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Background Infections are major causes of disease in cancer patients and pose a major obstacle to the success of cancer care. The global rise of antimicrobial resistance threatens to make these obstacles even greater and hinder continuing progress in cancer care. To prevent and handle such infections, a better understanding of the risk factors are needed. This internally funded systematic review (PROSPERO registration: CRD42021282769) aims to review what risk factors for resistant infections and deaths due to resistant infections have been investigated, and with what methodological approaches. Methods We employed two broad searches of antimicrobial resistance in cancer patients, using terms associated with antimicrobial resistant infections, in MEDLINE and Embase through Ovid, in addition to Cinahl through EBSCOhost and Web of Science Core Collection. Primary, observational studies in English from January 2015 to November 2021 on human cancer patients that explicitly modelled infection or mortality associated with antimicrobial resistance in a multivariable model were included. We extracted data on the study populations and their malignancies, risk factors, the microbial aetiology, methods for variable selection, and assessed the risk of bias using the NHLBI Study Quality Assessment Tools. Results Two searches yielded a total of 27151 unique records, of which 144 studies were included after screening and reading. Of the outcomes studied, mortality was the most common (68/144, 47%). Forty-five percent (65/144) of the studies focused on haemato-oncological patients, and 27% (39/144) studied several bacteria or fungi. Studies included a median of 200 patients and 46 events. One-hundred-and-three (72%) studies used a p-value-based variable selection. Studies included a median of seven variables in the final (and largest) model, which yielded a median of 6.9 events per variable. An in-depth example of vancomycin-resistant enterococci was reported. Conclusions We found the current research on this topic to be heterogeneous, in both the methodological and epidemiological approach. Methodological choices resulting in very diverse models made it difficult or even impossible to draw statistical inferences and summarise what risk factors were of clinical relevance. The development and adherence to more standardised protocols that build on existing literature is urgent.

Background Infections are major causes of disease in cancer patients and pose a major obstacle to the success of cancer care. The global rise of antimicrobial resistance threatens to make these obstacles even greater and hinder continuing progress in cancer care. To prevent and handle such infections, better models of clinical outcomes building on current knowledge are needed. This internally funded systematic review (PROSPERO registration: CRD42021282769) aimed to review multivariable models of resistant infections/colonisations and corresponding mortality, what risk factors have been investigated, and with what methodological approaches. Methods We employed two broad searches of antimicrobial resistance in cancer patients, using terms associated with antimicrobial resistance, in MEDLINE and Embase through Ovid, in addition to Cinahl through EBSCOhost and Web of Science Core Collection. Primary, observational studies in English from January 2015 to November 2021 on human cancer patients that explicitly modelled infection/colonisation or mortality associated with antimicrobial resistance in a multivariable model were included. We extracted data on the study populations and their malignancies, risk factors, microbial aetiology, and methods for variable selection, and assessed the risk of bias using the NHLBI Study Quality Assessment Tools. Results Two searches yielded a total of 27,151 unique records, of which 144 studies were included after screening and reading. Of the outcomes studied, mortality was the most common (68/144, 47%). Forty-five per cent (65/144) of the studies focused on haemato-oncological patients, and 27% (39/144) studied several bacteria or fungi. Studies included a median of 200 patients and 46 events. One-hundred-and-three (72%) studies used a p-value-based variable selection. Studies included a median of seven variables in the final (and largest) model, which yielded a median of 7 events per variable. An in-depth example of vancomycin-resistant enterococci was reported. Conclusions We found the current research to be heterogeneous in the approaches to studying this topic. Methodological choices resulting in very diverse models made it difficult or even impossible to draw statistical inferences and summarise what risk factors were of clinical relevance. The development and adherence to more standardised protocols that build on existing literature are urgent.

Aim This observational study investigated the microbiology of blood culture positive sepsis episodes and susceptibility to empiric antibiotics in early-onset sepsis (EOS) and late-onset sepsis (LOS) in a level four neonatal intensive care unit (NICU) from 2010-2019. Methods It was based on patient records and data that Oslo University Hospital, Norway, routinely submitted to the Norwegian Neonatal Network database. Clinical data were merged with blood culture results, including antibiotic susceptibility. Results We studied 5,249 infants admitted to the NICU 6,321 times and identified 324 positive blood cultures from 287 infants, with 30 EOS and 305 LOS episodes. Frequent causative agents for EOS were group B streptococci (33.3%), Escherichia coli (20.0%) and Staphylococcus aureus (16.7%). All were susceptible to empiric ampicillin and gentamicin. LOS was most frequently caused by coagulase-negative staphylococci (CONS) (73.8%), Staphylococcus aureus (15.7%) and Enterococci (6.9%). CONS, Staphylococcus aureus, Enterococci, Escherichia coli, Klebsiella and Enterobacter represented 91.9% of LOS episodes and were susceptible to vancomycin and cefotaxime (96.1%), vancomycin and gentamicin (97.0%) and cloxacillin and gentamicin (38.1%). Conclusion Empiric treatment with ampicillin and gentamicin was adequate for EOS. Combining vancomycin and gentamicin may be a safer alternative to cefotaxime for LOS, as this reduces exposure to broad-spectrum antibiotics.

