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  • CONNECT Study Consortium COS Dev G; Hermelijn, Sergei; Kersten, Casper; Mullassery, Dhanya; Suominen, Janne (2021)
    Introduction A worldwide lack of consensus exists on the optimal management of asymptomatic congenital pulmonary airway malformation (CPAM) even though the incidence is increasing. Either a surgical resection is performed or a wait-and-see policy is employed, depending on the treating physician. Management is largely based on expert opinion and scientific evidence is scarce. Wide variations in outcome measures are seen between studies making comparison difficult thus highlighting the lack of universal consensus in outcome measures as well. We aim to define a core outcome set which will include the most important core outcome parameters for paediatric patients with an asymptomatic CPAM. Methods and analysis This study will include a critical appraisal of the current literature followed by a three-stage Delphi process with two stakeholder groups. One surgical group including paediatric as well as thoracic surgeons, and a non-surgeon group including paediatric pulmonologists, intensive care and neonatal specialists. All participants will score outcome parameters according to their level of importance and the most important parameters will be determined by consensus. Ethics and dissemination Electronic informed consent will be obtained from all participants. Ethical approval is not required. After the core outcome set has been defined, we intend to design an international randomised controlled trial: the COllaborative Neonatal NEtwork for the first CPAM Trial, which will be aimed at determining the optimal management of patients with asymptomatic CPAM.
  • Simonen, Piia; Arte, Elisa; Gylling, Helena (2021)
    Dietary modifications including plant stanol ester consumption are recommended measures to control serum and low-density lipoprotein (LDL)-cholesterol concentrations, but obesity can affect their responses. We investigated whether body mass index (BMI) affects serum cholesterol levels during plant stanol (mainly sitostanol) ester consumption. This ad hoc analysis was based on earlier results of a cross-over, randomized controlled trial of postmenopausal women consuming rapeseed oil-based margarine without or with plant stanol ester (3 g plant stanols/day) for seven weeks. We classified the subjects as normal-weight (BMI 25 kg/m(2), n = 11, mean 28.4 kg/m(2)), and recalculated the results, focusing on cholesterol absorption, cholesterol synthesis, and fecal steroid outputs. Serum cholesterol levels were similar in the groups during the control diet. Plant stanol ester reduced serum cholesterol by 0.63 +/- 0.19 mmol/L (11%) in normal-weight and by 0.75 +/- 0.13 mmol/L (12%) in overweight/obese subjects (p < 0.05 for both), and cholesterol absorption was reduced in both groups. However, relative and dietary cholesterol absorption were more effectively reduced in normal-weight subjects. In conclusion, overweight/obesity did not interfere with the serum cholesterol response to plant stanol ester consumption despite substantial differences in cholesterol metabolism between the groups.
  • Wu, Chen; Twort, Victoria G; Newcomb, Richard D; Buckley, Thomas R (2021)
    Some animal groups, such as stick insects (Phasmatodea), have repeatedly evolved alternative reproductive strategies, including parthenogenesis. Genomic studies have found modification of the genes underlying meiosis exists in some of these animals. Here we examine the evolution of copy number, evolutionary rate, and gene expression in candidate meiotic genes of the New Zealand geographic parthenogenetic stick insect Clitarchus hookeri. We characterized 101 genes from a de novo transcriptome assembly from female and male gonads that have homology with meiotic genes from other arthropods. For each gene we determined copy number, the pattern of gene duplication relative to other arthropod orthologs, and the potential for meiosis-specific expression. There are five genes duplicated in C. hookeri, including one also duplicated in the stick insect Timema cristinae, that are not or are uncommonly duplicated in other arthropods. These included two sister chromatid cohesion associated genes (SA2 and SCC2), a recombination gene (HOP1), an RNA-silencing gene (AGO2) and a cell-cycle regulation gene (WEE1). Interestingly, WEE1 and SA2 are also duplicated in the cyclical parthenogenetic aphid Acyrthosiphon pisum and Daphnia duplex, respectively, indicating possible roles in the evolution of reproductive mode. Three of these genes (SA2, SCC2, and WEE1) have one copy displaying gonad-specific expression. All genes, with the exception of WEE1, have significantly different nonsynonymous/synonymous ratios between the gene duplicates, indicative of a shift in evolutionary constraints following duplication. These results suggest that stick insects may have evolved genes with novel functions in gamete production by gene duplication.
