Recent Submissions

  • Distinction between the effects of parental and fetal genomes on fetal growth.

    Juliusdottir, Thorhildur; Steinthorsdottir, Valgerdur; Stefansdottir, Lilja; Sveinbjornsson, Gardar; Ivarsdottir, Erna V; Thorolfsdottir, Rosa B; Sigurdsson, Jon K; Tragante, Vinicius; Hjorleifsson, Kristjan E; Helgadottir, Anna; et al. (Nature Publishing Group, 2021-07-19)
    Birth weight is a common measure of fetal growth that is associated with a range of health outcomes. It is directly affected by the fetal genome and indirectly by the maternal genome. We performed genome-wide association studies on birth weight in the genomes of the child and parents and further analyzed birth length and ponderal index, yielding a total of 243 fetal growth variants. We clustered those variants based on the effects of transmitted and nontransmitted alleles on birth weight. Out of 141 clustered variants, 22 were consistent with parent-of-origin-specific effects. We further used haplotype-specific polygenic risk scores to directly test the relationship between adult traits and birth weight. Our results indicate that the maternal genome contributes to increased birth weight through blood-glucose-raising alleles while blood-pressure-raising alleles reduce birth weight largely through the fetal genome.
  • Molecular benchmarks of a SARS-CoV-2 epidemic.

    Jonsson, Hakon; Magnusson, Olafur T; Melsted, Pall; Berglund, Jonas; Agustsdottir, Arna B; Eiríksdottir, Berglind; Fridriksdottir, Run; Garðarsdottir, Elisabet Eir; Georgsson, Gudmundur; Gretarsdottir, Olafia S; et al. (Nature Publishing Group, 2021-06-15)
    A pressing concern in the SARS-CoV-2 epidemic and other viral outbreaks, is the extent to which the containment measures are halting the viral spread. A straightforward way to assess this is to tally the active cases and the recovered ones throughout the epidemic. Here, we show how epidemic control can be assessed with molecular information during a well characterized epidemic in Iceland. We demonstrate how the viral concentration decreased in those newly diagnosed as the epidemic transitioned from exponential growth phase to containment phase. The viral concentration in the cases identified in population screening decreased faster than in those symptomatic and considered at high risk and that were targeted by the healthcare system. The viral concentration persists in recovering individuals as we found that half of the cases are still positive after two weeks. We demonstrate that accumulation of mutations in SARS-CoV-2 genome can be exploited to track the rate of new viral generations throughout the different phases of the epidemic, where the accumulation of mutations decreases as the transmission rate decreases in the containment phase. Overall, the molecular signatures of SARS-CoV-2 infections contain valuable epidemiological information that can be used to assess the effectiveness of containment measures.
  • Understanding Nurses' Knowledge and Attitudes Toward Pain Assessment in Dementia: A Literature Review.

    Jonsdottir, Thorbjorg; Gunnarsson, Esther Christina; 1Faculty of Nursing, School of Health Sciences, University of Akureyri, Akureyri, Iceland; School of Health Sciences, Faculty of Nursing, University of Akureyriv/Nordurslod, Akureyri, Iceland. Electronic address: 2Faculty of Nursing, School of Health Sciences, University of Akureyri, Akureyri, Iceland; The National University Hospital of Iceland, Eiriksgata, Reykjavik, Iceland. (Elsevier, 2020-12-14)
    Background: Pain is underrecognized and undertreated in patients with dementia. It has been suggested that nurses' attitudinal barriers may contribute to the challenges surrounding pain assessment and management in dementia. Aims: This integrative literature review aims to identify and explore nurses' knowledge and attitudes towards pain assessment in older people with dementia and how it may affect pain management in this patient group. Method: Electronic searches were conducted in Web of Science, MEDLINE, Scopus, ProQuest, PubMed, and EBSCOhost from January 2008 to December 2018 for articles specifically focusing on nurses' knowledge and attitudes towards pain assessment in older patients with dementia. Results: Ten studies were included in the review after meeting the inclusion criteria. Data extracted from each study included study design, aims and objectives, setting/sample, findings, and limitations. Patients with dementia are at greater risk of experiencing underassessment, undertreatment, and delayed treatment of pain due to nurses' knowledge deficits and uncertainty in the decision-making process. Nurses see providing comfort and reducing pain as ethical obligation. However, they find pain assessment a challenge due to the complexity of recognizing painful behaviors, and difficulty differentiating between pain and behavioral disturbances in dementia. Poor multidisciplinary communication, time constraints, and workload pressure, as well as uncertainty about opioid use, are important barriers to effective pain assessment and management among patients with dementia. Conclusion: It is essential that nurses gain confidence in distinguishing signs and symptoms of pain from behavioral changes in dementia. It is important to improve interdisciplinary communication and to get physicians to listen and prioritize pain assessment and management.
  • Effectiveness of a couple-based intervention on sexuality and intimacy among women in active cancer treatment: A quasi-experimental study.

