• Exploratory assessment of pineal gland volume, composition, and urinary 6-sulfatoxymelatonin levels on prostate cancer risk.

      Bazzi, Latifa A; Sigurdardottir, Lara G; Sigurdsson, Sigurdur; Valdimarsdottir, Unnur; Torfadottir, Johanna; Aspelund, Thor; Czeisler, Charles A; Lockley, Steven W; Jonsson, Eirikur; Launer, Lenore; et al. (Wiley, 2021-04-16)
      Introduction: Melatonin levels are partially driven by the parenchyma volume of the pineal gland. Low urinary levels of 6-sulfatoxymelatonin have been associated with increased risk of advanced prostate cancer, but the relationship between pineal gland volume and composition and prostate cancer risk has not been examined. Materials and methods: We utilized data from 864 men from the AGES-Reykjavik Study with complete pineal gland volumes and urinary 6-sulfatoxymelatonin measurements. Pineal parenchyma, calcification, and cyst volumes were calculated from brain magnetic resonance imaging. Levels of 6-sulfatoxymelatonin were assayed from prediagnostic urine samples. We calculated Pearson correlation coefficients between parenchyma volume and urinary 6-sulfatoxymelatonin levels. We used Cox proportional hazards regression to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) comparing prostate cancer risk across parenchyma volume tertiles and across categories factoring in parenchyma volume, gland composition, and urinary 6-sulfatoxymelatonin level. Results: Parenchyma volume was moderately correlated with urinary 6-sulfatoxymelatonin level (r = .24; p < .01). There was no statistically significant association between parenchyma volume tertile and prostate cancer risk. Men with high parenchyma volume, pineal cysts and calcifications, and low urinary 6-sulfatoxymelatonin levels had almost twice the risk of total prostate cancer as men with low parenchyma volume, no pineal calcifications or cysts, and low urinary 6-sulfatoxymelatonin levels (HR: 1.98; 95% CI: 1.02, 3.84; p: .04). Conclusions: Although parenchyma volume is not associated with prostate cancer risk, pineal gland composition and other circadian dynamics may influence risk for prostate cancer. Additional studies are needed to examine the interplay of pineal gland volume, composition, and melatonin levels on prostate cancer risk. Keywords: circadian rhythm; melatonin; pineal gland; prostate cancer.
    • HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry.

      Konte, Bettina; Walters, James T R; Rujescu, Dan; Legge, Sophie E; Pardiñas, Antonio F; Cohen, Dan; Pirmohamed, Munir; Tiihonen, Jari; Hartmann, Annette M; Bogers, Jan P; et al. (Nature Publishing Group, 2021-04-12)
      The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E-06) and agranulocytosis (OR = 10.49, P = 1.83E-06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E-08; agranulocytosis: OR = 16.31, P = 1.39E-06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.
    • Lower or higher oxygenation targets for acute hypoxemic respiratory failure

      Schjørring, Olav L.; Klitgaard, Thomas L.; Perner, Anders; Wetterslev, Jørn; Lange, Theis; Siegemund, Martin; Bäcklund, Minna; Keus, Frederik; Laake, Jon H.; Morgan, Matthew; et al. (Massachusetts Medical Society, 2021-04-08)
      BACKGROUND Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher target. METHODS In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days. RESULTS At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P=0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P=0.24). CONCLUSIONS Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days.
    • Acute gastrointestinal bleeding among patients on antiplatelet and anticoagulant therapy after percutaneous coronary intervention.

      Sveinsdottir, Asdis; Gudmundsdottir, Ingibjörg J; Hreinsson, Johann P; Andersen, Karl; Björnsson, Einar S; 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Department of Internal Medicine, Division of Cardiology, Landspitali - The National University Hospital of Iceland, Reykajvik, Iceland. 3Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. 4Department of Internal Medicine, Division of Gastroenterology and Hepatology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. (Taylor & Francis, 2021-04-01)
      Background: Patients undergoing percutaneous coronary intervention (PCI) require dual antiplatelet therapy and some require additional anticoagulation. We aimed to investigate the incidence of acute gastrointestinal bleeding (AGIB) among PCI patients receiving antiplatelet and anticoagulant therapy. Methods: A population-based study that included all patients undergoing PCI during 2008-2016 in Iceland. Data from the Icelandic Medicines Registry were obtained on all outpatient prescriptions 1 year after first PCI. Patients receiving single or dual-antiplatelet therapy with or without anticoagulation cotherapy were analyzed. Rehospitalization for AGIB and endoscopic data were obtained within the 12-month follow-up period. Results: A total of 5166 patients (male 75%) underwent PCI during the study period. The incidence of AGIB was 1% (54/5166) per year. The mean age among non-bleeders 65 (±11) years was lower than among bleeders 69 (±9) years (p = .002). The proportion of acute upper GIB (AUGIB) was 56%, whereas lower GIB occurred in 44%. Overall, 41% with AUGIB had PPIs compared to 39% of non-bleeders (NS). The incidence of AGIB among patients on single antiplatelet therapy combined with an anticoagulant was 2.5% compared to 0.9% among those on single antiplatelet treatment alone (p = .028). The number needed to harm (NNH) for treatment with single antiplatelet therapy and anticoagulant therapy compared to single antiplatelet therapy was 62 but no deaths related to AGIB. Conclusions: The 1-year incidence of AGIB was low with no mortality. Bleeding risk was found to be higher among patients on single antiplatelet therapy combined with anticoagulant therapy compared to patients on single antiplatelet therapy alone. Keywords: Acute gastrointestinal bleeding; anticoagulant therapy; antiplatelet therapy; dual antiplatelet therapy; incidence; number needed to harm; percutaneous coronary intervention.
    • Toward Predicting Motion Sickness Using Virtual Reality and a Moving Platform Assessing Brain, Muscles, and Heart Signals.