  • Di Minin, Enrico; Slotow, Rob; Fink, Christoph; Bauer, Hans; Paker, Craig (2021)
    African lions (Panthera leo) and African savanna (Loxodonta africana) and forest (L. cyclotis) elephants pose threats to people, crops, and livestock, and are themselves threatened with extinction. Here, we map these human-wildlife conflicts across Africa. Eighty-two percent of sites containing lions and elephants are adjacent to areas with considerable human pressure. Areas at severe risk of conflict (defined as high densities of humans, crops, and cattle) comprise 9% of the perimeter of these species' ranges and are found in 18 countries hosting, respectively, similar to 74% and 41% of African lion and elephant populations. Although a variety of alternative conflict-mitigation strategies could be deployed, we focus on assessing the potential of high-quality mitigation fences. Our spatial and economic assessments suggest that investments in the construction and maintenance of strategically located mitigation fences would be a cost-effective strategy to support local communities, protect people from dangerous wildlife, and prevent further declines in lion and elephant populations.
  • Resal, Tamas; Bor, Renata; Szanto, Kata; Fabian, Anna; Rutka, Mariann; Sacco, Marco; Ribaldone, Davide Guiseppe; Molander, Pauliina; Nancey, Stephane; Kopytov, Uri; Vavricka, Stephan; Drobne, David; Lukas, Milan; Farkas, Klaudia; Szepes, Zoltan; Molnar, Tamas (2021)
    Introduction: The coronavirus disease 2019 (COVID-19) pandemic poses a challenge to healthcare. Staff and patients are at increased risk during an examination or intervention, so certain restrictions ought to be introduced. Hence, we aimed to measure the effect of the pandemic on endoscopy units in real-life settings. Methods: This was an observational, cross-sectional, questionnaire-based study, carried out between 7 April and 15 June 2020. Responds came from many countries, and the participation was voluntary. The survey contained 40 questions, which evaluated the effect of the COVID-19 pandemic on the endoscopy units and assessed the infection control. Results: A total of 312 questionnaires were filled, 120 from Hungary, and 192 internationally, and 54 questionnaires (17.3%) were sent from high-risk countries; 84.9% of the gastroenterologists declared that they read the European Society of Gastrointestinal Endoscopy (ESGE) statement, while only 32.1% participated in any advanced training at their workplace. Overall, 92.1% of gastroenterologists realized risk stratification, and 72.1% claimed to have enough protective equipment. In 52.6% of the endoscopy units, at least one endoscopist had to discontinue the work due to any risk factor, while 40.6% reported that the reduced staff did not affect the workflow. Gastroenterologists considered that the five most important examinations both in low and high-risk patients are the following: lower/upper gastrointestinal (GI) bleeding with hemodynamic instability, endoscopic retrograde cholangiopancreatography (ERCP) in obstructive jaundice, foreign body in the esophagus, ERCP in acute biliary pancreatitis, and iron deficiency anemia with hemodynamic instability, which correlates well with the ESGE recommendation. Significant correlation was found in the usage of the necessary protective equipment in high-risk patients depending on the countries (p < 0.001). Conclusions: The survey found weak correlation in preliminary training depending on countries; nevertheless, in Hungary during the examined period, endoscopists considered the recommendations more strictly than in other countries. Although many physicians left the endoscopy lab, the workflow was not affected, probably due to the reduced number of examinations.