    Jonsdottir, Jona Ingibjorg; Vilhjalmsson, Runar; Svavarsdottir, Erla Kolbrun; 1Landspitali-The National University Hospital of Iceland, Hringbraut, 101, Reykjavik, Iceland; School of Health Sciences, Faculty of Nursing, University of Iceland, Eirberg, Eiríksgata 34, 101, Reykjavík, Iceland. Electronic address: 2School of Health Sciences, Faculty of Nursing, University of Iceland, Eirberg, Eiríksgata 34, 101, Reykjavík, Iceland. Electronic address: 3Landspitali-The National University Hospital of Iceland, Hringbraut, 101, Reykjavik, Iceland; School of Health Sciences, Faculty of Nursing, University of Iceland, Eirberg, Eiríksgata 34, 101, Reykjavík, Iceland. Electronic address: (Elsevier, 2021-05-11)
    Purpose: To evaluate the effectiveness of a strenghts-oriented therapeutic conversation intervention on confidence about how illness beliefs affect sexuality and intimacy and on perceived relationship quality among women in active cancer treatment and their partners. Methods: A quasi-experimental single-group pre-post-follow-up design was used. Women in active cancer treatment and their intimate partners were randomly assigned to a nurse-managed couple-based intervention (experimental group, n = 30 couples) or wait-list (delayed intervention) control group (n = 27 couples) plus 4 additional couples who pilot tested feasibility of the intervention, prior to the RCT. However, baseline differences in demographic and clinical variables prevented comparisons between groups. Therefore, a repeated-one-group pre-post test setup was used, comparing women with cancer and their partners over three time points. The intervention consisted of three Couple-Strengths-Oriented Therapeutic Conversations (CO-SOTC) sessions. The participants also had access to web-based evidence-based educational information. Data were collected before intervention (T1, baseline), one to two weeks post-intervention (T2), and after a follow-up session at three months (T3). Data from 60 couples (N = 120) were analyzed. Results: Significant differences were observed, for both women and intimate partners, over time in more confidence about how illness beliefs affected sexuality and intimacy (T1 versus T2, and T1 versus T3), and increased overall quality of the relationship (T1 versus T2, and T1 versus T3). No differences were found between dyad members' scores on illness beliefs or relationship quality at any time point. Conclusions: The CO-SOTC intervention was effective in supporting sexual adjustment among women in cancer treatment and their intimate partners. Trial registration number: NCT03936400 at Keywords: Advanced practice nursing; Couples therapy; Neoplasms; Psychosocial support systems; Sexual health; Sexuality; Spouses; Women.
  • Cyclodextrin-based formulation of carbonic anhydrase inhibitors for ocular delivery - A review.

    Jansook, Phatsawee; Hnin, Hay Marn; Loftsson, Thorsteinn; Stefánsson, Einar; 1Faculty of Pharmaceutical Sciences, Chulalongkorn University, 254 Phyathai Road, Pathumwan, Bangkok 10330, Thailand. Electronic address: 2Faculty of Pharmaceutical Sciences, Chulalongkorn University, 254 Phyathai Road, Pathumwan, Bangkok 10330, Thailand. 3Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107 Reykjavik, Iceland. 4Department of Ophthalmology, Faculty of Medicine, National University Hospital, University of Iceland, Landspitalinn, IS-101 Reykjavik, Iceland. (Elsevier, 2021-07-28)
    Carbonic anhydrase inhibitors (CAIs) are used as systemic and topical agents for lowering intraocular pressure (IOP) in patients with glaucoma. Owing to the wide distribution of CAs and their physiological functions in various tissues, systemic administration of CAIs may lead to unwanted side effects. Thus, exploration of drugs targeting the specific CA isoenzyme in ocular tissues and application of the same as topical eye drops would be desirable. However, the anatomical and physiological barriers of the eyes can limit drug availability at the site. The very low aqueous solubility of CAI agents can further hamper drug bioavailability, consequently resulting in insufficient therapeutic efficacy. Solubilization of drugs using cyclodextrin (CD) complexes can enhance both solubility and permeability of the drugs. The use of CD for such purposes and development and testing of topical CAI eye drops containing CD have been discussed in detail. Further, pharmaceutical nanotechnology platforms were discussed in terms of investigation of their IOP-lowering efficacies. Future prospects in drug discovery and the use of CD nanoparticles and CD-based nanocarriers to develop potential topical CAI formulations have also been described here. Keywords: Carbonic anhydrase inhibitor; Cyclodextrin; Glaucoma; Intraocular pressure; Nanocarrier; Solubilization.
  • Retinal oxygen saturation changes progressively over time in diabetic retinopathy.