PurposeThe Oslo Ischaemia Study was designed to investigate the prevalence and predictors of silent coronary disease in Norwegian middle-aged men, specifically validating exercise electrocardiography (ECG) findings compared with angiography. The study has been important in investigating long-term predictors of cardiovascular morbidity and mortality, as well as investigating a broad spectrum of epidemiological and public health perspectives.ParticipantsIn 1972–1975, 2014 healthy men, 40–59 years old, were enrolled in the study. Comprehensive clinical examination included an ECG-monitored exercise test at baseline and follow-ups. The cohort has been re-examined four times during 20 years. Linkage to health records and national health registries has ensured complete endpoint registration of morbidity until the end of 2006, and cancer and mortality until the end of 2017.Findings to dateThe early study results provided new evidence, as many participants with a positive exercise ECG, but no chest pain (‘silent ischaemia’), did not have significant coronary artery stenosis after all. Still, they were over-represented with coronary disease after years of follow-up. Furthermore, participants with the highest physical fitness had lower risk of cardiovascular disease, and the magnitude of blood pressure responses to moderate exercise was shown to influence the risk of cardiovascular disease and mortality. With time, follow-up data allowed the scope of research to expand into other fields of medicine, with the aim of investigating predictors and the importance of lifestyle and risk factors.Future plansRecently, the Oslo Ischaemia Study has been found worthy, as the first scientific study, to be preserved by The National Archives of Norway. All the study material will be digitised, free to use and accessible for all. In 2030, the Oslo Ischaemia Study will be linked to the Norwegian Cause of Death Registry to obtain complete follow-up to death. Thus, a broad spectrum of additional opportunities opens.

Background Vancomycin-resistant enterococci (VRE) represent several types of transferable vancomycin resistance gene clusters. The vanD type, associated with moderate to high level vancomycin resistance, has only sporadically been described in clinical isolates. The aim of this study was to perform a genetic characterization of the first VanD-type VRE strains detected in Norway. Methods The VanD-type VRE-strains (n = 6) from two patient cases were examined by antimicrobial susceptibility testing and whole genome sequencing (WGS) to uncover Van-phenotype, strain phylogeny, the vanD gene clusters, and their genetic surroundings. The putative transferability of vanD was examined by circularization PCR and filter mating. Results The VanD-type Enterococcus faecium (n = 4) and Enterococcus casseliflavus (n = 2) strains recovered from two cases (A and B), expressed moderate to high level vancomycin resistance (MIC 64—>256 mg/L) and various levels of teicoplanin susceptibility (MIC 2—>256 mg/L). WGS analyses revealed phylogenetically different E. faecium strains (A1, A2, and A3 of case A and B1 from case B) as well as vanD gene clusters located on different novel genomic islands (GIs). The E. casseliflavus strains (B2 and B3 of case B) were not clonally related, but harbored nearly identical novel GIs. The vanD cluster of case B strains represents a novel vanD-subtype. All the vanD-GIs were integrated at the same chromosomal site and contained genes consistent with a Clostridiales origin. Circular forms of the vanD-GIs were detected in all strains except B1. Transfer of vanD to an E. faecium recipient was unsuccessful. Conclusions We describe the first VanD-type E. casseliflavus strains, a novel vanD-subtype, and three novel vanD-GIs with a genetic content consistent with a Clostridiales order origin. Despite temporal occurrence, case A and B E. faecium strains were phylogenetically diverse and harbored different vanD subtypes and vanD-GIs.

Shiga toxin-producing Escherichia coli (STEC) may cause severe disease mainly due to the ability to produce Shiga toxins (Stx) encoded on bacteriophages. In Norway, more than 30% of the reported cases with STEC O145:H25 develop hemolytic uremic syndrome (HUS), and most cases, with known travel history, acquired the infection domestically. To describe phage characteristics associated with high virulence, we extracted the Stx2a phage sequences from eight clinical Norwegian O145:H25 STEC to conduct in-depth molecular characterization using long and short read sequencing. The Stx2a phages were annotated, characterized, and compared with previously published Stx2a phages isolated from STEC of different serotypes. The Norwegian O145:H25 Stx2a phages showed high sequence identity (>99%) with 100% coverage. The Stx2a phages were located at the integration site yciD, were approximately 45 kbp long, and harbored several virulence-associated genes, in addition to stx2a, such as nanS and nleC. We observed high sequence identity (>98%) and coverage (≥94%) between Norwegian O145:H25 Stx2a phages and publicly available Stx2a phages from O145:H25 and O145:H28 STEC, isolated from HUS cases in the USA and a hemorrhagic diarrhea case from Japan, respectively. However, low similarity was seen when comparing the Norwegian O145:H25 Stx2a phage to Stx2a phages from STEC of other serotypes. In all the Norwegian O145:H25 STEC, we identified a second phage or remnants of a phage (a shadow phage, 61 kbp) inserted at the same integration site as the Stx2a phage. The shadow phage shared similarity with the Stx2a phage, but lacked stx2a and harbored effector genes not present in the Stx2a phage. We identified a conserved Stx2a phage among the Norwegian O145:H25 STEC that shared integration site with a shadow phage in all isolates. Both phage and shadow phage harbored several virulence-associated genes that may contribute to the increased pathogenicity of O145:H25 STEC.