  • Sturgeon, Catharine; Butler, Stephen A.; Gould, Fiona; Johnson, Sarah; Rowlands, Sam; Stenman, Ulf-Håkan; Grenache, David G. (2021)
    Homepregnancy tests (HPTs) available in Europe include accuracy and other performance claims listed on their packaging. Due to the lack of guidance on the standardisation of such products, it is often difficult to replicate these claims when tested on a clinical sample, whether in a laboratory setting or by lay users. The In Vitro Diagnostic Regulation is a set of requirements that mandate comprehensive validation data on human pregnancy tests and other in vitro devices. It is due to replace the current European Directive (98/79/EC) and fully implemented in Europe by 2022. In June 2019, a panel of seven experts convened to discuss the validation studies required to provide the information needed to meet the new regulation for HPTs in Europe and proposed 15 recommendations for best practice. Defining best practice at all stages of validation of these important tests may ensure that tests marketed inEurope are fit for purpose, enabling lay users to be confident of the high quality of the HPT results they obtain. The panelists believe that the recommendations proposed here for the validation of HPTs may constructively contribute to improved standardisation of validation procedures in Europe.
  • Li, Weilong; Baumbach, Jan; Mohammadnejad, Afsaneh; Lund, Jesper; Larsen, Martin Jakob; Hjelmborg, Jacob v. B.; Mengel-From, Jonas; Christensen, Kaare; Christiansen, Lene; Tan, Qihua (2020)
    Objective: The body mass index (BMI) measured as weight in relation to height is an important monitor for obesity and diabetes, with individual variation under control by genetic and environmental factors. In transcriptome-wide association studies on BMI, the genetic contribution calls for controlling of genetic confounding that affects both BMI and gene expression. We performed a global gene expression profiling of BMI on peripheral blood cells using monozygotic twins for efficient handling of genetic make-ups. Methods: We applied a generalized association method to genome-wide gene expression data on 229 pairs of monozygotic twins (age 56-80 years) for detecting diverse patterns of correlation between BMI and gene expression. Results: We detected seven probes associated with BMI with p<1e-04, among them two probes with p<1e-05 (p=2.83e-06 AAK1; p=7.83e-06 LILRA3). In total, the analysis found 1579 probes with nominal p<0.05. Biological pathway analysis of enriched pathways found 50 KEGG and 45 Reactome pathways (FDR<0.05). The identified top functional pathways included immune function, JAK-STAT signalling, insulin signalling and regulation of energy metabolism. Conclusion: This transcriptome-wide association study using monozygotic twins and generalized correlation identified differentially expressed genes and a broad spectrum of enriched biological pathways that may implicate metabolic health.
  • Fuentes, Blanca; Ntaios, George; Putaala, Jukka (2021)
  • Lu, FeiFei; Wang, Zhaohua; Toppinen, Anne; D'amato, Dalia; Wen, Zuomin (2021)
  • FinnGen Consortium; Bowden, Sarah J.; Bodinier, Barbara; Kalliala, Ilkka; Kyrgiou, Maria (2021)
    Background Most uterine cervical high-risk human papillomavirus (HPV) infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies (GWASs) report associations between the HLA region and cervical cancer. Adopting a genome-wide approach, we aimed to compare genetic variation in women with invasive cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 with that in healthy controls. Methods We did a GWAS in a cohort of unrelated European individuals using data from UK Biobank, a population-based cohort including 273 377 women aged 40-69 years at recruitment between March 13, 2006, and Oct 1, 2010. We used an additive univariate logistic regression model to analyse genetic variants associated with invasive cervical cancer or CIN3. We sought replication of candidate associations in FinnGen, a large independent dataset of 128 123 individuals. We also did a two-sample mendelian randomisation approach to explore the role of risk factors in the genetic risk of cervical cancer. Findings We included 4769 CIN3 and invasive cervical cancer case samples and 145 545 control samples in the GWAS. Of 9 600 464 assayed and imputed single-nucleotide polymorphisms (SNPs), six independent variants were associated with CIN3 and invasive cervical cancer. These included novel loci rs10175462 (PAX8; odds ratio [OR] 0.87, 95% CI 0.84-0.91; p=1.07 x 10(-9)) and rs27069 (CLPTM1L; 0.88, 0.84-0.92; p=2.51 x 10(-9)), and previously