    Hardarson, Sveinn Hakon; Stefánsson, Einar; Bek, Toke; 1Institute of Physiology, Department of Medicine, University of Iceland, Reykjavik, Iceland. 2Department of Ophthalmology, Landspitali University Hospital, Reykjavik, Iceland. 3Department of Ophthalmology, Aarhus University Hospital, Aarhus N, Denmark. (Public Library of Science, 2021-05-12)
    Purpose: According to cross-sectional studies, oxygen saturation is elevated in retinal vessels in diabetic patients. We evaluated how retinal oxygenation (metabolic marker), vessel diameters and retinopathy grade (structural markers) change over time in diabetic patients. Design: Prospective cohort study following screening in a hospital setting. Methods: Retinal oximetry images were acquired in 214 patients with the Oxymap T1 oximeter. Imaging was repeated after a median of 3.0 years (range 0.76-6.8 years). Oxygen saturation and vessel diameters were measured in the right eye. Semiquantitative grading of retinopathy according to international guidelines and red lesion count were performed on fundus photographs. Results: Retinopathy grade according to the international semiquantitative grading system was unchanged. Arteriolar saturation increased by 0.75±0.15 percentage points per year of follow-up (p<0.0001). Venular saturation increased by 1.74±0.26 percentage points per year (p<0.0001) and arteriovenous difference decreased by 0.99±0.20 percentage points per year (p<0.0001). Arteriolar diameters decreased by 2.7±8.5μm (p<0.0001) between visits and venular diameters decreased by 2.4±9.1μm (p = 0.0002). Median increase in red lesion count between visits was 2 lesions (range -128 to 212 lesions, p<0.0001). The change in red lesion count and change in diameters did not correlate with the length of follow-up (p>0.44). Conclusions: Oxygen saturation in larger retinal vessels can increase and arteriovenous difference can decrease over time in diabetic patients without any observable changes in retinopathy grade. The results suggest that changes in retinal oxygen saturation may precede progression of diabetic retinopathy or that oxygen saturation is more sensitive to disease progression than retinopathy grade.
  • The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis.

    Ivarsdottir, Erna V; Holm, Hilma; Benonisdottir, Stefania; Olafsdottir, Thorhildur; Sveinbjornsson, Gardar; Thorleifsson, Gudmar; Eggertsson, Hannes P; Halldorsson, Gisli H; Hjorleifsson, Kristjan E; Melsted, Pall; et al. (Nature Publishing Group, 2021-06-09)
    Age-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P = 1.7 × 10-22 and OR = 4.2 for heterozygotes, P = 5.7 × 10-27, respectively). We constructed an ARHI genetic risk score (GRS) using common variants and showed that a common variant GRS can identify individuals at risk comparable to carriers of rare high penetrance variants. Furthermore, we found that ARHI and tinnitus share genetic causes. This study sheds a new light on the genetic architecture of ARHI, through several rare variants in both Mendelian deafness genes and genes not previously linked to hearing.
  • Optimal communication associated with lower risk of acute traumatic stress after lung cancer diagnosis.

    Hardardottir, Hronn; Aspelund, Thor; Zhu, Jianwei; Fall, Katja; Hauksdottir, Arna; Fang, Fang; Lu, Donghao; Janson, Christer; Jonsson, Steinn; Valdimarsdottir, Heiddis; et al. (Springer, 2021-07-17)
    Purpose: The aim of this study was to assess the role of the patient's background and perceived healthcare-related factors in symptoms of acute stress after lung cancer diagnosis. Methods: The study population consisted of 89 individuals referred for diagnostic work-up at Landspitali National University Hospital in Iceland and subsequently diagnosed with lung cancer. Before diagnosis, the patients completed questionnaires on sociodemographic characteristics, pre-diagnostic distress (Hospital Anxiety and Depression Scale), social support, and resilience. At a median of 16 days after diagnosis, the patients reported symptoms of acute stress on the Impact of Event Scale-Revised (IES-R) and experience of communication and support from healthcare professionals and family during the diagnostic period. Results: Patients were on average 68 years and 52% reported high levels of post-diagnostic acute stress (IES-R > 23) while 24% reported symptoms suggestive of clinical significance (IES-R > 32). Prior history of cancer (β = 6.7, 95% CI: 0.1 to 13.3) and pre-diagnostic distress were associated with higher levels of post-diagnostic acute stress (β = 8.8, 95% CI: 2.7 to 14.9), while high educational level (β = - 7.9, 95% CI: - 14.8 to - 1.1) was associated with lower levels. Controlling for the abovementioned factors, the patients' perception of optimal doctor-patient (β = - 9.1, 95% CI: - 14.9 to - 3.3) and family communication (β = - 8.6, 95% CI: - 14.3 to - 2.9) was inversely associated with levels of post-diagnostic acute stress after lung cancer diagnosis. Conclusions: A high proportion of patients with newly diagnosed lung cancer experience high levels of acute traumatic stress of potential clinical significance. Efforts to improve doctor-patient and family communication may mitigate the risk of these adverse symptoms. Keywords: Doctor-patient communication; Lung cancer diagnosis; Post-diagnostic acute stress; Posttraumatic stress disorder (PTSD); Prospective cohort study.
  • Cardiac arrest due to accidental overdose with norepinephrine dissolved in crystalloid.