Background: The pathophysiology in atopic dermatitis (AD) is not fully understood, but immune dysfunction, skin barrier defects, and alterations of the skin microbiota are thought to play important roles. AD skin is frequently colonized with Staphylococcus aureus (S. aureus) and microbial diversity on lesional skin (LS) is reduced compared to on healthy skin. Treatment with narrow-band ultraviolet B (nb-UVB) leads to clinical improvement of the eczema and reduced abundance of S. aureus. However, in-depth knowledge of the temporal dynamics of the skin microbiota in AD in response to nb-UVB treatment is lacking and could provide important clues to decipher whether the microbial changes are primary drivers of the disease, or secondary to the inflammatory process. Objectives: To map the temporal shifts in the microbiota of the skin, nose, and throat in adult AD patients after nb-UVB treatment. Methods: Skin swabs were taken from lesional AD skin (n = 16) before and after 3 treatments of nb-UVB, and after 6–8 weeks of full-body treatment. We also obtained samples from non-lesional skin (NLS) and from the nose and throat. All samples were characterized by 16S rRNA gene sequencing. Results: We observed shifts towards higher diversity in the microbiota of lesional AD skin after 6–8 weeks of treatment, while the microbiota of NLS and of the nose/throat remained unchanged. After only 3 treatments with nb-UVB, there were no significant changes in the microbiota. Conclusion: Nb-UVB induces changes in the skin microbiota towards higher diversity, but the microbiota of the nose and throat are not altered.

The aims of this study were to describe the distribution of the most common erm genes in a collection of Norwegian Bacteroides isolates and to investigate whether the phenotypic tests for determining inducible clindamycin resistance among Bacteroides species recommended by EUCAST, NordicAST and the manufacturer of E-test®, are effective. We investigated 175 unique Bacteroides isolates for the presence of erm(B), erm(F) and erm(G) genes, determined their minimum inhibitory concentrations (MICs) to clindamycin and categorised their susceptibility according to EUCAST breakpoints. 27 isolates were resistant to clindamycin. Furthermore, we investigated whether these recommended methods could detect inducible resistance in the Bacteroides isolates: 1) EUCAST recommendation: Dissociated resistance to erythromycin (clindamycin susceptible with erythromycin MIC > 32 mg/L), 2) NordicAST recommendation: Double disk diffusion test (DDD) or 3) Manufacturer of E-test®’s recommendation: prolonged incubation of clindamycin E-test® for 48 h. erm genes were detected in 30 (17%, 95% CI 12%–23%) of 175 Bacteroides isolates with erm(F) as the dominating gene. There were six (4%, 95% CI 1%–7%) of 148 clindamycin susceptible isolates harbouring erm genes, they were considered inducibly resistant to clindamycin. None of the methods for phenotypic detection of inducible clindamycin resistance performed satisfactory with sensitivities of 33%, 17% and 0% and specificities of 90%, 99% and 97% for dissociated resistance, DDD and prolonged incubation of clindamycin E-test®, respectively. In our view, the scientific basis for investigating every Bacteroides isolate for inducible resistance to clindamycin is weak. Molecular detection of erm genes may prove a better option than the phenotypic methods we evaluated.

Background In hospitalised patients with diarrhoea a positive campylobacter stool Polymerase Chain Reaction (PCR) test with negative culture results as well as Enteropathogenic Escherichia coli (EPEC) positive stool PCRs, challenges the clinician and may lead the unexperienced clinician astray. The aim of the study was to elucidate the clinical significance of positive Campylobacter and/or EPEC test results in hospitalised patients with diarrhoea. Methods We conducted a retrospective case-case study. Case groups with 1) EPEC only and 2) EPEC in combination with any other pathogen in the PCR multiplex array, 3) PCR positive/culture negative Campylobacter, and 4) PCR positive/culture positive Campylobacter were compared. Medical records were reviewed and cases classified according to pre-specified clinical criteria as infectious gastroenteritis or non-infectious causes for diarrhoea. We analyzed the association between laboratory findings (the 4 subgroups) and the pre-specified clinical classification. We further sequenced culture negative campylobacter samples and tested EPEC for bundle forming pilus A (bfpA) gene, distinguishing typical from atypical EPEC. Results A total of 291 patients were included, 169 were PCR positive for Campylobacter and 122 for EPEC. For both pathogens, co-infections were more common in culture negative/PCR positive samples than in culture positive samples. Clinical characteristics differed significantly in and between groups. Campylobacter culture positive patients had very high prevalence of characteristics of acute infectious gastroenteritis, whereas patients with PCR positive test results only often had an alternative explanation for their diarrhoea. Culture positives were almost exclusively C. jejuni/coli, whereas in culture negatives, constituting a third of the total PCR positives, C. concisus was the most frequent species. The vast majority of EPEC only positives had documented non-infectious factors that could explain diarrhoea. The EPEC co-infected group mimicked the culture positive campylobacter group, with most patients fulfilling the infectious gastroenteritis criteria. Conclusions In hospitalised patients, positive PCR results for campylobacter and EPEC should be interpreted in a clinical context after evaluation of non-infectious diarrhoea associated conditions, and cannot be used as a stand-alone diagnostic tool.