reported signals at rs9272050 (HLA-DQA1; 1.27, 1.21-1.32; p=2.51 x 10(-28)), rs6938453 (MICA; 0.79, 0.75-0 .83; p=1.97 x 10-(17)), rs55986091 (HLA-DQB1; 0.66, 0 .60-0.72; p=6.42 x 10-(22)), and rs9266183 (HLA-B; 0.73, 0.64-0.83; p=1.53 x 10(-6)). Three SNPs were replicated in the independent Finnish dataset of 1648 invasive cervical cancer cases: PAX8 (rs10175462; p=0.015), CLPTM1L (rs27069; p=2.54 x 10(-7)), and HLA-DQA1 (rs9272050; p=7.90 x 10(-8)). Mendelian randomisation further supported the complementary role of smoking (OR 2.46, 95% CI 1.64-3.69), older age at first pregnancy (0.80, 0.68-0.95), and number of sexual partners (1.95, 1.44-2.63) in the risk of developing cervical cancer. Interpretation Our results provide new evidence for the genetic susceptibility to cervical cancer, specifically the PAX8, CLPTM1L, and HLA genes, suggesting disruption in apoptotic and immune function pathways. Future studies integrating host and viral, genetic, and epigenetic variation, could further elucidate complex host-viral interactions. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
  • Kraav, Siiri-Liisi; Lehto, Soili M.; Kauhanen, Jussi; Hantunen, Sari; Tolmunen, Tommi (2021)
    Globally, cancer is the second leading cause of death. Loneliness has been suggested as a risk factor for cancer mortality. However, connections between loneliness, social isolation, and cancer are poorly understood. In our longitudinal study (mean follow-up: 20.44 years) of 2570 middle-aged men, loneliness, social isolation, and health-related factors were measured at baseline. Cox proportional hazards analysis was used to examine the association between cancer incidence, loneliness, and social isolation. The effect of relationship status on cancer mortality among cancer patients was tested with the Kaplan-Meier method. Loneliness was associated with total cancer incidence after adjustments for tested lifestyle and health-related covariates. Social Isolation was associated with total cancer incidence, except when adjusted for lifestyle, diet, or Human Population Laboratory (HPL) Depression Scale scores. Loneliness was associated with lung cancer incidence, except when adjusted for HPL Depression Scale scores. There was no significant association between social isolation and lung cancer. Neither loneliness nor social isolation were connected with prostate or colorectal cancer. Being single at baseline was associated with worse survival outcomes for cancer patients. Our findings suggest that regardless of the social network size, loneliness among middle-aged men is associated with an increased likelihood of cancer.
  • Laurila, Terhi K.; Sinclair, Victoria A.; Gregow, Hilppa (2021)
    This study presents the monthly 10‐m wind speed climatology, decadal variability and possible trends in the North Atlantic and Europe from ERA5 reanalysis from 1979 to 2018 and investigates the physical reasons for the decadal variability. Additionally, temporal time series are examined in three locations: the central North Atlantic, Finland and Iberian Peninsula. The 40‐year mean and the 98th percentile wind speeds emphasize a distinct land‐sea contrast and a seasonal variation with the strongest winds over the ocean and during winter. The strongest winds and the highest variability are associated with the storm tracks and local wind phenomena such as the mistral. The extremeness of the winds is examined with an extreme wind factor (the 98th percentile divided by mean wind speeds) which in all months is higher in southern Europe than in northern Europe. Mostly no linear trends in 10‐m wind speeds are identified in the three locations but large annual and decadal variability is evident. The decadal 10‐m wind speeds were stronger than average in the 1990s in northern Europe and in the 1980s and 2010s in southern Europe. These decadal changes were largely explained by the positioning of the jet stream and storm tracks and the strength of the north–south pressure gradient in the North Atlantic. The 10‐m winds have a positive correlation with the North Atlantic Oscillation in the central North Atlantic and Finland on annual scales and during cold season months and a negative correlation in Iberian Peninsula mostly from July to March. The Atlantic Multi‐decadal Oscillation has a moderate negative correlation with the winds in the central North Atlantic but no correlation in Finland and Iberian Peninsula. Overall, our results emphasize that while linear trends in wind speeds may show a general long‐term trend, more information on the changes is obtained by analysing long‐term variability.