    Hansel, Jan; Ármannsson, Gunnar Skúli; 1Department of Anaesthetics, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UK 2Department of Anaesthesia and Intensive Care, Landspítali University Hospital, Reykjavík, Iceland. (BMJ Pub. Group, 2020-12-09)
    Vasoactive agents should be administered through a controlled well-marked infusor pump, ideally via a central venous catheter if given over longer periods of time. During transfer of haemodynamically unstable patients with limited staffing and resources on site, a peripheral vasopressor infusion is sometimes resorted to as a temporary measure of optimising haemodynamic parameters. We report a case of accidental norepinephrine overdose after such practice, resulting in cardiac arrest. It illustrates the importance of careful use and labelling of vasoactive agents during the transport and handover of critically ill patients. Finally, we explore human factor issues associated with transfer from the pre-hospital to the in-hospital environment when such preparations are used. Keywords: adult intensive care; anaesthesia; resuscitation; safety; toxicology.
  • Are the target exposure index and deviation index used efficiently?

    Guðjónsdóttir, J; Paalsson, K E; Sveinsdóttir, G P; 1University of Iceland, Faculty of Medicine, Radiography, Stapa við Hringbraut 31, 101 Reykjavík, Iceland; Icelandic Radiation Safety Authority, Rauðarárstígur 10, 105 Reykjavík, Iceland. Electronic address: 2Landspítali - the National University Hospital of Iceland, 101 Reykjavík, Iceland. 3University of Iceland, Faculty of Medicine, Radiography, Stapa við Hringbraut 31, 101 Reykjavík, Iceland. Electronic address: (Elsevier, 2021-03-09)
    Exposure index (EI) is important to evaluate correct exposure in radiography and thus important for image quality. The purpose of this study was to evaluate whether the target exposure index (EIT) and deviation index (DI) were used efficiently.
  • Fertility preservation in boys: recent developments and new insights .

    Goossens, E; Jahnukainen, K; Mitchell, R T; van Pelt, Amm; Pennings, G; Rives, N; Poels, J; Wyns, C; Lane, S; Rodriguez-Wallberg, K A; et al. (Oxford University Press, 2020-06-06)
    Background: Infertility is an important side effect of treatments used for cancer and other non-malignant conditions in males. This may be due to the loss of spermatogonial stem cells (SSCs) and/or altered functionality of testicular somatic cells (e.g. Sertoli cells, Leydig cells). Whereas sperm cryopreservation is the first-line procedure to preserve fertility in post-pubertal males, this option does not exist for prepubertal boys. For patients unable to produce sperm and at high risk of losing their fertility, testicular tissue freezing is now proposed as an alternative experimental option to safeguard their fertility. Objective and rationale: With this review, we aim to provide an update on clinical practices and experimental methods, as well as to describe patient management inclusion strategies used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss. Search methods: Based on the expertise of the participating centres and a literature search of the progress in clinical practices, patient management strategies and experimental methods used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss were identified. In addition, a survey was conducted amongst European and North American centres/networks that have published papers on their testicular tissue banking activity. Outcomes: Since the first publication on murine SSC transplantation in 1994, remarkable progress has been made towards clinical application: cryopreservation protocols for testicular tissue have been developed in animal models and are now offered to patients in clinics as a still experimental procedure. Transplantation methods have been adapted for human testis, and the efficiency and safety of the technique are being evaluated in mouse and primate models. However, important practical, medical and ethical issues must be resolved before fertility restoration can be applied in the clinic.Since the previous survey conducted in 2012, the implementation of testicular tissue cryopreservation as a means to preserve the fertility of prepubertal boys has increased. Data have been collected from 24 co-ordinating centres worldwide, which are actively offering testis tissue cryobanking to safeguard the future fertility of boys. More than 1033 young patients (age range 3 months to 18 years) have already undergone testicular tissue retrieval and storage for fertility preservation. Limitations reasons for caution: The review does not include the data of all reproductive centres worldwide. Other centres might be offering testicular tissue cryopreservation. Therefore, the numbers might be not representative for the entire field in reproductive medicine and biology worldwide. The key ethical issue regarding fertility preservation in prepubertal boys remains the experimental nature of the intervention. Wider implications: The revised procedures can be implemented by the multi-disciplinary teams offering and/or developing treatment strategies to preserve the fertility of prepubertal boys who have a high risk of fertility loss. Study funding/competing interests: The work was funded by ESHRE. None of the authors has a conflict of interest. Keywords: cryopreservation; fertility preservation; fertility restoration; in vitro spermatogenesis; prepubertal boys; spermatogonial stem cell; testicular tissue freezing; testis; transplantation.
  • Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database.