Significance Methicillin-resistant Staphylococcus aureus (MRSA), traditionally associated with hospitals, is increasingly circulating in the community. This imposes, in turn, a potential burden on hospital infection control due to a more frequent hospitalization of colonized patients. We developed an individual-based model, reproducing community and healthcare settings, to understand the epidemiological drivers of MRSA and the connections between the society and the healthcare institutions. We show that in Norway, a low-prevalence country, the rise of infections is driven by an increasing inflow of cases from abroad rather than by an ongoing epidemic. We demonstrate the major role played by households in transmitting MRSA and show that the burden on hospitals from the growing community circulation is still limited thanks to aggressive infection-control protocols., Methicillin-resistant Staphylococcus aureus (MRSA) is a primarily nosocomial pathogen that, in recent years, has increasingly spread to the general population. The rising prevalence of MRSA in the community implies more frequent introductions in healthcare settings that could jeopardize the effectiveness of infection-control procedures. To investigate the epidemiological dynamics of MRSA in a low-prevalence country, we developed an individual-based model (IBM) reproducing the population’s sociodemography, explicitly representing households, hospitals, and nursing homes. The model was calibrated to surveillance data from the Norwegian national registry (2008–2015) and to published household prevalence data. We estimated an effective reproductive number of 0.68 (95% CI 0.47–0.90), suggesting that the observed rise in MRSA infections is not due to an ongoing epidemic but driven by more frequent acquisitions abroad. As a result of MRSA importations, an almost twofold increase in the prevalence of carriage was estimated over the study period, in 2015 reaching a value of 0.37% (0.25–0.54%) in the community and 1.11% (0.79–1.59%) in hospitalized patients. Household transmission accounted for half of new MRSA acquisitions, indicating this setting as a potential target for preventive strategies. However, nosocomial acquisition was still the primary source of symptomatic disease, which reinforces the importance of hospital-based transmission control. Although our results indicate little reason for concern about MRSA transmission in low-prevalence settings in the immediate future, the increases in importation and global circulation highlight the need for coordinated initiatives to reduce the spread of antibiotic resistance worldwide.

Purpose Antimicrobial treatment of Shiga toxin-producing Escherichia coli (STEC) infections is controversial because antimicrobials may stimulate Shiga toxin (Stx) production, and thereby increase the risk of developing haemolytic uremic syndrome (HUS). Previous in vitro studies have shown this mainly in infections caused by STEC serotype O157:H7. The aim of this study was to investigate induction of Stx transcription and production in different serotypes of STEC isolated from severely ill patients, following their exposure in vitro to six different classes of antimicrobials. Methods We investigated Stx transcription and production in 12 high-virulent STEC strains, all carrying the stx2a gene, of six different serotypes following their exposure to six classes of antimicrobials. Liquid cultures of the STEC strains were incubated with sub-inhibitory concentrations of the antimicrobials. We used reverse-transcription quantitative PCR to measure the relative expression of Stx2a mRNA and an enzyme-linked immunosorbent assay to quantify Stx production. Results In general the antibiotics tested showed only minor effects on transcriptional levels of Stx2a. Ciprofloxacin caused an increase of Stx production in all but two strains, while gentamicin, meropenem and azithromycin did not induce Stx production in any of the STEC strains examined. STEC O104:H4 was the serotype that in greatest extent responded to antimicrobial exposure with an increase of stx2a transcription and Stx production. Conclusion Gentamicin, meropenem and azithromycin exposure did not result in elevated Stx production. We recommend that this finding is investigated further in the search for candidates for future antimicrobial treatment of STEC.

Staphylococcus aureus bloodstream infections (SABSI) are associated with a high burden of morbidity and mortality. The impact of specific S. aureus genotypes on outcome is unclear. The aim of this study was to evaluate the epidemiology and outcome of SABSI, with a special emphasis on the impact of bacterial clonal lineage on mortality. We conducted a 3-year population-based prospective study between 2011 and 2014, including 303 consecutive adult patients. Clinical data were obtained from interviews and medical records. S. aureus isolates were genotyped using DNA microarrays. The incidence rate of SABSI was 27.6 per 100,000 inhabitants [95 % confidence interval (CI) 24.6–31.0]. The median age of the patients was 71 years (interquartile range 56–81 years) and 61.4 % were male. Most SABSI (70.6 %) occurred in hospitals or associated to healthcare, and 34.1 % of these were associated with intravascular catheters. Only five (1.6 %) SABSI were caused by methicillin-resistant S. aureus (MRSA). The 30-day case fatality rate was 20.8 % (95 % CI 16.6–25.7). S. aureus clonal complex 30 [hazard ratio (HR) 3.9; 95 % CI 1.8–8.5, p = 0.001], unknown focus of infection (HR 4.5; 95 % CI 1.9–10.8, p = 0.001) and respiratory tract infection (HR 12.7; 95 % CI 4.6–34.6, p

Background Preterm infants have low gut microbial diversity and few anaerobes. It is unclear whether the low diversity pertains to prematurity itself or is due to differences in delivery mode, feeding mode or exposure to antibiotics. Methods The Norwegian Microbiota Study (NoMIC) was established to examine the colonization of the infant gut and health outcomes. 16S rRNA gene Illumina amplicon-sequenced samples from 519 children (160 preterms), collected at 10 days, 4 months and 1 year postnatally, were used to calculate alpha diversity. Short-chain fatty acids (SCFA) were analysed with gas chromatography and quantified using flame ionization detection. We regressed alpha diversity on gestational age, taking into account possible confounding and mediating factors, such as breastfeeding and antibiotics. Taxonomic differences were tested using Analysis of Composition of Microbiomes (ANCOM) and SCFA profile (as a functional indicator of the microbiota) was tested by Wilcoxon rank-sum. Results Preterm infants had 0.45 Shannon units lower bacterial diversity at 10 days postnatally compared with infants born at term (95% confidence interval: -0.60, -0.32). Breastfeeding status and antibiotic exposure were not significant mediators of the gestational age-diversity association, although time spent in the neonatal intensive care unit was. Vaginally born, exclusively breastfed preterm infantss not exposed to antibiotics at 10 days postnatally had fewer Firmicutes and more Proteobacteria than children born at term and an SCFA profile indicating lower saccharolytic fermentation. Conclusions Preterm infants had distinct gut microbiome composition and function in the early postnatal period, not explained by factors more common in preterms, such as shorter breastfeeding duration, more antibiotics or caesarean delivery.

