Recent Submissions

  • 'You should always look at the washing machine without actually being in it!' Thematic framework analysis of patients' understanding of transdiagnostic cognitive behaviour therapy and its mechanisms.

    Sighvatsson, Magnus Blondahl; Salkovskis, Paul M; Sigurdsson, Engilbert; Valdimarsdottir, Heiddis B; Thorsdottir, Fanney; Sigurdsson, Jon Fridrik; 1University of Iceland, Reykjavík, Iceland. 2Reykjavik University, Iceland. 3University of Oxford, UK. 4Landspitali-The National University Hospital of Iceland, Reykjavík, Iceland. 5Mount Sinai School of Medicine, New York City, New York, USA. (Wiley, 2019-02-07)
    Objective: Transdiagnostic cognitive behaviour therapy (TCBT) is an efficacious treatment for anxiety and depression, but its mechanisms of change remain poorly understood. The current study used thematic framework analysis to analyse how patients, recruited in a recent trial on transdiagnostic group CBT (TGCBT), understood the treatment and its mechanisms. Design: Cross-sectional thematic framework analysis. Method: The sample included 24 participants suffering from anxiety and/or depression, divided into two groups by treatment efficacy (i.e., group doing well and group doing not so well) in order to evaluate whether different understandings of the treatment affected its efficacy. The participants were interviewed and completed self-report measures. They were encouraged to discuss what they believed to be helpful and unhelpful in the TGCBT and what they believed to be the mechanisms of change in the treatment. Each interview was recorded, transcribed verbatim and themes were identified. Results: The analysis revealed four overarching themes and 18 subthemes. The overarching themes were as follows: Cognitive and behavioural flexibility, Awareness/understanding of symptoms and triggers, Therapeutic alliance and engagement, and finally Attitudes towards treatment. Four of the 18 subthemes corresponded to a differentiation between the groups: Cognitive flexibility and Comparison with others in the group on the one hand and Cognitive inflexibility and Negative attitudes towards treatment on the other. Conclusion: The most important difference between the groups appeared to be CBT-specific, that is, cognitive flexibility that characterized the group doing well where thematic analysis did not indicate that other themes were important. Practitioner points: Findings The analysis revealed four overarching themes and 18 subthemes, four of which corresponded to the difference between the two groups of participants based on treatment efficacy. The four differentiating subthemes were cognitive flexibility and comparison with others, which characterized the group doing well, and cognitive inflexibility and negative attitude towards treatment, which characterized the group doing less well. The theme evaluated as the most important for the efficacy of the transdiagnostic cognitive behaviour therapy and patients' understanding of the treatment was cognitive flexibility, which characterized the group doing well. Limitations Use of qualitative methodology restricts the generalizability of our results. Data are built on answers from only 24 participants.
  • Changes in the left temporal microstate are a sign of cognitive decline in patients with Alzheimer's disease.

    Musaeus, Christian S; Engedal, Knut; Høgh, Peter; Jelic, Vesna; Khanna, Arjun R; Kjaer, Troels Wesenberg; Mørup, Morten; Naik, Mala; Oeksengaard, Anne-Rita; Santarnecchi, Emiliano; et al. (Wiley, 2020-04-27)
    Introduction: Large-scale brain networks are disrupted in the early stages of Alzheimer's disease (AD). Electroencephalography microstate analysis, a promising method for studying brain networks, parses EEG signals into topographies representing discrete, sequential network activations. Prior studies indicate that patients with AD show a pattern of global microstate disorganization. We investigated whether any specific microstate changes could be found in patients with AD and mild cognitive impairment (MCI) compared to healthy controls (HC). Materials and methods: Standard EEGs were obtained from 135 HC, 117 patients with MCI, and 117 patients with AD from six Nordic memory clinics. We parsed the data into four archetypal microstates. Results: There was significantly increased duration, occurrence, and coverage of microstate A in patients with AD and MCI compared to HC. When looking at microstates in specific frequency bands, we found that microstate A was affected in delta (1-4 Hz), theta (4-8 Hz), and beta (13-30 Hz), while microstate D was affected only in the delta and theta bands. Microstate features were able to separate HC from AD with an accuracy of 69.8% and HC from MCI with an accuracy of 58.7%. Conclusions: Further studies are needed to evaluate whether microstates represent a valuable disease classifier. Overall, patients with AD and MCI, as compared to HC, show specific microstate alterations, which are limited to specific frequency bands. These alterations suggest disruption of large-scale cortical networks in AD and MCI, which may be limited to specific frequency bands.
  • Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.