    Fridriksdottir, Run; Jonsson, Arnar J; Jensson, Brynjar O; Sverrisson, Kristinn O; Arnadottir, Gudny A; Skarphedinsdottir, Sigurbjorg J; Katrinardottir, Hildigunnur; Snaebjornsdottir, Steinunn; Jonsson, Hakon; Eiriksson, Ogmundur; et al. (Nature Publishing Group, 2021-08-31)
    Malignant hyperthermia (MH) susceptibility is a rare life-threatening disorder that occurs upon exposure to a triggering agent. MH is commonly due to protein-altering variants in RYR1 and CACNA1S. The American College of Medical Genetics and Genomics recommends that when pathogenic and likely pathogenic variants in RYR1 and CACNA1S are incidentally found, they should be reported to the carriers. The detection of actionable variants allows the avoidance of exposure to triggering agents during anesthesia. First, we report a 10-year-old Icelandic proband with a suspected MH event, harboring a heterozygous missense variant NM_000540.2:c.6710G>A r.(6710g>a) p.(Cys2237Tyr) in the RYR1 gene that is likely pathogenic. The variant is private to four individuals within a three-generation family and absent from 62,240 whole-genome sequenced (WGS) Icelanders. Haplotype sharing and WGS revealed that the variant occurred as a somatic mosaicism also present in germline of the proband's paternal grandmother. Second, using a set of 62,240 Icelanders with WGS, we assessed the carrier frequency of actionable pathogenic and likely pathogenic variants in RYR1 and CACNA1S. We observed 13 actionable variants in RYR1, based on ClinVar classifications, carried by 43 Icelanders, and no actionable variant in CACNA1S. One in 1450 Icelanders carries an actionable variant for MH. Extensive sequencing allows for better classification and precise dating of variants, and WGS of a large fraction of the population has led to incidental findings of actionable MH genotypes.
  • Changes in obstetric interventions and preterm birth during COVID-19: A nationwide study from Iceland.

    Einarsdóttir, Kristjana; Swift, Emma Marie; Zoega, Helga; 1Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Faculty of Nursing/Department of Midwifery, University of Iceland, Reykjavík, Iceland. 3Women's Clinic, Landspitali National University Hospital of Iceland, Reykjavik, Iceland. 4Centre for Big Data Research in Health, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia. (Wiley, 2021-07-28)
    Introduction: Previous evidence has been conflicting regarding the effect of coronavirus disease 2019 (COVID-19) pandemic lockdowns on obstetric intervention and preterm birth rates. The literature to date suggests potentially differential underlying mechanisms based on country economic setting. We aimed to study these outcomes in an Icelandic population where uniform lockdown measures were implemented across the country. Material and methods: The study included all singleton births (n = 20 680) during 2016-2020 identified from the population-based Icelandic Medical Birth Register. We defined two lockdown periods during March-May and October-December in 2020 according to government implemented nationwide lockdown. We compared monthly rates of cesarean section, induction of labor and preterm birth during lockdown with the same time periods in the 4 previous years (2016-2019) using logit binomial regression adjusted for confounders. Results: Our results indicated a reduction in the overall cesarean section rate, which was mainly evident for elective cesarean section, both during the first (adjusted odd ratio [aOR] 0.71, 95% CI 0.51-0.99) and second (aOR 0.72, 95% CI 0.52-0.99) lockdown periods, and not for emergency cesarean section. No change during lockdown was observed in induction of labor. Our results also suggested a reduction in the overall preterm birth rate during the first lockdown (aOR 0.69, 95% CI 0.49-0.97) and in the months immediately following the lockdown (June-September) (aOR 0.67, 95% CI 0.49-0.89). The reduction during the first lockdown was mainly evident for medically indicated preterm birth (although not statistically significant) and the reduction during June-September was mainly evident for spontaneous preterm birth. Conclusions: This study suggested a reduction in elective cesarean section during COVID-19 lockdown, possibly reflecting changes in prioritization of non-urgent health care during lockdown. We also found a reduction in overall preterm birth during the first lockdown and spontaneous preterm birth following the first lockdown, but further research is needed to shed light on the underlying mechanisms for these findings. Keywords: COVID-19; cesarean section; induction of labor; lockdown; preterm birth.
  • Outcome of COVID-19 in Patients With Autoimmune Hepatitis: An International Multicenter Study.