Background Norway has one of the lowest prevalences of methicillin-resistant Staphylococcus aureus (MRSA) infections in the world. This study exploits the extensive data on MRSA infections in the Norwegian surveillance system to investigate the important factors defining the MRSA epidemiology. Methods We performed a quasi-Poisson regression of the monthly notification rate (NR) of MRSA infections reported from January 2006 to December 2015, comparing the time trend among people with an immigrant vs. Norwegian background and domestic vs. imported infections, stratified by age groups. Findings A total of 5289 MRSA infections were reported during the study period, of which 2255 (42·6%) were acquired in Norway, 1370 (25·9%) abroad, and 1664 (31·5%) with an unknown place of acquisition. Overall, the monthly NR increased significantly from 2006 to 2015 (+0·8% each month). The monthly increase in immigrants (+1·3%) was steeper than that in people with a Norwegian background (+0·6%). There was a significant growth (+0·4%) in the rate of domestically acquired infections, however, the NR of infections acquired abroad increased faster (+0·8%). For both imported and domestic infections, the increase occurred in persons aged < 70 years. Interpretation Our analysis suggests that immigration and importation, especially among persons aged < 40 years, represent important factors for the increasing notification rate of MRSA infections in Norway.

Summary Background There has been a marked increase in the incidence of meticillin-resistant Staphylococcus aureus (MRSA) during the past decade in Norway; a country with one of the lowest prevalence rates and an active ‘search-and-destroy’ policy applied to hospital settings. Aim To characterize the trends of notification rates of community-associated (CA) and healthcare-associated (HA) MRSA in Norway, and explore the diversity and circulation of MRSA spa types within and outside healthcare settings. Methods A registry-based study on notified MRSA infections and colonizations was conducted in Norway between 2006 and 2015. The diversity and abundance of CA- and HA-MRSA spa types were compared using novel ecological diversity measures (Hill numbers). Findings During the study period, the monthly notification rate increased 6.9-fold and 1.8-fold among CA- and HA-MRSA, respectively; the increase was steeper among colonizations than infections. In both settings, the distribution of spa types was uneven, with a few dominant spa types and many singletons. The spa-type diversity of CA-MRSA was higher than HA-MRSA in terms of different types (685 vs 481), and increased during the study period. However, the diversity associated with the dominant spa types was similar and remained stable. A high overlap of spa types was estimated between the settings; spa-t002, t019 and t008 were the most common. Conclusion The present findings suggest a strong connection between CA- and HA-MRSA epidemiology in Norway. If the fast-growing trend of CA-MRSA continues in the years to come, it may challenge current guidelines and infection control of MRSA in healthcare environments.

Background Although diet is known to have a major modulatory influence on gut microbiota, knowledge of the specific roles of particular vitamins, minerals, and other nutrients is limited. Modulation of the composition of the microbiota in pregnant women is especially important as maternal microbes are transferred during delivery and initiate the colonization process in the infant. We studied the associations between intake of specific dietary nutrients during pregnancy and gut microbiota composition. Methods Utilizing the Norwegian NoMIC cohort, we examined the relations between intakes of 28 dietary macro- and micronutrients during pregnancy, derived from food frequency questionnaires administered to 60 women in the second trimester, and observed taxonomic differences in their gut microbiota four days after delivery (assessed through Illumina 16S rRNA amplicon analysis). Results Higher dietary intakes of fat-soluble vitamins, especially vitamin D, were associated with reduced microbial alpha diversity (p value

This study provides strong, novel evidence that humans may introduce methicillin-resistant Staphylococcus aureus CC398 into closed pig populations; it also demonstrates that stringent control and eradication measures were effective and prevented dissemination from pig farms to the general human population., Background. Emerging livestock-associated methicillin-resistant Staphylococcus aureus (MRSA) persist in livestock populations and represent a reservoir for transmission to humans. Understanding the routes of introduction and further transmission is crucial to control this threat to human health. Methods. All reported cases of livestock-associated MRSA (CC398) in humans and pigs in Norway between 2008 and 2014 were included. Data were collected during an extensive outbreak investigation, including contact tracing and stringent surveillance. Whole-genome sequencing of isolates from all human cases and pig farms was performed to support and expand the epidemiological findings. The national strategy furthermore included a “search-and-destroy” policy at the pig farm level. Results. Three outbreak clusters were identified, including 26 pig farms, 2 slaughterhouses, and 36 humans. Primary introductions likely occurred by human transmission to 3 sow farms with secondary transmission to other pig farms, mainly through animal trade and to a lesser extent via humans or livestock trucks. All MRSA CC398 isolated from humans without an epidemiological link to the outbreaks were genetically distinct from isolates within the outbreak clusters indicating limited dissemination to the general population. Conclusions. This study identified preventable routes of MRSA CC398 introduction and transmission: human occupational exposure, trade of pigs and livestock transport vehicles. These findings are essential for keeping pig populations MRSA free and, from a “One Health” perspective, preventing pig farms from becoming reservoirs for MRSA transmission to humans.