    Oskarsson, Gudjon R; Oddsson, Asmundur; Magnusson, Magnus K; Kristjansson, Ragnar P; Halldorsson, Gisli H; Ferkingstad, Egil; Zink, Florian; Helgadottir, Anna; Ivarsdottir, Erna V; Arnadottir, Gudny A; et al. (Nature Publishing Group, 2020-04-23)
    Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (EffectCys506Ser = -1.61 SD, CI95 = [-1.98, -1.35]; EffectLys334Ter = 0.63 SD, CI95 = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10-14). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.
  • Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy.

    Klinkhammer, Barbara Mara; Djudjaj, Sonja; Kunter, Uta; Palsson, Runolfur; Edvardsson, Vidar Orn; Wiech, Thorsten; Thorsteinsdottir, Margret; Hardarson, Sverrir; Foresto-Neto, Orestes; Mulay, Shrikant R; et al. (American Society of Nephrology, 2020-02-21)
    Background: Hereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown. Methods: Using animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies. Results: Adenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy. Conclusions: Rodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.
  • Severe desaturations increase psychomotor vigilance task-based median reaction time and number of lapses in obstructive sleep apnoea patients.

    Kainulainen, Samu; Duce, Brett; Korkalainen, Henri; Oksenberg, Arie; Leino, Akseli; Arnardottir, Erna S; Kulkas, Antti; Myllymaa, Sami; Töyräs, Juha; Leppänen, Timo; et al. (European Respiratory Society, 2020-04-09)
    Current diagnostic parameters estimating obstructive sleep apnoea (OSA) severity have a poor connection to the psychomotor vigilance of OSA patients. Thus, we aimed to investigate how the severity of apnoeas, hypopnoeas and intermittent hypoxaemia is associated with impaired vigilance.We retrospectively examined type I polysomnography data and corresponding psychomotor vigilance tasks (PVTs) of 743 consecutive OSA patients (apnoea-hypopnoea index (AHI) ≥5 events·h-1). Conventional diagnostic parameters (e.g. AHI and oxygen desaturation index (ODI)) and novel parameters (e.g. desaturation severity and obstruction severity) incorporating duration of apnoeas and hypopnoeas as well as depth and duration of desaturations were assessed. Patients were grouped into quartiles based on PVT outcome variables. The odds of belonging to the worst-performing quartile were assessed. Analyses were performed for all PVT outcome variables using binomial logistic regression.A relative 10% increase in median depth of desaturations elevated the odds (ORrange 1.20-1.37, p<0.05) of prolonged mean and median reaction times as well as increased lapse count. Similarly, an increase in desaturation severity (ORrange 1.26-1.52, p<0.05) associated with prolonged median reaction time. Female sex (ORrange 2.21-6.02, p<0.01), Epworth Sleepiness Scale score (ORrange 1.05-1.07, p<0.01) and older age (ORrange 1.01-1.05, p<0.05) were significant risk factors in all analyses. In contrast, increases in conventional AHI, ODI and arousal index were not associated with deteriorated PVT performance.These results show that our novel parameters describing the severity of intermittent hypoxaemia are significantly associated with increased risk of impaired PVT performance, whereas conventional OSA severity and sleep fragmentation metrics are not. These results underline the importance of developing the assessment of OSA severity beyond the AHI.
  • Effect of two different nutritional supplements on postprandial glucose response and energy- and protein intake in hospitalised patients with COPD: A randomised cross-over study.