      Recenti, Marco; Ricciardi, Carlo; Aubonnet, Romain; Picone, Ilaria; Jacob, Deborah; Svansson, Halldór Á R; Agnarsdóttir, Sólveig; Karlsson, Gunnar H; Baeringsdóttir, Valdís; Petersen, Hannes; et al. (Frontiers Media, 2021-04-01)
      Motion sickness (MS) and postural control (PC) conditions are common complaints among those who passively travel. Many theories explaining a probable cause for MS have been proposed but the most prominent is the sensory conflict theory, stating that a mismatch between vestibular and visual signals causes MS. Few measurements have been made to understand and quantify the interplay between muscle activation, brain activity, and heart behavior during this condition. We introduce here a novel multimetric system called BioVRSea based on virtual reality (VR), a mechanical platform and several biomedical sensors to study the physiology associated with MS and seasickness. This study reports the results from 28 individuals: the subjects stand on the platform wearing VR goggles, a 64-channel EEG dry-electrode cap, two EMG sensors on the gastrocnemius muscles, and a sensor on the chest that captures the heart rate (HR). The virtual environment shows a boat surrounded by waves whose frequency and amplitude are synchronized with the platform movement. Three measurement protocols are performed by each subject, after each of which they answer the Motion Sickness Susceptibility Questionnaire. Nineteen parameters are extracted from the biomedical sensors (5 from EEG, 12 from EMG and, 2 from HR) and 13 from the questionnaire. Eight binary indexes are computed to quantify the symptoms combining all of them in the Motion Sickness Index (I MS ). These parameters create the MS database composed of 83 measurements. All indexes undergo univariate statistical analysis, with EMG parameters being most significant, in contrast to EEG parameters. Machine learning (ML) gives good results in the classification of the binary indexes, finding random forest to be the best algorithm (accuracy of 74.7 for I MS ). The feature importance analysis showed that muscle parameters are the most relevant, and for EEG analysis, beta wave results were the most important. The present work serves as the first step in identifying the key physiological factors that differentiate those who suffer from MS from those who do not using the novel BioVRSea system. Coupled with ML, BioVRSea is of value in the evaluation of PC disruptions, which are among the most disturbing and costly health conditions affecting humans.
    • Long-Term Effect of Receiving a Family Strengths-Oriented Intervention on Family Cancer Caregiver Stress, Anxiety, and Depression Symptoms: A Longitudinal Quasi-Experimental Study.

      Petursdottir, Asta B; Rayens, Mary Kay; Sigurdardottir, Valgerdur; Svavarsdottir, Erla Kolbrun; 1School of Health Sciences, Faculty of Nursing, University of Iceland, Reykjavík, Iceland. 2Landspitali The National University Hospital, Reykjavík, Iceland. 3University of Kentucky, Lexington, USA. (SAGE Publications, 2021-03-31)
      The aim of this longitudinal study was to evaluate the long-term effects of providing a therapeutic conversation intervention, based on Family Systems Nursing, to family caregivers of a close relative with advanced cancer over the period before and during bereavement. To prevent adverse outcomes, caregivers need ongoing support that begins pre-loss and extends into the post-loss period. This study employed a one-group pre-test, post-test quasi-experimental design. Twenty-four caregivers participated in two intervention trials conducted over a 42-month period, receiving two intervention sessions pre-loss (Trial 1) and one intervention session post-loss (Trial 2). Significant decreases in anxiety and stress were noted over the three post-loss assessments. The final post-loss stress outcome was significantly lower than the first pre-loss score. For the depression score, there was not a significant change over time within the pre- or post-loss period. The findings provide evidence of decreasing anxiety and stress following the implementation of an extended family nursing intervention for bereaved family caregivers. Keywords: Family Systems Nursing; advanced cancer; bereavement; family caregiver; longitudinal research; palliative care.
    • Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