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

The aim of this study was to investigate the patterns and dynamics of the microbiota in the airways of ventilated patients. Seventy-four mechanically-ventilated patients were recruited consecutively, and oropharyngeal, tracheal and bronchoalveolar (BAL) fluid specimens were collected 48 h after intubation, and every 72 h thereafter until the patient was extubated or a total of five sample sets had been collected. Ventilator-associated pneumonia (VAP) pathogens were identified, quantified and genotyped. Microbial findings were highly correlated both between airway locations and over time when samples were taken no more than 72 h apart. If no VAP pathogen was present in the oral flora, it was unlikely to be found in a lower airway sample; i.e., the positive predictive value of the oropharyngeal sample was 0.73 (95% CI 0.67–0.80), and the negative predictive value was 0.95 (95% CI 0.92–0.99). Colonisation with Enterobacteriacae, non-fermentative bacteria and Staphylococcus aureus was monoclonal in the airways and over time, whereas colonisation with microbes normally found in the oropharynx, i.e., Haemophilus influenzae, Haemophilus parainfluenzae and Streptococcus pneumoniae , was polyclonal. When antibiotics were used, the chance of recovering VAP pathogens from all sampling sites was reduced three-fold. No correlation was observed between a bacterial count of ≥10 4 CFU/mL in BAL fluid and chest X-rays compatible with VAP.

Background: Contaminated oral swabs caused a nationwide monoclonal Pseudomonas aeruginosa outbreak involving 27 Norwegian hospitals. The aim of the study was to study the consequences on mortality and morbidity of the introduction of this P. aeruginosa strain to intensive care unit (ICU) patients. Methods: Forty-four out of 96 patients admitted to the general ICU of Akershus University Hospital during the outbreak, ventilated for more than 24 h and with at least one microbiological sample, were included and followed until death or hospital discharge. All isolated P. aeruginosa strains were genotyped. Demographic data, admission diagnosis, Simplified Acute Physiology Score II (SAPS II), Sequential Organ Failure Assessment (SOFA) score, comorbidities, and antibiotics used in the first week were recorded. Results: The outbreak strain was found in 18 patients (41%) of whom seven became infected. Median time to the first positive culture was 4 days. These 18 patients spent a significantly longer time on mechanical ventilation (P =0.03) and had a significantly higher hospital mortality, 55.5% vs. 19.2% (P =0.03), than non-colonized patients. The number of patients with severe underlying disease was significantly higher (P =0.01) and the decline in SOFA score was significantly slower in the pseudomonas group (P =0.02). Irrespective of colonization status, patients with severe underlying disease had a significantly higher mortality (58%) than those without (16%) (P =0.009). Conclusion: Use of contaminated oral swabs led to a high rate of early airways colonization. Patients with severe underlying disease were more likely to become colonized, but whether colonization has any influence on hospital mortality requires further study.

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

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

To assess whether fasting blood glucose is independently related to blood pressure at rest and during exercise, and to development of elevated blood pressure.Cross-sectional and prospective cohort study of 2014 apparently healthy middle-aged men.The baseline survey included carefully standardized blood pressure measurements at rest and during exercise testing, an intravenous glucose tolerance test and a panel of fasting blood tests, including fasting blood glucose. Results from 7-years follow-up provided data on development of elevated blood pressure.Strong associations were found between quartiles of fasting blood glucose and baseline resting and/or exercise levels of blood pressure, and also development of elevated blood pressure over 7 years. Physical fitness, calculated from an exercise test, had a strong modulating effect on blood pressure at all levels of fasting blood glucose. In multivariate models - after adjusting for intravenous glucose tolerance, physical fitness, age, body mass index, triglycerides and cholesterol - fasting blood glucose was strongly associated with blood pressure at rest (coefficient = 2.83, P = 0.0004) and during exercise (coefficient = 6.57, P0.0001), and further to development of treated hypertension and/or elevated blood pressure [odds ratio (OR), 1.17; 95% confidence interval (CI), 1.05-1.31].In healthy non-diabetic and non-hypertensive men, strong associations were found between fasting blood glucose and blood pressure at rest and during exercise and to development of elevated blood pressure after 7-years follow-up. Fasting glucose metabolism deserves scrutiny when studying the pathogenesis of hypertension.

Standardization of blood pressure (BP) measurement is important for both clinical and epidemiological purposes. The aim of the present study was to investigate early vs late morning measurements of BP and heart rate in healthy subjects. During the years 1972-75, healthy men aged 40-59 years (n = 2014) participated in a cardiovascular survey in Oslo. Two to four men underwent the examination program per day; it included height/weight, a spirographic study, chest X-ray, a number of blood tests, case history, clinical examination, resting ECG and physical exercise testing. BP and heart rate measurements were meticulously standardized. When adjusting for age, smoking habits and season of year we found that men who were examined as number one in the row of two to four subjects each morning had higher systolic BP (3.6 mmHg, p < 0.001) and heart rate (3.6 beats/min, p < 0.001) at rest compared to others. They were virtually identical in all other aspects. These differences in systolic BP and heart rate at rest disappeared during bicycle exercise. Thus, we suggest that the increased BP and heart rate at rest represent a stress reaction to being number one in a row of subjects to be examined, i.e. a bias in BP and heart rate measurements, possibly of both clinical and epidemiological importance.