    Ingadottir, Arora Ros; Bjorgvinsdottir, Eva Bjorg; Beck, Anne Marie; Baldwin, Christine; Weekes, C Elizabeth; Geirsdottir, Olof Gudny; Ramel, Alfons; Birgisdottir, Bryndis Eva; Gislason, Thorarinn; Gunnarsdottir, Ingibjorg; et al. (Elsevier, 2019-04-25)
    Introduction: Oral nutrition support is frequently used in treatment of malnutrition in patients with chronic obstructive pulmonary disease (COPD). Considering the use of corticoidsteroids in patients with COPD, little is known about the effect on postprandial glucose response and if they might interfere with glucose control. Our aims were to compare the effect of a liquid oral nutritional supplement (ONS) and semi solid inbetween meal snack (snack) on postprandial glucose and energy- and protein intake, and to compare the effect of timing of each intervention on postprandial glucose and energy- and protein intake. Methods: Patients with COPD (n = 17) admitted to the Department of Pulmonary Medicine, Iceland and defined as at low or medium nutritional risk (score 0-3) were recruited. In a randomised cross-over design, subjects consumed ONS or snack either in a fasting state (study 1) or following breakfast (study 2) and postprandial glucose responses were assessed at regular intervals for two hours (t = 15, t = 30, t = 45, t = 60, t = 90, t = 120 min). Energy- and protein intake was estimated using a validated plate diagram sheet. Wilcoxon Signed-Rank test was used to compare the two interventions. Results: In study 2, following breakfast, postprandial glucose was significantly higher after consuming ONS than the snack after 60 min (9.7 ± 2.4 mmol/L vs. 8.2 ± 3.2 mmol/L, p = 0.013 and 120 min 9.2 ± 3.2 mmol/L vs. 7.9 ± 2.4 mmol/L, p = 0.021, respectively). No difference was found in postprandial glucose concentrations between ONS and the snack when consumed after overnight fasting (study 1). No difference in energy or protein intake from hospital food was seen between supplement types neither in study 1 or 2. Conclusion: Lower postprandial glucose concentrations were associated with the snack compared to ONS when taken after a meal compared to either type directly after overnight fasting. The clinical relevance of higher postprandial blood glucose after consuming a liquid ONS after breakfast compared with a semi solid snack needs to be studied further.
  • Profiling inflammatory response in lesions of cutaneous leishmaniasis patients using a non-invasive sampling method combined with a high-throughput protein detection assay

    Taslimi, Yasaman; Agbajogu, Christopher; Brynjolfsson, Siggeir Fannar; Masoudzadeh, Nasrin; Mashayekhi, Vahid; Gharibzadeh, Safoora; Östensson, Malin; Nakka, Sravya Sowdamini; Mizbani, Amir; Rafati, Sima; et al. (Elsevier Science, 2020-06-01)
    Background: Cutaneous leishmaniasis (CL) is an infection caused by Leishmania (L.) protozoa transmitted through the bite of infected sand fly. Previously, invasive sampling of blood and skin along with low throughput methods were used for determination of inflammatory response in CL patients. Aims/methodology: We established a novel approach based on a non-invasive adhesive tape-disc sampling combined with a powerful multiplexing technique called proximity extension assay for profiling 92 inflammatory cytokines, chemokines and surface molecules in the lesions of CL patients infected with L. tropica. Sample collection was done non-invasively by using adhesive tape-discs from lesion and normal skin of 33 L. tropica positive patients. Results: Out of 92 inflammatory proteins, the level of 34 proteins was significantly increased in the lesions of CL patients compared to their normal skin. This includes the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL5, CXCL9, CXCL10 and CXCL11, together with the interleukins IL-6, IL-8, IL-18, LIF and OSM. The remaining significantly changed inflammatory proteins include 7 surface molecules and receptors: CD5, CD40, CDCP1, 4E-BP1, TNFRSF9, IL-18R1 and OPG as well as 16 other cytokines and proteins: MMP-1, CSF-1, VEGFA, uPA, EN-RAGE, LAP TGF-β1, HGF, MMP-10, CASP-8, TNFSF14, STAMPB, ADA, TRAIL and ST1A1. Further, 13 proteins showed an increasing trend, albeit not statistically significant, in the CL lesions, including TGF-α, CCL23, MCP-2, IL-12B, CXCL6, IL-24, FGF-19, TNFβ, CD6, TRANCE, IL10, SIR2 and CCL20. Conclusion: We herein report a novel approach based on a non-invasive sampling method combined with the high-throughput protein assay for profiling inflammatory proteins in CL lesions. Using this approach, we could profile inflammatory proteins in the lesions from CL patients. This new non-invasive approach may have implications for studying skin inflammatory mediators in CL and other skin disorders.
  • Femoral nerve blocks for the treatment of acute pre-hospital pain: A systematic review with meta-analysis.

    Raatiniemi, Lasse; Magnusson, Vidar; Hyldmo, Per K; Friesgaard, Kristian D; Kongstad, Poul; Kurola, Jouni; Larsen, Robert; Rehn, Marius; Rognås, Leif; Sandberg, Mårten; et al. (Wiley, 2020-04-09)
    Background: Pain management is one of the most important interventions in the emergency medical services. The femoral nerve block (FNB) is, among other things, indicated for pre- and post-operative pain management for patients with femoral fractures but its role in the pre-hospital setting has not been determined. The aim of this review was to assess the effect and safety of the FNB in comparison to other forms of analgesia (or no treatment) for managing acute lower extremity pain in adult patients in the pre-hospital setting. Methods: A systematic review (PROSPERO registration (CRD42018114399)) was conducted. The Cochrane and GRADE methods were used to assess outcomes. Two authors independently reviewed each study for eligibility, extracted the data and performed risk of bias assessments. Results: Four studies with a total of 252 patients were included. Two RCTs (114 patients) showed that FNB may reduce pain more effectively than metamizole (mean difference 32 mm on a 100 mm VAS (95% CI 24 to 40)). One RCT (48 patients) compared the FNB with lidocaine and magnesium sulphate to FNB with lidocaine alone and was only included here for information regarding adverse effects. One case series included 90 patients. Few adverse events were reported in the included studies. The certainty of evidence was very low. We found no studies comparing FNB to inhaled analgesics, opioids or ketamine. Conclusions: Evidence regarding the effectiveness and adverse effects of pre-hospital FNB is limited. Studies comparing pre-hospital FNB to inhaled analgesics, opioids or ketamine are lacking.
  • Women and intimate partner violence: Prevalence of hospital visits and nature of injuries in the Icelandic population.