      Sheppard, Sarah E; Campbell, Ian M; Harr, Margaret H; Gold, Nina; Li, Dong; Bjornsson, Hans T; Cohen, Julie S; Fahrner, Jill A; Fatemi, Ali; Harris, Jacqueline R; et al. (Wiley, 2021-03-30)
      Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS. Keywords: KMT2A; MLL1; Wiedemann-Steiner syndrome; hypertrichosis; syndromic intellectual disability; syndromic short stature.
    • Statins are associated with increased risk of squamous cell carcinoma of the skin: a whole-population study from Iceland.

      Adalsteinsson, Jonas A; Muzumdar, Sonal; Waldman, Reid; Hu, Chaoran; Wu, Rong; Ratner, Désirée; Feng, Hao; Ungar, Jonathan; Silverberg, Jonathan I; Olafsdottir, Gudridur H; et al. (Springer, 2021-03-27)
      Statins have been associated with an increased risk of keratinocyte carcinoma but data are limited and conflicting. Statins are hypothesized to contribute to KC through immunomodulation. A whole-population case-control study of the Icelandic population was conducted using the Icelandic Cancer Registry and Icelandic Prescription Medicine Register. These are high-quality registers which include all cancer diagnoses, as well as every prescription in the country. Cases included all first-time histologically confirmed diagnoses of (BCC), in situ squamous cell carcinoma (SCCis) and invasive SCC between 2003 and 2017. Each case was paired with 10 age- and sex-matched controls. Multivariate conditional logistic regression analysis was performed. Four thousand seven hundred patients with BCC, 1167 patients with SCCis and 1013 patients with invasive SCC were identified and paired with 47,292, 11,961 and 10,367 controls, respectively. Overall statin use was associated with an increased risk of invasive SCC and SCCis but not BCC (adjusted OR [95% CI]: 1.29 [1.11-1.50]; 1.43 [1.24-1.64]; 1.03 [0.95-1.12], respectively). Subgroup analysis demonstrated that statins were significantly associated with invasive SCC and SCCis in patients over 60, but not in those under 60. Atorvastatin was only associated with an increased risk of SCCis; whereas, simvastatin was associated with an increased risk of both invasive SCC and SCCis. This whole-population study of Iceland demonstrates that statin exposure is associated with increased risk of SCC, but not BCC, in a low UV environment. The reasons are unclear, but our results may suggest that individuals receiving atorvastatin and simvastatin have differing levels of baseline keratinocyte cancer risk or that properties of a statin other than 'statin intensity' affect association with SCC. Keywords: Atorvastatin; Basal cell carcinoma; Nonmelanoma skin cancer; Simvastatin; Squamous cell carcinoma; Statins.
    • Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency.

      Runolfsdottir, Hrafnhildur L; Sayer, John A; Indridason, Olafur S; Edvardsson, Vidar O; Jensson, Brynjar O; Arnadottir, Gudny A; Gudjonsson, Sigurjon A; Fridriksdottir, Run; Katrinardottir, Hildigunnur; Gudbjartsson, Daniel; et al. (Nature Publishing Group, 2021-03-11)
      Adenine phosphoribosyltransferase deficiency is a rare, autosomal recessive disorder of purine metabolism that causes nephrolithiasis and progressive chronic kidney disease. The small number of reported cases indicates an extremely low prevalence, although it has been suggested that missed diagnoses may play a role. We assessed the prevalence of APRT deficiency based on the frequency of causally-related APRT sequence variants in a diverse set of large genomic databases. A thorough search was carried out for all APRT variants that have been confirmed as pathogenic under recessive mode of inheritance, and the frequency of the identified variants examined in six population genomic databases: the deCODE genetics database, the UK Biobank, the 100,000 Genomes Project, the Genome Aggregation Database, the Human Genetic Variation Database and the Korean Variant Archive. The estimated frequency of homozygous genotypes was calculated using the Hardy-Weinberg equation. Sixty-two pathogenic APRT variants were identified, including six novel variants. Most common were the missense variants c.407T>C (p.(Met136Thr)) in Japan and c.194A>T (p.(Asp65Val)) in Iceland, as well as the splice-site variant c.400 + 2dup (p.(Ala108Glufs*3)) in the European population. Twenty-nine variants were detected in at least one of the six genomic databases. The highest cumulative minor allele frequency (cMAF) of pathogenic variants outside of Japan and Iceland was observed in the Irish population (0.2%), though no APRT deficiency cases have been reported in Ireland. The large number of cases in Japan and Iceland is consistent with a founder effect in these populations. There is no evidence for widespread underdiagnosis based on the current analysis.
    • Stroke survivors' experiences with rebuilding life in the community and exercising at home: A qualitative study.