  • Jamialahmadi, Oveis; Mancina, Rosellina Margherita; Ciociola, Ester; Tavaglione, Federica; Luukkonen, Panu K.; Baselli, Guido; Malvestiti, Francesco; Thuillier, Dorothee; Raverdy, Violeta; Mannisto, Ville; Pipitone, Rosaria Maria; Pennisi, Grazia; Prati, Daniele; Spagnuolo, Rocco; Petta, Salvatore; Pihlajamaki, Jussi; Pattou, Francois; Yki-Järvinen, Hannele; Valenti, Luca; Romeo, Stefano (2021)
    BACKGROUND & AIMS: Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered. METHODS: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine amino transferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8930 participants in whom liver fat measurement was available, and replicated 2 genetic variants in 3 independent cohorts comprising 2621 individuals with available liver biopsy. RESULTS: We identified 190 genetic variants independently associated with alanine aminotransferase after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver. CONCLUSIONS: We identified 2 novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression.
  • Lilja, Markus Jukka; Koskinen, Anni; Virkkula, Paula; Vento, Seija Inkeri; Myller, Jyri; Hammaren-Malmi, Sari; Laulajainen-Hongisto, Anu; Hytönen, Maija; Mäkitie, Antti; Numminen, Jura; Sillanpää, Saara; Raitiola, Hannu; Rautiainen, Markus; Toppila-Salmi, Sanna Katriina (2021)
    Objectives: The aim was to compare the control of chronic rhinosinusitis with nasal polyps (CRSwNP) after endoscopic sinus surgery (ESS), in patients with/without nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NERD). Study Desing: A retrospective hospital-based sample of CRSwNP patients with/without NERD with follow-up. Setting: Tertiary rhinology centers. Methods: Electronic patient record data from 116 CRSwNP patients (46 with NERD and 70 without NERD) undergoing ESS during 2001-17 were studied. Mean follow-up time was 9.9 years (range 1.1-15.3). Endpoints reflecting uncontrolled CRSwNP were revision ESS, and need for rescue/advanced therapy (e.g. antibiotics, oral corticosteroids and/or biological therapy) during follow-up. NERD was variable of interest and gender, age, asthma, allergic rhinitis (AR), smoking, Lund-Mackay (LM) score of sinus computed tomography scans previous ESS and baseline total ethmoidectomy were used as covariates. Results: Twenty-one (49.7%) NERD patients and 18 (25.7%) non-NERD patients underwent revision ESS within a mean +/- SD of 4.3 +/- 2.8 and 3.7 +/- 2.6 years, respectively (p = .013, by Logrank test). In Cox ' s regression models, NERD, female gender, young age, asthma, AR, previous ESS, and lack of total ethmoidectomy were associated with revision-ESS. In adjusted model, only the total ethmoidectomy predicted revision-free survival. In adjusted logistic regression model, there was an insignificant trend that NERD and LM score were associated with the need for rescue/advanced therapy in the follow-up. Conclusions: Patients with NERD had higher risk of uncontrolled CRSwNP than patient group without NERD, as measured by revision ESS and/or need for rescue/advanced therapy in the follow-up. In addition, baseline total ethmoidectomy was associated with revision-free survival.
  • Ramos-Diaz, Jose Martin; Sulyok, Michael; Jacobsen, Sven-Erik; Jouppila, Kirsi; Nathanail, Alexis V (2021)
    The consumption of high-quality Andean grains (a.k.a. pseudocereals) is increasing worldwide, and yet very little is known about the susceptibility of these crops to mycotoxin contamination. In this survey study, a multi-analyte liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was utilised to determine mycotoxin and fungal metabolite levels in Andean grains (quinoa and kañiwa) in comparison to cereal grains (barley, oats and wheat), cultivated in both South American (Bolivia and Peru) and North European (Denmark, Finland and Latvia) countries. A total of 101 analytes were detected at varying levels, primarily produced by Penicillium spp., Fusarium spp. and Aspergillus spp., depending on the type of crop, geographical location and agricultural practices used. Generally, Andean grains from South America showed lower mycotoxin contamination (concentration and assortment) than those from North Europe, while the opposite occurred with cereal grains. Mycotoxin contamination profiles exhibited marked differences between Andean and cereal grains, even when harvested from the same regions, highlighting the need for crop-specific approaches for mycotoxin risk mitigation. Lastly, the efficacy of grain cleaning in respect to total mycotoxin content was assessed, which resulted in significantly lower levels (overall reduction approx. 50%) in cleaned samples for the majority of contaminants.