    Jónasdóttir, Drífa; Thorsteinsdottir, Thordis; Ásgeirsdóttir, Tinna Laufey; Lund, Sigrún H; Arnarsson, Eiríkur Örn; Ashikali, Eleni; Líndal, Þórhildur; Mogensen, Brynjólfur; 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Research Institute in Emergency Medicine, Reykjavik, Iceland. 3Faculty of Nursing, University of Iceland, Reykjavik, Iceland. 4Faculty of Economics, University of Iceland, Reykjavik, Iceland. 5The Centre of Public Health Sciences, University of Iceland, Reykjavik, Iceland. 6Department of Psychiatry, Landspitali National University Hospital, Reykjavik, Iceland. 7Formerly at School of Psychology, University of Sussex, Brighton, UK. 8The Ombudsman for Children in Iceland, Reykjavik, Iceland. 9Emergency Department, Landspitali National University Hospital, Reykjavik, Iceland. (SAGE Publications, 2020-04-20)
    Aims: The purpose of this study was to analyse the prevalence of hospital visits and nature of injuries caused by intimate partner violence (IPV) against women and associated costs. Methods: All visits to Landspitali National University Hospital by women 18 years or older subjected to IPV, inflicted by a current or former male partner during 2005-2014, were observed and analysed. Information was obtained on number, date and time of visits and admissions, place of occurrence, patients' and perpetrators' age and relationship, number of perpetrators, medical diagnosis, aetiology, injury severity and cost. Results: The number of new hospital visits due to IPV was 1454, of which 92.6% were to the Emergency Department. The average age of the women was 34 years and 3.2% were admitted. According to the Injury Severity Score, physical injuries were mostly minor (92.4%) and mainly located on the upper body (64.3%) - namely, face, head and neck (37.1%) and upper limbs (27.2%). The majority of injuries were superficial (76.2%) and punching (29.7%), shoving (17.8%), kicking (10.5%) and attempted strangulation (9.8%) were the most common types of aetiology. Repeated new visits were 37.8%. The total cost for the hospital relating to IPV was €783,330. Conclusions: The total number of new visits resulting from IPV was 1454, and prevalence was 1.69 per 1000 women in the capital area over the research period. The majority of women were shown to have minor physical injuries of a superficial nature, located on the upper body. Although a low percentage of women were admitted, the associated cost for visits and admissions was substantial.
  • Increase in the incidence of alcoholic pancreatitis and alcoholic liver disease in Iceland: impact of alcohol consumption.

    Hauksson, Kristjan; Arnardottir, Margret; Agustsson, Arnar S; Magnusdottir, Berglind A; Baldursdottir, Maria B; Lund, Sigrun H; Kalaitzakis, Evangelos; Björnsson, Einar S; 1Department of Gastroenterology, Landspitali University Hospital, Reykjavik, Iceland. 2Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 3Decode Genetics, Reykjavik, Iceland, Copenhagen, Denmark. 4Digestive Disease Center, Copenhagen University Hospital/Herlev, University of Copenhagen, Copenhagen, Denmark. (Taylor & Francis, 2020-04-14)
    Objective: To analyze the incidence of acute alcoholic pancreatitis and of severe alcoholic liver disease (ALD) and its association with per capita alcohol consumption with identification of both alcoholic cirrhosis (AC) and severe alcoholic hepatitis (AH), in a population-based setting.Methods: A search was undertaken in diagnoses database for diagnostic codes in order to find patients hospitalized with incident acute alcoholic pancreatitis (AP) and alcoholic liver disease in Iceland in 2001-2015. Diagnoses were verified in all patients who were retrospectively reviewed. Those with ALD had either AC or AH. Alcohol sales during the study period were obtained from Statistics Iceland.Results: Overall, 273 patients with acute AP, mean age at diagnosis 50 (14) years, 74% males and 159 patients with ALD, mean age 57 (11) years, 73% males, were identified. Mean per capita alcohol consumption was 6.95 (0.4) liters and increased by 21% over the study period. The annual incidence of AP increased from 4.2 per 100.000 to 9.5 and ALD from 1.6 to 6.1 per 100.000. Trend analysis showed a significant annual increase of 7% (RR 1.07, 95%CI 1.04-1.10) for AP and an annual increase of 10.5% (RR 1.10, 95%CI 1.06-1.15) for ALD. The increase was only significant in males.Conclusions: Increase per capita alcohol consumption over a 15 year study period was associated with an increase in the incidence of severe alcoholic liver disease and alcohol-related acute pancreatitis in males but not in females.
  • Risk of hernia formation after radical prostatectomy: a comparison between open and robot-assisted laparoscopic radical prostatectomy within the prospectively controlled LAPPRO trial.