      van Dongen, Lisa; Hafsteinsdóttir, Thóra B; Parker, Ethna; Bjartmarz, Ingibjörg; Hjaltadóttir, Ingibjörg; Jónsdóttir, Helga; 1Julius Center for Health Sciences and Primary Care, Nursing Science Department, University Medical Center Utrecht, Utrecht, The Netherlands. 2Faculty of Nursing, School of Health Sciences, University of Iceland, Reykjavík, Iceland. 3Landspítali University Hospital, Reykjavík, Iceland. (Wiley, 2021-03-10)
      Aim: This study aimed to explore how stroke survivors deal with stroke-related impairments when rebuilding their lives in the community and their experiences of exercising at home. Design: An explorative and descriptive qualitative study. Methods: A purposive sample of ten stroke survivors residing at home was recruited to explore experiences of rebuilding their lives in the community and exercising at home. One focus group interview was conducted followed by semi-structured interviews. Data were analysed using thematic analysis. Results: Three main themes were identified: "Framing exercise within the context of everyday life" describes how stroke survivors integrate exercise in everyday activities with varying success and the social importance of exercising; "Managing the challenges of physical impairment" describes the taxing undertakings in daily living, loss of concentration and identity; "Long-term challenges of everyday life" describes how the stroke survivors manage depression and live with a sense of uncertainty. Keywords: home rehabilitation; qualitative research; rehabilitation; stroke patients; stroke rehabilitation.
    • Health technology assessment through Six Sigma Methodology to assess cemented and uncemented protheses in total hip arthroplasty.

      Latessa, Imma; Ricciardi, Carlo; Jacob, Deborah; Jónsson, Halldór; Gambacorta, Monica; Improta, Giovanni; Gargiulo, Paolo; 1University Hospital of Naples "Federico II", Department of Public Health, Naples, Italy; Reykjavík University, Institute for Biomedical and Neural Engineering, Reykjavík. immalatessa@gmail.com. 2Reykjavík University, Institute for Biomedical and Neural Engineering, Reykjavík, Iceland; University Hospital of Naples 'Federico II', Department of Advanced Biomedical Sciences, Naples. carloricciardi.93@gmail.com. 3Reykjavík University, Institute for Biomedical and Neural Engineering, Reykjavík. dcrjacob@gmail.com. 4University of Iceland, Faculty of Medicine, Reykjavík, Iceland; Landspítali Hospital, Orthopaedic Clinic, Reykjavík. halldor@landspitali.is. 5Umberto I Hospital, Local Health Unit of Salerno, Salerno. m.gambacorta@aslsalerno.it. 6University Hospital of Naples "Federico II", Department of Public Health, Naples. ing.improta@gmail.com. 7Reykjavík University, Institute for Biomedical and Neural Engineering, Reykjavík, Iceland; Landspítali Hospital, Department of Science, Reykjavík. paologar@landspitali.is. (PagePress, 2021-03-09)
      The purpose of this study is to use Health Technology Assessment (HTA) through the Six Sigma (SS) and DMAIC (Define, Measure, Analyse, Improve, Control) problem-solving strategies for comparing cemented and uncemented prostheses in terms of the costs incurred for Total hip arthroplasty (THA) and the length of hospital stay (LOS). Multinomial logistic regression analysis for modelling the data was also performed. Quantitative parameters extracted from gait analysis, electromyography and computed tomography images were used to compare the approaches, but the analysis did not show statistical significance. The variables regarding costs were studied with the Mann-Whitney and Kruskal-Wallis tests. No statistically significant difference between cemented and uncemented prosthesis for the total cost of LOS was found, but the cost of the surgeon had an influence on the overall expenses, affecting the cemented prosthetic approach. The material costs of surgery for the uncemented prosthesis and the cost of theatre of surgery for the cemented prosthesis were the most influential. Multinomial logistic regression identified the Vastus Lateralis variable as statistically significant. The overall accuracy of the model is 93.0%. The use of SS and DMAIC cycle as tools of HTA proved that the cemented and uncemented approaches for THA have similar costs and LOSy.
    • Diffuse idiopathic skeletal hyperostosis in elderly Icelanders and its association with the metabolic syndrome: the AGES-Reykjavik Study.

