 2007–30.6. 2008 ble alle chlamydiaprøver ved Fürst Medisinsk Laboratorium dobbeltanalysert. Deteksjon av C trachomatis ble utført på isolert DNA med Cobas TaqMan 48 (Roche Diagnostics). Deteksjon og verifikasjon av nvC trachomatis ble utført med egenutviklede sanntid polymerasekjedereaksjonsmetoder.

Resultater. 61 av 23 726 pasienter ble identifisert som bærere av nvC trachomatis. Andelen C trachomatis-bærere som var nvC trachomatis-positive økte fra 1,0 % i første kvartal 2007 til 3,2 % i andre kvartal 2008.

Fortolkning. Våre resultater viser en langsom, men jevn økning i andelen nvC trachomatis-positive prøver. Sammenliknet med tidligere prevalenstall rapportert i Sverige (25–80 %), er forekomsten av nvC trachomatis lav i våre data. Epidemiologien til nvC trachomatis bidrar til kunnskapen om spredning av seksuelt overførbare infeksjoner og understreker at man finner bare det man leter etter.

Det finnes over tusen odontologiske legeringer på markedet i dag, og bruken av uedle legeringer har i stor grad erstattet bruken av gullbaserte legeringer. Felles for disse legeringene er at de er i kontakt med oralt vev, og at metaller lekker fra legeringene ut i munnhulen. Det stilles derfor mange spørsmål om den biologiske sikkerheten omkring bruken av disse legeringene. Korrosjonstester, hvor de ulike legeringene blir utsatt for det samme sure miljøet som finnes i munnhulen, har vist at uedle legeringer lekker ut større konsentrasjoner av metaller sammenlignet med edle legeringer.

Nordisk Institutt for Odontologiske Materialer (NIOM) har undersøkt ekstrakter av ulike legeringer i cellekulturer og sett på hvilken påvirkning de har på cellene. I den sammenheng ønsket de å kvantifisere utlekking av metaller fra de ulike legeringene i cellekulturmediet for å bestemme konsentrasjonen av de ulike grunnstoffene som cellene hadde blitt utsatt for.  Fürst Medisinsk Laboratorium fikk i oppdrag å utvikle en metode for kvantitativ bestemmelse av grunnstoffer i Minimal Essential Medium with Earle’s salts (MEM).

Atten ulike odontologiske legeringer, hovedsakelig uedle, ble sandlåst, slipt og renset før inkubering i MEM cellekulturmedium under bevegelse i tre døgn ved 37 C. Legeringene ble deretter fjernet fra mediet og løsningene ble analysert ved induktivt koplet plasma massespektrometri (ICP-MS).  Alle prøvene ble analysert for grunnstoffene litium (Li), beryllium (Be), aluminium (Al), vanadium (V), mangan (Mn), kobolt (Co), nikkel (Ni), kobber (Cu), sink (Zn), gallium (Ga), arsen (As), selen (Se), rubidium (Rb), strontium (Sr), yttrium (Y), zirkonium (Zr), niob (Nb), molybden (Mo), ruthenium (Ru), palladium (Pd), sølv (Ag), kadmium (Cd), indium (In), tinn (Sn), antimon (Sb), cesium (Cs), barium (Ba), lantan (La), cerium (Ce), praseodym (Pr), neodym (Nd), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), hafnium (Hf), tantal (Ta), wolfram (W), rhenium (Re), osmium (Os), iridium (Ir), platina (Pt), gull (Au), bly (Pb), vismut (Bi) og thorium (Th). Resultater fra analysering av de odontologiske legeringene viste bare utlekking av de metallene som var oppgitt fra produsenten av legeringene, og det er kun disse grunnstoffene som er presentert i resultatkapittelet. Som korrosjonstestene gav også her de uedle legeringene et høyere utslipp av metaller enn de edle legeringene. 

Målemetoden som ble utviklet på ICP-MS gav tifredsstillende deteksjons- og kvantifiseringsgrenser, gjenfinning, presisjon og nøyaktighet for grunnstoffene Cr, Mn, Co, Ni, Cu, Zn, Ga, Nb, Mo, In, Sn, W, Pt og Au. Metoden gav bare ca 80 % gjenfinning av Ag og den kunne ikke brukes for bestemmelse av Pd < 50 µg/L. Metoden hadde ikke tilstrekkelig sensitivitet for bestemmelse av Fe på det nivået som lakk fra de 18 legeringene som ble analysert i denne oppgaven. Den største usikkerheten i metoden lå i prepareringen av løsningene. For mye manipulering av noen av legeringene ødela det beskyttende oksidlaget som ble dannet på overflaten og økte dermed utlekking av metaller.

Nordisk referanseintervallprosjekt (NORIP) ble iverksatt i 1999-2000. initiativtakere var opprinnelig  heidi Steensland og Petter Urdal som ved hjelp av NFKK fikk etablert en samnordisk gruppe som koordinerte studiet: Peter Felding,  Leifur Franzson, Veli Kairisto, Per Hyltoft Pedersen, Pål Rustad og Per Simonsson.

Friske individer mellom 18 og 80 år ble rekruttert på i alt 80 laboratorier i de nordiske landene og det ble samlet inn serum, plasma og fullblod . Prøvetakingen var nøye standardisert . Prøvene ble analysert for de vanligste komponentene i medisinsk biokjemi lokalt på de deltakende laboratoriene sammen med kontroller fra prosjektet, spesielt det som etter hvert ble kalt NFKK Reference Serum X. I tillegg ble materiale frosset ved – 80° C