    Nilsson, H; Stranne, J; Hugosson, J; Wessman, C; Steineck, G; Bjartell, A; Carlsson, S; Thorsteinsdottir, T; Tyritzis, S I; Lantz, A; et al. (Springer, 2020-04-11)
    Purpose: In addition to incisional hernia, inguinal hernia is a recognized complication to radical retropubic prostatectomy. To compare the risk of developing inguinal and incisional hernias after open radical prostatectomy compared to robot-assisted laparoscopic prostatectomy. Method: Patients planned for prostatectomy were enrolled in the prospective, controlled LAPPRO trial between September 2008 and November 2011 at 14 hospitals in Sweden. Information regarding patient characteristics, operative techniques and occurrence of postoperative inguinal and incisional hernia were retrieved using six clinical record forms and four validated questionnaires. Results: 3447 patients operated with radical prostatectomy were analyzed. Within 24 months, 262 patients developed an inguinal hernia, 189 (7.3%) after robot-assisted laparoscopic prostatectomy and 73 (8.4%) after open radical prostatectomy. The relative risk of having an inguinal hernia after robot-assisted laparoscopic prostatectomy was 18% lower compared to open radical retropubic prostatectomy, a non-significant difference. Risk factors for developing an inguinal hernia after prostatectomy were increased age, low BMI and previous hernia repair. The incidence of incisional hernia was low regardless of surgical technique. Limitations are the non-randomised setting. Conclusions: We found no difference in incidence of inguinal hernia after open retropubic and robot-assisted laparoscopic radical prostatectomy. The low incidence of incisional hernia after both procedures did not allow for statistical analysis. Risk factors for developing an inguinal hernia after prostatectomy were increased age and BMI.
  • Use of serotonin reuptake inhibitors is not associated with increased bleeding after CABG.

    Heimisdottir, Alexandra A; Enger, Eric; Morelli, Simon; Johannesdottir, Hera; Helgadottir, Solveig; Sigurðsson, Engilbert; Gudbjartsson, Tomas; 1Department of Cardiothoracic Surgery, Landspitali University Hospital, Reykjavik, Iceland. 2Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 3Department of Medicine and Health, Linköping University, Linköping, Sweden. 4Anesthesiology and Intensive Care, Akademiska University Hospital, Uppsala, Sweden. 5Department of Psychiatry, Landspitali University Hospital, Reykjavik, Iceland. 6Department of Cardiothoracic Surgery, Landspitali University Hospital, Reykjavik, Iceland. 7Faculty of Medicine, University of Iceland, Reykjavik, Iceland. (Springer, 2020-04-11)
    Objectives: Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs) are the most commonly prescribed antidepressants worldwide. Studies suggest that SSRI/SNRIs can increase bleeding following different surgical procedures, including open heart surgery, but results are conflicting. The objective of this study was to analyse their effects on bleeding after coronary artery bypass grafting (CABG). Methods: Of 1237 patients that underwent CABG in Iceland in 2007-2016, 97 (7.8%) used SSRIs/SNRIs preoperatively and were compared to a reference group (n = 1140). Bleeding was assessed using 24-h chest-tube output, number of RBC units transfused and reoperation for bleeding. Thirty-day mortality rates and incidence of complications were also compared. Results: The two groups were comparable with respect to preoperative and operative variables, with the exception of BMI being significantly higher in the SSRI/SNRI group (30.2 vs. 28.3 kg/m2, p < 0.001). No significant differences were observed between groups in 24-h chest-tube output [815 (SSRI/SNRI) vs. 877 ml (reference), p = 0.26], number of RBC units transfused (2.2 vs. 2.2, p = 0.99) or the rate of reoperation for bleeding (4.1% vs. 6.0%, p = 0.61). The incidences of complications and 30-day mortality rate were also similar. Conclusions: Using three different criteria, preoperative use of SSRIs/SNRIs was not shown to increase bleeding after CABG. Furthermore, short-term complications as well as 30-day mortality rates did not differ from those of controls. Thus, temporary cessation of SSRI/SNRI treatment prior to CABG to decrease the risk of bleeding is unwarranted.
  • Visualizing metabolic network dynamics through time-series metabolomic data.