      Auðunsson, A B; Elíasson, G J; Steingrímsson, E; Aspelund, T; Sigurdsson, S; Launer, L; Gudnason, V; Jonsson, H; 1Department of Radiology, Landspitali University Hospital, Reykjavík, Iceland. 2Department of Radiology, Domus Medica, Reykjavík, Iceland. 3Icelandic Heart Association, Kopavogur, Iceland. 4Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 5National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. 6Department of Rheumatology, Landspitali University Hospital, Reykjavík, Iceland. (Taylor & Francis, 2021-03-07)
      Objective: To describe the prevalence of diffuse idiopathic skeletal hyperostosis (DISH) in a large population-based study of elderly Icelanders, with particular reference to weight-related factors and the metabolic syndrome.Method: The study population comprised 5321 participants aged 68-96 years (2276 males, mean ± sd age 76 ± 5 , and 3045 females, age 77 ± 6) from the AGES-Reykjavik Study. DISH diagnosis was based on computed tomography (CT) scans, and interpreted strictly by the Resnick criteria and additional suggestions for CT interpretation by Oudkerk et al. Radiology readings were taken by a radiology resident and sample readings by two experienced radiologists.Results: A diagnosis of DISH was made in 13.7% of males and 2.8% of females. There was no association with age, but a strong association was seen with the metabolic syndrome [odds ratio (OR) 2.12, 95% confidence interval (CI) 1.69-2.64, p = 3.9 × 10-11]. Among the components of the metabolic syndrome, the association with DISH was significant for the insulin resistance criterion (OR 1.66, 95% CI 1.32-2.01, p < 0.001) and the body mass index (BMI) criterion (OR 2.16, 95% CI 1.70-2.74, p < 0.001). Other weight-related variables (midlife BMI, weight, and abdominal circumference) showed similar associations.Conclusions: This study, which to our knowledge is the largest published study on the prevalence of DISH, shows an association with the metabolic syndrome, particularly with the insulin resistance and BMI criteria. This is analogous with previous reports linking DISH with metabolic causes. In this age category, we did not observe any increase in prevalence with age.
    • Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010.

      Loeber, J Gerard; Platis, Dimitris; Zetterström, Rolf H; Almashanu, Shlomo; Boemer, François; Bonham, James R; Borde, Patricia; Brincat, Ian; Cheillan, David; Dekkers, Eugenie; et al. (MDPI, 2021-03-05)
      Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together. Keywords: ISNS; International Society for Neonatal Screening; congenital endocrine disorders; congenital metabolic disorders; dried blood spot screening; neonatal screening; newborn screening; public health; rare diseases.
    • How do we use biologics in rheumatoid arthritis patients with a history of malignancy? An assessment of treatment patterns using Scandinavian registers.

      Chatzidionysiou, Katerina; Delcoigne, Bénédicte; Frisell, Thomas; Hetland, Merete L; Glintborg, Bente; Dreyer, Lene; Cordtz, René; Zobbe, Kristian; Nordström, Dan; Trokovic, Nina; et al. (BMJ Publishing Group, 2021-03)
    • Ábendingar og árangur ósæðarlokuísetningar með þræðingartækni (TAVI) á Íslandi

      Katrín Júníana Lárusdóttir; Hjalti Guðmundsson; Árni Johnsen; Martin Ingi Sigurðsson; Tómas Guðbjartsson; Ingibjörg Jóna Guðmundsdóttir; 1 Læknadeild Háskóla Íslands, 2 hjartalækningadeild, 3 hjarta- og lungnaskurðdeild, 4 svæfinga- og gjörgæsludeild Landspítala (Læknafélag Íslands, 2021-03)
      INNGANGUR Ósæðarlokuþrengsl eru algengasti lokusjúkdómurinn á Vesturlöndum. Hefðbundin meðferð við alvarlegum þrengslum hefur verið opin ósæðarlokuskipti en síðastliðin ár hefur ósæðarlokuísetning með þræðingartækni (TAVI) rutt sér til rúms hér á landi sem erlendis. Markmið rannsóknarinnar var að kanna árangur TAVI-aðgerða á Íslandi með áherslu á ábendingar, fylgikvilla og lifun. EFNIVIÐUR OG AÐFERÐIR Rannsóknin var afturskyggn og tók til allra TAVI-aðgerða sem framkvæmdar hafa verið á Íslandi frá janúar 2012 til loka júní 2020. Skráðir voru bakgrunnsþættir sjúklinga, afdrif og fylgikvillar en einnig heildarlifun sem borin var saman við íslenskt viðmiðunarþýði af sama kyni og aldri. Meðal eftirfylgd var 2,4 ár. NIÐURSTÖÐUR Alls voru framkvæmdar 189 aðgerðir (meðalaldur 83 ± 6 ár, 41,8% konur), allar með sjálfþenjandi lífrænni gerviloku. Flestir sjúklingar (81,5%) höfðu alvarleg hjartabilunareinkenni (NYHA-flokkar III-IV) og miðgildi EuroSCORE-II var 4,9 (bil 0,9-32). Á hjartaómskoðun fyrir aðgerð var hámarks þrýstingsfallandi að meðaltali 78 mmHg og lokuflatarmál 0,67 cm2 . Rúmlega fjórðungur (26,5%) sjúklinga þurfti ísetningu varanlegs gangráðs í kjölfar TAVI-aðgerðar. Aðrir fylgikvillar voru oftast æðatengdir (13,8%), en hjartaþröng greindist í 3,2% tilfella og heilablóðfall í 2,6%. . Mikill randstæður leki við gerviloku sást hjá 0,5% sjúklinga. Dánartíðni innan 30 daga frá aðgerð var 1,6% (n=3) og lifun einu ári frá aðgerðadegi 93,5% (95% ÖB: 89.8-97.3). Heildarlifun var sambærileg lifun viðmiðunarþýðis af sama kyni og sama aldri (p=0,23). ÁLYKTANIR Árangur TAVI-aðgerða hér á landi er mjög góður, ekki síst þegar litið er til lágrar 30 daga dánartíðni og heildarlifunar sem var sambærileg og hjá viðmiðunarþýði. Auk þess var tíðni alvarlegra fylgikvilla lág.
    • Severe volcanic SO exposure and respiratory morbidity in the Icelandic population - a register study.