To evaluate the effect of Norwegian antibiotic prophylaxis guidelines on rates of superficial and deep surgical-site infections (SSIs) associated with cesarean delivery (CD).A cross-sectional study was conducted that analyzed the physician-diagnosed SSIs by regimen of antibiotic prophylaxis among women who underwent planned or emergency CD at one of 42 hospitals between January 1, 2008, and December 31, 2010. The antibiotic prophylaxis regimen was verified using a hospital survey, whereas guideline compliance was assessed as part of the mandatory Norwegian Surveillance System for Healthcare-Associated Infections.Data for 4498 patients were used. Hospitals that practiced antibiotic prophylaxis for all CDs (n=4) provided antibiotics more often in both emergency and planned CDs than did those that used this approach for emergency CDs only (n=33) or had no written guidelines or used prophylaxis on indication only (n=5) (P0.001). The provision of antibiotic prophylaxis for all cases of CD was associated with markedly lowered rates of superficial SSIs among planned CDs, whereas no differences in rates of deep SSIs were observed between the guidelines in either planned or emergency CDs.Hospitals that provided antibiotic prophylaxis to all women undergoing CD reported high compliance and had reduced rates of superficial SSIs among planned CDs.

The aim of the study was to review the epidemiology and prognosis of candidemia in a secondary hospital, and to examine the intra-hospital distribution of candidemia patients. Study design is a retrospective cohort study. Trough 2002-2012, 110 cases of candidemia were diagnosed, giving an incidence of 2, 6/100,000 citizens/year. Overall prognosis of candidemia was dismal, with a 30 days case fatality rate of 49% and one year case fatality rate of 64%. Candidemia was a terminal event in 55% of 30 days non-survivors, defined as Candida blood cultures reported positive on the day of death or thereafter (39%), or treatment refrained due to hopeless short-term prognosis (16%). In terminal event candidemias, advanced or incurable cancer was present in 29%. Non-survivors at 30 days were 9 years (median) older than survivors. In 30 days survivors, candidemia was not recognised before discharge in 13% of cases. No treatment were given and no deaths or complications were observed in this group. Candidemia patients were grouped into 8 patient categories: Abdominal surgery (35%), urology (13%), other surgery (11%), pneumonia (13%), haematological malignancy (7%), intravenous drug abuse (4%), other medical (15%), and new-borns (3%). Candidemia was diagnosed while admitted in the ICU in 46% of patients. Urology related cases were all diagnosed in the general ward. Multiple surgical procedures were done in 60% of abdominal surgery patients. Antibiotics were administered prior to candidemia in 87% of patients, with median duration 17 (1-108) days. Neutropenia was less common than expected in patients with candidemia (8/105) and closely associated to haematological malignancy (6/8). Compared with previous national figures the epidemiology of invasive candidiasis seems not to have changed over the last decade.

SUMMARY Aims To study the glucose disappearance rate and fasting blood glucose as predictors of Type 2 diabetes in a 22.5-year prospective follow-up of 1947 healthy non-diabetic men. Subjects and methods Of a cohort of 2014 Caucasian men, the 1947 who had both fasting blood glucose

Aims Since atherosclerosis is a chronic inflammation and the erythrocyte sedimentation rate is an appropriate test for monitoring chronic inflammatory responses, we wanted to investigate whether the erythrocyte sedimentation rate might carry prognostic information on the risk of sustaining coronary heart disease events. Method The erythrocyte sedimentation rate was determined in 2014 apparently healthy men aged 40-60 years during an extensive cardiovascular survey in 1972-75, and the test was repeated in an identical follow-up examination 7 years later. Cause-specific mortality and rates of non-fatal myocardial infarction were followed for 23 years. Results The erythrocyte sedimentation rate was strongly correlated with age, haemoglobin level, smoking status, total cholesterol level and systolic blood pressure. After adjusting for all these associations in multivariate Cox regression analyses, the erythrocyte sedimentation rate emerged as a strong short- and long-term predictor of coronary heart disease mortality, particularly in men who had developed angina pectoris and/or had a positive exercise ECG test at the second survey. Increases in non-coronary heart disease deaths and in non-fatal myocardial infarctions were only seen in the upper erythrocyte sedimentation rate range. Conclusions The erythrocyte sedimentation rate is a strong predictor of coronary heart disease mortality, and appears to be a marker of aggressive forms of coronary heart disease. The erythrocyte sedimentation rate probably gives substantial information in addition to that given by fibrinogen on the risk of coronary heart disease death.

OBJECTIVE: Because of the available conflicting epidemiological data, we investigated the possible impact of fasting blood glucose as a risk factor for cardiovascular death in nondiabetic men. This study reports the results from a 22-year prospective study on fasting blood glucose as a predictor of cardiovascular death. RESEARCH DESIGN AND METHODS: Of the 1,998 apparently healthy nondiabetic men (aged 40-59 years), a total of 1,973 with fasting blood glucose < 110 mg/dl were included in the study in which also a number of conventional risk factors were measured at baseline. RESULTS: After 22 years of follow-up, 483 men had died, 53% from cardiovascular diseases. After dividing men into quartiles of fasting blood glucose level, it was found that men in the highest glucose quartile (fasting blood glucose > 85 mg/dl) had a significantly higher mortality rate from cardiovascular diseases compared with those in the three lowest quartiles. Even after adjusting for age, smoking habits, serum lipids, blood pressure, forced expiratory volume in 1 s, and physical fitness (Cox model), the relative risk of cardiovascular death for men with fasting blood glucose > 85 mg/dl remained 1.4 (95% CI 1.04-1.8). Noncardiovascular deaths were unrelated to fasting blood glucose level. CONCLUSIONS: Fasting blood glucose values in the upper normal range appears to be an important independent predictor of cardiovascular death in nondiabetic apparently healthy middle-aged men.