    Buchweitz, Lea F; Yurkovich, James T; Blessing, Christoph; Kohler, Veronika; Schwarzkopf, Fabian; King, Zachary A; Yang, Laurence; Jóhannsson, Freyr; Sigurjónsson, Ólafur E; Rolfsson, Óttar; et al. (BioMed Central, 2020-04-03)
    Background: New technologies have given rise to an abundance of -omics data, particularly metabolomic data. The scale of these data introduces new challenges for the interpretation and extraction of knowledge, requiring the development of innovative computational visualization methodologies. Here, we present GEM-Vis, an original method for the visualization of time-course metabolomic data within the context of metabolic network maps. We demonstrate the utility of the GEM-Vis method by examining previously published data for two cellular systems-the human platelet and erythrocyte under cold storage for use in transfusion medicine. Results: The results comprise two animated videos that allow for new insights into the metabolic state of both cell types. In the case study of the platelet metabolome during storage, the new visualization technique elucidates a nicotinamide accumulation that mirrors that of hypoxanthine and might, therefore, reflect similar pathway usage. This visual analysis provides a possible explanation for why the salvage reactions in purine metabolism exhibit lower activity during the first few days of the storage period. The second case study displays drastic changes in specific erythrocyte metabolite pools at different times during storage at different temperatures. Conclusions: The new visualization technique GEM-Vis introduced in this article constitutes a well-suitable approach for large-scale network exploration and advances hypothesis generation. This method can be applied to any system with data and a metabolic map to promote visualization and understand physiology at the network level. More broadly, we hope that our approach will provide the blueprints for new visualizations of other longitudinal -omics data types. The supplement includes a comprehensive user's guide and links to a series of tutorial videos that explain how to prepare model and data files, and how to use the software SBMLsimulator in combination with further tools to create similar animations as highlighted in the case studies.
  • Current use of noninvasive prenatal testing in Europe, Australia and the USA: A graphical presentation.

    Gadsbøll, Kasper; Petersen, Olav B; Gatinois, Vincent; Strange, Heather; Jacobsson, Bo; Wapner, Ronald; Vermeesch, Joris R; Vogel, Ida; 1Center for Fetal Medicine, Pregnancy and Ultrasound, University Hospital Rigshospitalet, Copenhagen, Denmark. 2Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 3Chromosome Genetics Laboratory, CHU Montpellier, University of Montpellier, Montpellier, France. 4Centre for Trials Research, Cardiff University, Cardiff, UK. 5Sahlgrenska University Hospital, Gothenburg, Sweden. 6Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA. 7Department of Human Genetics, KU Leuven, Leuven, Belgium. 8Department of Clinical Genetics, Aarhus University/Aarhus University Hospital, Aarhus, Denmark. 9Center for Fetal Diagnostics, Aarhus University/Aarhus University Hospital, Aarhus, Denmark. (Wiley, 2020-03-16)
    Introduction: Noninvasive prenatal testing (NIPT) using cell-free fetal DNA has increasingly been adopted as a screening tool for fetal aneuploidies. Several studies have discussed benefits and limitations of NIPT compared with both ultrasound and invasive procedures, but in spite of some shortcomings NIPT has become extensively used within the last 5 years. This study aims to describe the current use of NIPT in Europe, Australia and the USA. Material and methods: We conducted a survey to describe the current use of NIPT. Colleagues filled in a simple email-based questionnaire on NIPT in their own country, providing information on (a) access to NIPT, (b) NIPT's chromosomal coverage, (c) financial coverage of NIPT for the patient and (d) the proportion of women using NIPT in pregnancy. Some data are best clinical estimates, due to a lack of national data. Results: In Europe, 14 countries have adopted NIPT into a national policy/program. Two countries (Belgium and the Netherlands) offer NIPT for all pregnant women, whereas most other European countries have implemented NIPT as an offer for higher risk women after first trimester screening. In Australia, either combined first trimester screening (cFTS) or NIPT is used as a primary prenatal screening test. In the USA, there are no national consensus policies on the use of NIPT; however, NIPT is widely implemented. In most European countries offering NIPT, the proportion of women using NIPT is well below 25%. In the Netherlands, Austria, Italy, Spain and most Australian and American States, 25%-50% of women have NIPT performed and in Belgium testing is above 75%. In most countries, NIPT reports on trisomy 13, 18 and 21, and often also on sex chromosome aneuploidies. Only in Belgium, the Netherlands, Lithuania, Greece, Cyprus and Italy is NIPT offered predominantly as a genome-wide test (including some microdeletions or a whole genome coverage). Conclusions: Noninvasive prenatal testing has been widely adopted throughout Europe, Australia and the USA, but only a few countries/states have a national policy on the use of NIPT. The variation in NIPT utilization is considerable.
  • Risk Factors for Hen's Egg Allergy in Europe: EuroPrevall Birth Cohort.