      Carlsen, Hanne Krage; Valdimarsdóttir, Unnur; Briem, Haraldur; Dominici, Francesca; Finnbjornsdottir, Ragnhildur Gudrun; Jóhannsson, Thorsteinn; Aspelund, Thor; Gislason, Thorarinn; Gudnason, Thorolfur; 1Centre of Public Health Sciences, University of Iceland, Sturlugata 8, Reykjavík, 102, Iceland. hkc1@hi.is. 2Environment and Natural resources, University of Iceland, Sturlugata 7, University of Iceland, 102, Reykjavík, Iceland. hkc1@hi.is. 3Section of Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, University of Gothenburg, Medicinaregatan 16A, 40530, Gothenburg, Sweden. hkc1@hi.is. 4Centre of Public Health Sciences, University of Iceland, Sturlugata 8, Reykjavík, 102, Iceland. 5Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA. 6Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 6, SE-171 77, Stockholm, Sweden. 7Chief Epidemiologist, Directorate of Health, Centre for Health Threats and Communicable Diseases, Barónsstigur 57, 101, Reykjavík, Iceland. 8The Environment Agency of Iceland, Suðurlandsbraut 24, 108, Reykjavík, Iceland. 9School of Health Sciences, University of Iceland, Sæmundargata 2, 101, Reykjavík, Iceland. 10Landspitali - the National University Hospital, Fossvogur, 108, Reykjavík, Iceland. 11Faculty of medicine, University of Iceland, Vatnsmýrarvegi 16, 101, Reykjavík, Iceland. (BioMed Central, 2021-02-27)
      Background: The Holuhraun volcanic eruption September 2014 to February 2015 emitted large amounts of sulfur dioxide (SO2). The aim of this study was to determine the association between volcanic SO2 gases on general population respiratory health some 250 km from the eruption site, in the Icelandic capital area. Methods: Respiratory health outcomes were: asthma medication dispensing (AMD) from the Icelandic Medicines Register, medical doctor consultations in primary care (PCMD) and hospital emergency department visits (HED) in Reykjavík (population: 215000) for respiratory disease from 1 January 2010 to 31 December 2014. The associations between daily counts of health events and daily mean SO2 concentration and high SO2 levels (24-h mean SO2 > 125 μg/m3) were analysed using generalized additive models. Results: After the eruption began, AMD was higher than before (129.4 vs. 158.4 individuals per day, p < 0.05). For PCMD and HED, there were no significant differences between the number of daily events before and after the eruption (142.2 vs 144.8 and 18.3 vs 17.5, respectively). In regression analysis adjusted for other pollutants, SO2 was associated with estimated increases in AMD by 0.99% (95% CI 0.39-1.58%) per 10 μg/m3 at lag 0-2, in PCMD for respiratory causes 1.26% (95% CI 0.72-1.80%) per 10 μg/m3 SO2 at lag 0-2, and in HED by 1.02% (95% CI 0.02-2.03%) per 10 μg/m3 SO2 at lag 0-2. For days over the health limit, the estimated increases were 10.9% (95% CI 2.1-19.6%), 17.2% (95% CI 10.0-24.4%) for AMD and PCMD. Dispensing of short-acting medication increased significantly by 1.09% (95% CI 0.49-1.70%), and PCMD for respiratory infections and asthma and COPD diagnoses and increased significantly by 1.12% (95% CI 0.54-1.71%) and 2.08% (1.13-3.04%). Conclusion: High levels of volcanic SO2 are associated with increases in dispensing of AMD, and health care utilization in primary and tertiary care. Individuals with prevalent respiratory disease may be particularly susceptible. Keywords: Atmospheric transport; Epidemiology; Public health; Respiratory disease; Volcanic eruption.
    • Mode of delivery was associated with transient changes in the metabolomic profile of neonates.