    Efe, Cumali; Dhanasekaran, Renumathy; Lammert, Craig; Ebik, Berat; Higuera-de la Tijera, Fatima; Aloman, Costica; Rıza Calışkan, Ali; Peralta, Mirta; Gerussi, Alessio; Massoumi, Hatef; et al. (Wiley, 2021-06)
    Background and aims: Data regarding outcome of COVID-19 in patients with autoimmune hepatitis (AIH) are lacking. Approach and results: We performed a retrospective study on patients with AIH and COVID-19 from 34 centers in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes, defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity score-matched cohort of patients without AIH but with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase > 2 × the upper limit of normal) during COVID-19 was also evaluated. We included 110 patients with AIH (80% female) with a median age of 49 (range, 18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (P = 0.041; OR, 3.36; 95% CI, 1.05-10.78), while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (P = 0.009; OR, 0.26; 95% CI, 0.09-0.71). The rates of severe COVID-19 (15.5% versus 20.2%, P = 0.231) and all-cause mortality (10% versus 11.5%, P = 0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (P < 0.001; OR, 17.46; 95% CI, 4.22-72.13). Continuation of immunosuppression or presence of liver injury during COVID-19 was not associated with severe COVID-19. Conclusions: This international, multicenter study reveals that patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD. Cirrhosis was the strongest predictor for severe COVID-19 in patients with AIH. Maintenance of immunosuppression during COVID-19 was not associated with increased risk for severe COVID-19 but did lower the risk for new-onset liver injury during COVID-19.
  • Comparison of Respiratory Support After Delivery in Infants Born Before 28 Weeks' Gestational Age: The CORSAD Randomized Clinical Trial.

    Donaldsson, Snorri; Drevhammar, Thomas; Li, Yinghua; Bartocci, Marco; Rettedal, Siren Irene; Lundberg, Fredrik; Odelberg-Johnson, Per; Szczapa, Tomasz; Thordarson, Thordur; Pilypiene, Ingrida; et al. (American Medical Association, 2021-09)
    Importance: Establishing stable breathing is a key event for preterm infants after birth. Delivery of pressure-stable continuous positive airway pressure and avoiding face mask use could be of importance in the delivery room. Objective: To determine whether using a new respiratory support system with low imposed work of breathing and short binasal prongs decreases delivery room intubations or death compared with a standard T-piece system with a face mask. Design, setting, and participants: In this unblinded randomized clinical trial, mothers threatening preterm delivery before week 28 of gestation were screened. A total of 365 mothers were enrolled, and 250 infants were randomized before birth and 246 liveborn infants were treated. The trial was conducted in 7 neonatal intensive care units in 5 European countries from March 2016 to May 2020. The follow-up period was 72 hours after intervention. Interventions: Infants were randomized to either the new respiratory support system with short binasal prongs (n = 124 infants) or the standard T-piece system with face mask (n = 122 infants). The intervention was providing continuous positive airway pressure for 10 to 30 minutes and positive pressure ventilation, if needed, with the randomized system. Main outcomes and measures: The primary outcome was delivery room intubation or death within 30 minutes of birth. Secondary outcomes included respiratory and safety variables. Results: Of 246 liveborn infants treated, the mean (SD) gestational age was 25.9 (1.3) weeks, and 127 (51.6%) were female. A total of 41 infants (33.1%) receiving the new respiratory support system were intubated or died in the delivery room compared with 55 infants (45.1%) receiving standard care. The adjusted odds ratio was statistically significant after adjusting for stratification variables (adjusted odds ratio, 0.53; 95% CI, 0.30-0.94; P = .03). No significant differences were seen in secondary outcomes or safety variables. Conclusions and relevance: In this study, using the new respiratory support system reduced delivery room intubation in extremely preterm infants. Stabilizing preterm infants with a system that has low imposed work of breathing and binasal prongs as interface is safe and feasible.
  • NANS-CDG: Delineation of the Genetic, Biochemical, and Clinical Spectrum.