    Grimshaw, Kate E C; Roberts, Graham; Selby, Anna; Reich, Andreas; Butiene, Indra; Clausen, Michael; Dubakiene, Ruta; Fiandor, Ana; Fiocchi, Alessandro; Grabenhenrich, Linus B; et al. (Elsevier, 2019-12-14)
    Background: Hen's egg is one of the commonest causes of food allergy, but there are little data on its risk factors. Objective: To assess the risk factors, particularly eczema, for hen's egg allergy in the EuroPrevall birth cohort. Methods: In the pan-European EuroPrevall birth cohort, questionnaires were undertaken at 12 and 24 months or when parents reported symptoms. Children with suspected egg allergy were invited for skin prick testing, specific IgE assessment, and double-blind, placebo-controlled food challenge (DBPCFC) as indicated. Each egg allergy case (positive DBPCFC or egg-induced anaphylaxis) was allocated up to 2 age- and country-matched controls. Results: A total of 12,049 infants were recruited into the EuroPrevall birth cohort, and 9,336 (77.5%) were followed until 2 years. A total of 86 infants had egg allergy (84 by DBPCFC) and were matched with 140 controls. Independently associated with egg allergy were past/current eczema (adjusted odds ratio, 9.21; 95% CI, 2.65-32.04), Scoring Atopic Dermatitis (1.54 per 5 units; 1.28-1.86), antibiotics in the first week of life (6.17; 1.42-26.89), and current rhinitis (3.02; 1.04-8.78). Increasing eczema severity was associated with an increasing likelihood of egg allergy. Eczema was reported to have started 3.6 (SE, 0.5) months before egg allergy. Age of introduction of egg into the diet was not associated with egg allergy. Conclusions: Similar to peanut allergy, eczema was strongly associated with egg allergy development and the association increased with increasing eczema severity. The age of introduction of dietary egg was not a risk factor. The potential role of antibiotics in early life as a risk factor for egg allergy needs further examination.
  • Reduced Susceptibility of Streptococcus pyogenes to β-Lactam Antibiotics Associated with Mutations in the Gene Is Geographically Widespread.

    Musser, James M; Beres, Stephen B; Zhu, Luchang; Olsen, Randall J; Vuopio, Jaana; Hyyryläinen, Hanne-Leena; Gröndahl-Yli-Hannuksela, Kirsi; Kristinsson, Karl G; Darenberg, Jessica; Henriques-Normark, Birgitta; et al. (American Society for Microbiology, 2020-03-25)
    Recently, two related Streptococcus pyogenes strains with reduced susceptibility to ampicillin, amoxicillin, and cefotaxime, antibiotics commonly used to treat S. pyogenes infections, were reported. The two strains had the same nonsynonymous (amino acid-substituting) mutation in the pbp2x gene, encoding penicillin-binding protein 2X (PBP2X). This concerning report led us to investigate our library of 7,025 genome sequences of type emm1, emm28, and emm89S. pyogenes clinical strains recovered from intercontinental sources for mutations in pbp2x We identified 137 strains that, combined, had 37 nonsynonymous mutations in 36 codons in pbp2x Although to a lesser magnitude than the two previously published isolates, many of our strains had decreased susceptibility in vitro to multiple beta-lactam antibiotics. Many pbp2x mutations were found only in single strains, but 16 groups of two or more isolates of the same emm type had an identical amino acid replacement. Phylogenetic analysis showed that, with one exception, strains of the same emm type with the same amino acid replacement were clonally related by descent. This finding indicates that strains with some amino acid changes in PBP2X can successfully spread to new human hosts and cause invasive infections. Mapping of the amino acid changes onto a three-dimensional structure of the related Streptococcus pneumoniae PBP2X suggests that some substitutions are located in regions functionally important in related pathogenic bacterial species. Decreased beta-lactam susceptibility is geographically widespread in strains of numerically common emm gene subtypes. Enhanced surveillance and further epidemiological and molecular genetic study of this potential emergent antimicrobial problem are warranted.
  • International Severe Asthma Registry: Mission Statement