      Vidarsdottir, Harpa; Halldorsson, Thorhallur Ingi; Geirsson, Reynir Tomas; Bjarnason, Ragnar; Franzson, Leifur; Valdimarsdottir, Unnur Anna; Thorkelsson, Thordur; 1Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 2Department of Neonatology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden. 3Faculty for Food Science and Nutrition, School of Health Science, University of Iceland, Reykjavik, Iceland. 4Women's Clinic, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 5Children's Hospital Iceland, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 6Faculty of Pharmaceutical Sciences, School of Health Science, University of Iceland, Reykjavik, Iceland. 7Department of Genetics and Molecular Medicine, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 8Center for Public Health Science, School of Health Science, University of Iceland, Reykjavik, Iceland. 9Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 10Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA. (Wiley, 2021-02-26)
      Aims: To estimate potential differences in neonatal metabolomic profiles at birth and at the time of newborn screening by delivery mode. Methods: A prospective study at Women's Clinic at Landspitali-The National University Hospital of Iceland. Women having normal vaginal birth or elective caesarean section from November 2013 to April 2014 were offered participation. Blood samples from mothers before birth and umbilical cord at birth were collected and amino acids and acylcarnitines measured by tandem mass spectrometry. Results from the Newborn screening programme in Iceland were collected. Amino acids and acylcarnitines from different samples were compared by delivery mode. Results: Eighty three normal vaginal births and 32 elective caesarean sections were included. Mean differences at birth were higher for numerous amino acids, and some acylcarnitines in neonates born vaginally compared to elective caesarean section. Maternal blood samples and newborn screening results showed small differences that lost significance after correction for multiple testing. Many amino acids and some acylcarnitines were numerically higher in cord blood compared to maternal. Many amino acids and most acylcarnitines were numerically higher in newborn screening results compared to cord blood. Conclusion: We observed transient yet distinct differences in metabolomic profiles between neonates by delivery mode. Keywords: acylcarnitines; amino acids; delivery mode; metabolomic profile; newborn screening.
    • Factors associated with family functioning in patients with heart failure and their family members: An international cross-sectional study.

      Shamali, Mahdi; Konradsen, Hanne; Svavarsdottir, Erla K; Shahriari, Mohsen; Ketilsdottir, Audur; Østergaard, Birte; 1Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 2Department of Gastroenterology, Herlev and Gentofte University Hospital, Copenhagen, Denmark. 3Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 4Division of Nursing, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden. 5School of Health Sciences, Faculty of Nursing, University of Iceland, Reykjavík, Iceland. 6Nursing and Midwifery Care Research Center, Adult Health Nursing Department, School of Nursing and Midwifery, Isfahan University of Medical Sciences, Isfahan, Iran. 7Landspitali the National and University Hospital and Faculty of Nursing, University of Iceland, Reykjavík, Iceland. (Wiley, 2021-02-24)
      Aims: To describe and compare family functioning, family health, and perceived social support from nurses and to identify the variables that are associated with family functioning in patients with heart failure (HF) and their family members in Denmark, Iran, and Iceland. Design: An international multi-centre cross-sectional study. Methods: A sample of 1382 participants (692 patients and 690 family members) from Denmark, Iceland, and Iran were included from January 2015 to May 2020. Data were collected using the Family Functioning, Health, and Social Support questionnaire. Results: The significant factors associated with family functioning in patients were country, New York Heart Association classification (NYHA), education level, age, family health, social support, and there was a significant interaction effect between NYHA class and gender. The significant factors associated with family functioning in family members were country, education level, work status, family health, and there was a significant interaction effect between education and work status. Conclusion: This study indicated that the strongest factor associated with higher family functioning was family health for both patients and family members. Women in NYHA class I and younger patients and those with an academic education had a lower level of family functioning. Moreover, unemployed family members with an elementary education and family members with elementary and high school educations who were self-employed or employees had a lower level of family functioning. Impact: This is the first international study to investigate family functioning, family health, and social support and adds to the literature on the factors associated with family functioning in patients with HF and their family members. Our findings may help nurses to identify the most vulnerable families living with HF, thereby being able to provide special support to enhance their family functioning to promote self-management strategies. Keywords: family functioning; family health; family member; heart failure; social support.
    • Tumor co-expression of progranulin and sortilin as a prognostic biomarker in breast cancer.