  • Kim, Jisoo; Aaltonen, Mari; Pulkki, Jutta; Forma, Leena (Korea Institute for Health and Social Affairs, Sejong-si, South Korea, 2021)
  • Korhonen, Laura S.; Lukkarinen, Minna; Kantojärvi, Katri; Räty, Panu; Karlsson, Hasse; Paunio, Tiina; Peltola, Ville; Karlsson, Linnea (2021)
    Genetic variants may predispose children to recurrent respiratory infections (RRIs) but studies on genotype-environment interaction are rare. We hypothesized that the risk for RRIs is elevated in children with innate immune gene variants, and that prenatal exposure to maternal psychological distress further increases the risk. In a birth cohort, children with RRIs (n=96) were identified by the age of 24 months and compared with the remaining cohort children (n=894). The risk for RRIs in children with preselected genetic variants and the interaction between maternal distress during pregnancy and child genotype were assessed with logistic regression. The IL6 minor allele G was associated with elevated risk for RRIs (OR 1.55; 95% CI 1.14-2.12). Overall, there was no interaction between maternal psychological distress and child genotype. Exploratory analyses showed that, the association between the variant type of IL6 and the risk for RRIs was dependent on prenatal exposure to maternal psychological distress in males (OR 1.96; 95% CI 1.04-3.67). Our study didn't find genotype-environment interaction between prenatal maternal distress and child genotype. Exploratory analyses suggest sex differences in gene-environment interaction related to susceptibility to RRIs.
  • Mganga, Kevin Z; Kaindi, Eric; Ndathi, Aphaxard J. N.; Bosma, Luwieke; Kioko, Theophilus; Kadenyi, Nancy; Wambua, Stephen M.; van Steenbergen, Frank; Musimba, Nashon K. R. (2021)
  • Nioche, Aurélien; Murena, Pierre-Alexandre; de la Torre Ortiz, Carlos; Oulasvirta, Antti (ACM, 2021)
  • Möller, Vidar; Östholm-Balkhed, Åse; Berild, Dag; Fredriksson, Mats; Gottfredsson, Magnus; Holmbom, Martin; Järvinen, Asko; Kristjansson, Mar; Rydell, Ulf; Sonksen, Ute Wolff; Kolmos, Hans Joern; Hanberger, Håkan (2021)
    Background The Nordic countries have comparable nationwide antibiotic resistance surveillance systems and individual antibiotic stewardship programmes. The aim of this study was to assess antibiotic resistance among major pathogens in relation to practice guidelines for hospital antibiotic treatment and antibiotic use in Nordic countries 2010-2018. Methods Antibiotic resistance among invasive isolates from 2010-2018 and aggregated antibiotic use were obtained from the European Centre for Disease Prevention and Control. Hospital practice guidelines were obtained from national or regional guidelines. Results Antibiotic resistance levels among Escherichia coli and Klebsiella pneumoniae were similar in all Nordic countries in 2018 and low compared to the European mean. Guidelines for acute pyelonephritis varied; 2nd generation cephalosporin (Finland), 3rd generation cephalosporins (Sweden, Norway), ampicillin with an aminoglycoside or aminoglycoside monotherapy (Denmark, Iceland and Norway). Corresponding guidelines for sepsis of unknown origin were 2nd (Finland) or 3rd (Sweden, Norway, Iceland) generation cephalosporins, carbapenems, (Sweden) combinations of penicillin with an aminoglycoside (Norway, Denmark), or piperacillin-tazobactam (all Nordic countries). Methicillin-resistant Staphylococcus aureus rates were 0-2% and empirical treatment with anti-MRSA antibiotics was not recommended in any country. Rates of penicillin non-susceptibility among Streptococcus pneumoniae were low (

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