    Canonica, G. Walter; Alacqua, Marianna; Altraja, Alan; Backer, Vibeke; Bel, Elisabeth; Bjermer, Leif; Bjornsdottir, Unnur; Bourdin, Arnaud; Brusselle, Guy G.; Christoff, George C.; et al. (Elsevier, 2020-04-01)
    Regional and/or national severe asthma registries provide valuable country-specific information. However, they are often limited in scope within the broader definitions of severe asthma, have insufficient statistical power to answer many research questions, lack intraoperability to share lessons learned, and have fundamental differences in data collected, making cross comparisons difficult. What is missing is a worldwide registry which brings all severe asthma data together in a cohesive way, under a single umbrella, based on standardized data collection protocols, permitting data to be shared seamlessly. The International Severe Asthma Registry (ISAR; is the first global adult severe asthma registry. It is a joint initiative where national registries (both newly created and preexisting) retain ownership of their own data but open their borders and share data with ISAR for ethically approved research purposes. Its strength comes from collection of patient-level, anonymous, longitudinal, real-life, standardized, high-quality data (using a core set of variables) from countries across the world, combined with organizational structure, database experience, inclusivity/openness, and clinical, academic, and database expertise. This gives ISAR sufficient statistical power to answer important research questions, sufficient data standardization to compare across countries and regions, and the structure and expertise necessary to ensure its continuance and the scientific integrity and clinical applicability of its research. ISAR offers a unique opportunity to implement existing knowledge, generate new knowledge, and identify the unknown, therefore promoting new research. The aim of this commentary is to fully describe how ISAR may improve our understanding of severe asthma.
  • Current Status and Future Prospects of Genome-Scale Metabolic Modeling to Optimize the Use of Mesenchymal Stem Cells in Regenerative Medicine.

    Sigmarsdóttir, Þóra; McGarrity, Sarah; Rolfsson, Óttar; Yurkovich, James T; Sigurjónsson, Ólafur E; 1The Blood Bank, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 2School of Science and Engineering, Reykjavik University, Reykjavik, Iceland. 3Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 4Institute for Systems Biology, Seattle, WA, United States. (Frontiers Media S.A., 2020-03-31)
    Mesenchymal stem cells are a promising source for externally grown tissue replacements and patient-specific immunomodulatory treatments. This promise has not yet been fulfilled in part due to production scaling issues and the need to maintain the correct phenotype after re-implantation. One aspect of extracorporeal growth that may be manipulated to optimize cell growth and differentiation is metabolism. The metabolism of MSCs changes during and in response to differentiation and immunomodulatory changes. MSC metabolism may be linked to functional differences but how this occurs and influences MSC function remains unclear. Understanding how MSC metabolism relates to cell function is however important as metabolite availability and environmental circumstances in the body may affect the success of implantation. Genome-scale constraint based metabolic modeling can be used as a tool to fill gaps in knowledge of MSC metabolism, acting as a framework to integrate and understand various data types (e.g., genomic, transcriptomic and metabolomic). These approaches have long been used to optimize the growth and productivity of bacterial production systems and are being increasingly used to provide insights into human health research. Production of tissue for implantation using MSCs requires both optimized production of cell mass and the understanding of the patient and phenotype specific metabolic situation. This review considers the current knowledge of MSC metabolism and how it may be optimized along with the current and future uses of genome scale constraint based metabolic modeling to further this aim.
  • Corrigendum to: Mendelian disorders of the epigenetic machinery: postnatal malleability and therapeutic prospects.

    Fahrner, Jill A; Bjornsson, Hans T; 1McKusick-Nathans Institute of Genetic Medicine, 21205. 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 3Landspitali University Hospital, Reykjavik 101, Iceland. 4Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland. (Oxford University Press, 2020-03)
  • Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome.

    Pilarowski, Genay O; Cazares, Tareian; Zhang, Li; Benjamin, Joel S; Liu, Ke; Jagannathan, Sajjeev; Mousa, Nadeem; Kasten, Jennifer; Barski, Artem; Lindsley, Andrew W; et al. (Elsevier, 2019-12-06)
    Background: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. Objective: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). Methods: We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/βGeo) mouse model and validated select findings in a patient with KS. Results: Compared with wild-type littermates, Kmt2d+/βGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/βGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/βGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. Conclusions: Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.

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