      Berger, Karoline; Rhost, Sara; Rafnsdóttir, Svanheiður; Hughes, Éamon; Magnusson, Ylva; Ekholm, Maria; Stål, Olle; Rydén, Lisa; Landberg, Göran; 1Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Box 425, Medicinaregatan 1G, SE-13 90, Gothenburg, Sweden. 2Present address: Department of Surgery, National University Hospital of Iceland, 13-A Hringbraut, Reykjavik, Iceland. 3Department of Oncology, Region Jönköping County, Jönköping, Sweden. 4Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. 5Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden. 6Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Box 425, Medicinaregatan 1G, SE-13 90, Gothenburg, Sweden. goran.landberg@gu.se. (BioMed Central, 2021-02-22)
      Background: The growth factor progranulin has been implicated in numerous biological processes such as wound healing, inflammation and progressive tumorigenesis. Both progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and have been associated with various clinical properties including tamoxifen resistance. Recent data further suggest that progranulin, via its receptor sortilin, drives breast cancer stem cell propagation in vitro and increases metastasis formation in an in vivo breast cancer xenograft model. In this retrospective biomarker analysis, we aimed to determine whether tumor co-expression of progranulin and sortilin has prognostic and treatment predictive values for breast cancer patients. Methods: We explored how co-expression of progranulin and sortilin was associated with established clinical markers by analyzing a tissue microarray including 560 randomized premenopausal breast cancer patients receiving either 2 years of tamoxifen treatment or no adjuvant treatment, with a median follow-up time of 28 years. Breast cancer-specific survival was analyzed using Kaplan-Meier and Cox Proportional Hazards regression models to assess the prognostic and predictive value of progranulin and sortilin in relation to known clinical markers. Results: Co-expression of progranulin and sortilin was observed in 20% of the breast cancer samples. In untreated patients, prognostic considerations could be detailed separately from treatment prediction and the high progranulin and sortilin expressing subgroup was significantly associated with breast cancer-specific death in multivariable analyses (HR=2.188, CI: 1.317-3.637, p=0.003) along with tumor size, high tumor grade and lymph node positivity. When comparing the untreated patients with tamoxifen treated patients in the ERα positive subgroup, co-expression of progranulin and sortilin was not linked to tamoxifen resistance. Conclusion: Data suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapies. Keywords: Biomarker; Breast cancer; Cancer stem cells; Estrogen receptor; Predictive; Prognostic; Progranulin; Sortilin; Tamoxifen; Targeted therapy.
    • Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome.

      Zhang, Li; Pilarowski, Genay; Pich, Emilio Merlo; Nakatani, Atsushi; Dunlop, John; Baba, Rina; Matsuda, Satoru; Daini, Masaki; Hattori, Yasushi; Matsumoto, Shigemitsu; et al. (Cell Press, 2021-02-18)
      Kabuki syndrome (KS) is a rare cause of intellectual disability primarily caused by loss-of-function mutations in lysine-specific methyltransferase 2D (KMT2D), which normally adds methyl marks to lysine 4 on histone 3. Previous studies have shown that a mouse model of KS (Kmt2d +/βGeo ) demonstrates disruption of adult neurogenesis and hippocampal memory. Proof-of-principle studies have shown postnatal rescue of neurological dysfunction following treatments that promote chromatin opening; however, these strategies are non-specific and do not directly address the primary defect of histone methylation. Since lysine-specific demethylase 1A (LSD1/KDM1A) normally removes the H3K4 methyl marks added by KMT2D, we hypothesized that inhibition of KDM1A demethylase activity may ameliorate molecular and phenotypic defects stemming from KMT2D loss. To test this hypothesis, we evaluated a recently developed KDM1A inhibitor (TAK-418) in Kmt2d +/βGeo mice. We found that orally administered TAK-418 increases the numbers of newly born doublecortin (DCX)+ cells and processes in the hippocampus in a dose-dependent manner. We also observed TAK-418-dependent rescue of histone modification defects in hippocampus both by western blot and chromatin immunoprecipitation sequencing (ChIP-seq). Treatment rescues gene expression abnormalities including those of immediate early genes such as FBJ osteosarcoma oncogene (Fos) and FBJ osteosarcoma oncogene homolog B (Fosb). After 2 weeks of TAK-418, Kmt2d +/βGeo mice demonstrated normalization of hippocampal memory defects. In summary, our data suggest that KDM1A inhibition is a plausible treatment strategy for KS and support the hypothesis that the epigenetic dysregulation secondary to KMT2D dysfunction plays a major role in the postnatal neurological disease phenotype in KS.