Prosthetic joint infections are difficult to eradicate, and antibiotic and surgical treatment strategies lack standardisation. The present study followed 29 patients (median age 72 years, median American Society of Anesthesia score of two) with early prosthetic joint infections. Treatment consisted of device retention, surgical debridement and therapy with rifampicin and ciprofloxacin for 3 months. This treatment regimen failed in five patients during the study, with a median observation period of 674 days. The results of this study confirm the findings of the only previous study on device retention with antibiotic treatment.

It is acknowledged that some obesity trajectories are set early in life, and that rapid weight gain in infancy is a risk factor for later development of obesity. Identifying modifiable factors associated with early rapid weight gain is a prerequisite for curtailing the growing worldwide obesity epidemic. Recently, much attention has been given to findings indicating that gut microbiota may play a role in obesity development. We aim at identifying how the development of early gut microbiota is associated with expected infant growth. We developed a novel procedure that allows for the identification of longitudinal gut microbiota patterns (corresponding to the gut ecosystem developing), which are associated with an outcome of interest, while appropriately controlling for the false discovery rate. Our method identified developmental pathways of Staphylococcus species and Escherichia coli that were associated with expected growth, and traditional methods indicated that the detection of Bacteroides species at day 30 was associated with growth. Our method should have wide future applicability for studying gut microbiota, and is particularly important for translational considerations, as it is critical to understand the timing of microbiome transitions prior to attempting to manipulate gut microbiota in early life., Author Summary Some obesity trajectories are set early in life, with rapid weight gain being a risk factor for later development of obesity. Recently, much attention has been given to findings indicating that gut microbiota may play a role in obesity development. The existence of time-dependent exposure windows, which rely on stimuli from the gut to initiate healthy development, gives the evolution of early life gut microbiota a critical role in human health. We identified children that followed their expected growth trajectories at six months of life, and those that had deviated. We then developed a novel statistical approach that allowed the identification of longitudinal gut microbiota patterns (e.g. a particular species was detected at days 4, 10, and 30 and not detected at day 120) that were associated with expected growth, while appropriately restricting the false discovery rate. We further identified when a deviation from the proposed longitudinal gut microbiota patterns would result in an abnormal growth outcome (either rapid or decreased growth at six months of life). We found developmental pathways of Staphylococcus species and Escherichia coli that were associated with expected growth, as well as indications that Bacteroides species at day 30 was associated with growth.

To determine whether men with possible angina (from their responses to the World Health Organization angina questionnaire) but a normal exercise ECG differ in long term rates of coronary heart disease events from men with no symptoms of angina.During 1972-75, 2014 apparently healthy men aged 40-59 years underwent an examination programme including case history, clinical examination, exercise ECG to exhaustion, and various other tests. All men completed the WHO angina questionnaire.Of 2014 men, 68 had possible angina, 1831 had no symptoms of angina, and 115 were excluded because they had definite angina or pathological exercise ECGs. All 68+1831 had normal exercise ECGs and none developed chest pain during the exercise test.At 26 years, men with possible angina had a coronary heart disease mortality of 25.0% (17/68) v 13.8% (252/1831) among men with no symptoms of angina (p0.013). They also had a higher incidence of coronary artery bypass grafting (CABG) (p0.0004) and acute myocardial infarction (p0.026). The excess coronary heart disease mortality among men with possible angina only started after 15 years, whereas differences in CABG/acute myocardial infarction started early. Multivariate analysis including well recognised coronary heart disease risk factors showed that possible angina was an independent risk factor (relative risk 1.79, 95% confidence interval 1.26 to 2.10).Men with possible angina, even with a normal exercise test, have a greater risk of dying from coronary heart disease, having an acute myocardial infarct, or needing a CABG than age matched counterparts with no symptoms of angina.

Aim It has recently been suggested that exercise testing may be more valuable prognostically than it is diagnostically in apparently healthy subjects. We wanted to compare the accuracy of CHD risk assessment based on classical risk factors with an assessment also based on multiple exercise test parameters. Methods and results In 1972–75, 2014 apparently healthy men aged 40–60 had a symptom limited exercise test during a cardiovascular survey. Three hundred died from CHD during 26 years of follow-up. Compared to Cox regression models solely including classical risk factors (CRF), models also including multiple exercise test parameters (CRF+X) were clearly superior (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(P{ 6.5 mmol/l (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(n=470\) \end{document}), the CRF and CRF+X models identified 67 vs. 110 men at the highest CHD risk level according to European guidelines (34.2% vs. 38.2% CHD mortality). Three in five CRF+X-identified smokers with cholesterol >6.5 mmol/l had CHD mortality similar to the mean of all 2014 men. Conclusion Integration of multiple exercise test parameters and conventional risk factors improved CHD risk assessment substantially – especially in smokers with high cholesterol.

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

OBJECTIVE: Although an excess transmission of type 2 diabetes from mothers has been documented, whether this is an independent trait or whether the effect can be detected early through risk factors for type 2 diabetes remains to be elucidated. The objective of this study was to investigate the prevalence of and the possible prospective effect of family history on type 2 diabetes incidence adjusted for multiple diabetes risk factors in a 22.5-year follow-up study of healthy men. RESEARCH DESIGN AND METHODS: A total of 1,947 apparently healthy nondiabetic men with fasting blood glucose (FBG) levels