    den Hollander, Bibiche; Rasing, Anne; Post, Merel A; Klein, Willemijn M; Oud, Machteld M; Brands, Marion M; de Boer, Lonneke; Engelke, Udo F H; van Essen, Peter; Fuchs, Sabine A; et al. (Frontiers Research Foundation, 2021-06-07)
    Background: NANS-CDG is a recently described congenital disorder of glycosylation caused by biallelic genetic variants in NANS, encoding an essential enzyme in de novo sialic acid synthesis. Sialic acid at the end of glycoconjugates plays a key role in biological processes such as brain and skeletal development. Here, we present an observational cohort study to delineate the genetic, biochemical, and clinical phenotype and assess possible correlations. Methods: Medical and laboratory records were reviewed with retrospective extraction and analysis of genetic, biochemical, and clinical data (2016-2020). Results: Nine NANS-CDG patients (nine families, six countries) referred to the Radboudumc CDG Center of Expertise were included. Phenotyping confirmed the hallmark features including intellectual developmental disorder (IDD) (n = 9/9; 100%), facial dysmorphisms (n = 9/9; 100%), neurologic impairment (n = 9/9; 100%), short stature (n = 8/9; 89%), skeletal dysplasia (n = 8/9; 89%), and short limbs (n = 8/9; 89%). Newly identified features include ophthalmological abnormalities (n = 6/9; 67%), an abnormal septum pellucidum (n = 6/9; 67%), (progressive) cerebral atrophy and ventricular dilatation (n = 5/9; 56%), gastrointestinal dysfunction (n = 5/9; 56%), thrombocytopenia (n = 5/9; 56%), and hypo-low-density lipoprotein cholesterol (n = 4/9; 44%). Biochemically, elevated urinary excretion of N-acetylmannosamine (ManNAc) is pathognomonic, the concentrations of which show a significant correlation with clinical severity. Genotypically, eight novel NANS variants were identified. Three severely affected patients harbored identical compound heterozygous pathogenic variants, one of whom was initiated on experimental prenatal and postnatal treatment with oral sialic acid. This patient showed markedly better psychomotor development than the other two genotypically identical males. Conclusions: ManNAc screening should be considered in all patients with IDD, short stature with short limbs, facial dysmorphisms, neurologic impairment, and an abnormal septum pellucidum +/- congenital and neurodegenerative lesions on brain imaging, to establish a precise diagnosis and contribute to prognostication. Personalized management includes accurate genetic counseling and access to proper supports and tailored care for gastrointestinal symptoms, thrombocytopenia, and epilepsy, as well as rehabilitation services for cognitive and physical impairments. Motivated by the short-term positive effects of experimental treatment with oral sialic, we have initiated this intervention with protocolized follow-up of neurologic, systemic, and growth outcomes in four patients. Research is ongoing to unravel pathophysiology and identify novel therapeutic targets.
  • Recommendation for validation and quality assurance of non-invasive prenatal testing for foetal blood groups and implications for IVD risk classification according to EU regulations.

    Clausen, Frederik Banch; Hellberg, Åsa; Bein, Gregor; Bugert, Peter; Schwartz, Dieter; Drnovsek, Tadeja Dovc; Finning, Kirstin; Guz, Katarzyna; Haimila, Katri; Henny, Christine; et al. (Wiley, 2021-06-21)
    Background and objectives: Non-invasive assays for predicting foetal blood group status in pregnancy serve as valuable clinical tools in the management of pregnancies at risk of detrimental consequences due to blood group antigen incompatibility. To secure clinical applicability, assays for non-invasive prenatal testing of foetal blood groups need to follow strict rules for validation and quality assurance. Here, we present a multi-national position paper with specific recommendations for validation and quality assurance for such assays and discuss their risk classification according to EU regulations. Materials and methods: We reviewed the literature covering validation for in-vitro diagnostic (IVD) assays in general and for non-invasive foetal RHD genotyping in particular. Recommendations were based on the result of discussions between co-authors. Results: In relation to Annex VIII of the In-Vitro-Diagnostic Medical Device Regulation 2017/746 of the European Parliament and the Council, assays for non-invasive prenatal testing of foetal blood groups are risk class D devices. In our opinion, screening for targeted anti-D prophylaxis for non-immunized RhD negative women should be placed under risk class C. To ensure high quality of non-invasive foetal blood group assays within and beyond the European Union, we present specific recommendations for validation and quality assurance in terms of analytical detection limit, range and linearity, precision, robustness, pre-analytics and use of controls in routine testing. With respect to immunized women, different requirements for validation and IVD risk classification are discussed. Conclusion: These recommendations should be followed to ensure appropriate assay performance and applicability for clinical use of both commercial and in-house assays. Keywords: EU; HDFN; blood group; cell-free DNA; foetal RHD genotyping; quality assurance; validation.
  • Prevalence and Population Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

    Burney, Peter; Patel, Jaymini; Minelli, Cosetta; Gnatiuc, Louisa; Amaral, André F S; Kocabaş, Ali; Cherkaski, Hamid Hacene; Gulsvik, Amund; Nielsen, Rune; Bateman, Eric; et al. (American Thoracic Society, 2020-11-10)
    Rationale: The Global Burden of Disease programme identified smoking, and ambient and household air pollution as the main drivers of death and disability from Chronic Obstructive Pulmonary Disease (COPD). Objective: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a post-bronchodilator one-second forced expiratory volume to forced vital capacity ratio < lower limit of normal, and the relative risks associated with different risk factors. Local RR were estimated using a Bayesian hierarchical model borrowing information from across sites. From these RR and the prevalence of risk factors, we estimated local Population Attributable Risks (PAR). Measurements and Main Results: Mean prevalence of CAO was 11.2% in men and 8.6% in women. Mean PAR for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index (BMI), and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: While smoking remains the most important risk factor for CAO, in some areas poor education, low BMI and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.
  • Evaluation of a Novel Teleradiology Technology for Image-Based Distant Consultations: Applications in Neurosurgery.

    Cewe, Paulina; Burström, Gustav; Drnasin, Ivan; Ohlsson, Marcus; Skulason, Halldor; Vucica, Stanislav; Elmi-Terander, Adrian; Edström, Erik; 1Department of Trauma and Musculoskeletal Radiology, Karolinska University Hospital, 171 64 Stockholm, Sweden. 2Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden. 3Department of Neurosurgery, Karolinska University Hospital, 171 64 Stockholm, Sweden. 4Image Over Globe, 21000 Split, Croatia. 5Department of Neuroradiology, Karolinska University Hospital, 171 64 Stockholm, Sweden. 6Department of Neurosurgery, Landspitali University Hospital, 101 Reykjavik, Iceland. (MDPI, 2021-08-04)
    In emergency settings, fast access to medical imaging for diagnostic is pivotal for clinical decision making. Hence, a need has emerged for solutions that allow rapid access to images on small mobile devices (SMD) without local data storage. Our objective was to evaluate access times to full quality anonymized DICOM datasets, comparing standard access through an authorized hospital computer (AHC) to a zero-footprint teleradiology technology (ZTT) used on a personal computer (PC) or SMD using national and international networks at a regional neurosurgical center. Image datasets were sent to a senior neurosurgeon, outside the hospital network using either an AHC and a VPN connection or a ZTT (Image Over Globe (IOG)), on a PC or an SMD. Time to access DICOM images was measured using both solutions. The mean time using AHC and VPN was 250 ± 10 s (median 249 s (233-274)) while the same procedure using IOG took 50 ± 8 s (median 49 s (42-60)) on a PC and 47 ± 20 s (median 39 (33-88)) on a SMD. Similarly, an international consultation was performed requiring 23 ± 5 s (median 21 (16-33)) and 27 ± 1 s (median 27 (25-29)) for PC and SMD respectively. IOG is a secure, rapid and easy to use telemedicine technology facilitating efficient clinical decision making and remote consultations. Keywords: clinical decision-making; neurosurgery; remote consultation; telemedicine; teleradiology.
  • Detailed Multiplex Analysis of SARS-CoV-2 Specific Antibodies in COVID-19 Disease.

    Brynjolfsson, Siggeir F; Sigurgrimsdottir, Hildur; Einarsdottir, Elin D; Bjornsdottir, Gudrun A; Armannsdottir, Brynja; Baldvinsdottir, Gudrun E; Bjarnason, Agnar; Gudlaugsson, Olafur; Gudmundsson, Sveinn; Sigurdardottir, Sigurveig T; et al. (Frontiers Research Foundation, 2021-06-10)
    A detailed understanding of the antibody response against SARS-CoV-2 is of high importance, especially with the emergence of novel vaccines. A multiplex-based assay, analyzing IgG, IgM, and IgA antibodies against the receptor binding domain (RBD), spike 1 (S1), and nucleocapsid proteins of the SARS-CoV-2 virus was set up. The multiplex-based analysis was calibrated against the Elecsys® Anti-SARS-CoV-2 assay on a Roche Cobas® instrument, using positive and negative samples. The calibration of the multiplex based assay yielded a sensitivity of 100% and a specificity of 97.7%. SARS-CoV-2 specific antibody levels were analyzed by multiplex in 251 samples from 221 patients. A significant increase in all antibody types (IgM, IgG, and IgA) against RBD was observed between the first and the third weeks of disease. Additionally, the S1 IgG antibody response increased significantly between weeks 1, 2, and 3 of disease. Class switching appeared to occur earlier for IgA than for IgG. Patients requiring hospital admission and intensive care had higher levels of SARS-CoV-2 specific IgA levels than outpatients. These findings describe the initial antibody response during the first weeks of disease and demonstrate the importance of analyzing different antibody isotypes against multiple antigens and include IgA when examining the immunological response to COVID-19.

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