Recent Submissions

  • Effect of Obstructive Sleep Apnea and Positive Airway Pressure Therapy on Cardiac Remodeling as Assessed by Cardiac Biomarker and Magnetic Resonance Imaging in Nonobese and Obese Adults.

    Xu, Liyue; Keenan, Brendan T; Maislin, David; Gislason, Thorarinn; Benediktsdóttir, Bryndís; Gudmundsdóttir, Sigrun; Gardarsdottir, Marianna; Staley, Bethany; Pack, Frances M; Guo, Xiaofeng; et al. (Lippincott, Williams & Wilkins, 2021-01-19)
    It is unknown whether obesity modifies the effect of obstructive sleep apnea (OSA) and positive airway pressure (PAP) therapy on cardiac remodeling and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. We compared NT-proBNP and cardiac magnetic resonance imaging in adults without OSA (n=56) and nonobese (n=73; body mass index <30 kg/m2) and obese (n=136; body mass index ≥30 kg/m2) adults with OSA. We also investigated these traits in nonobese (n=45) and obese (n=78) participants with OSA adherent to 4 months of PAP treatment. At baseline, left ventricular mass to end-diastolic volume ratio, a measure of left ventricular concentricity, was greater in both nonobese and obese participants with OSA compared with those without OSA. Participants with OSA and obesity exhibited reduced phasic right atrial function. No significant differences in baseline NT-proBNP were observed across groups. The effect of PAP treatment on NT-proBNP and left atrial volume index was significantly modified by obesity. In nonobese participants, PAP therapy was associated with a decrease in NT-proBNP (P<0.0001) without a change in left atrial volume index, whereas in obese participants, PAP was associated with an increase in left atrial volume index (P=0.006) without a change in NT-proBNP. OSA was associated with left ventricular concentric remodeling independent of obesity and right atrial dysfunction in participants who were obese. PAP treatment was associated with reduced NT-proBNP in nonobese participants with OSA, but left atrial enlargement in obese participants with OSA, suggesting that PAP-induced reduction in BNP release (which is known to occur during obstructive apnea episodes) may lead to volume retention in obese participants with OSA. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01578031.
  • Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR

    Bjornsson, Eythor; Gunnarsdottir, Kristbjorg; Halldorsson, Gisli H; Sigurdsson, Asgeir; Arnadottir, Gudny A; Jonsson, Hakon; Olafsdottir, Eva F; Niehus, Sebastian; Kehr, Birte; Sveinbjörnsson, Gardar; et al. (Lippincott Williams & Wilkins, 2020-12-14)
    Background: Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene (LDLR) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in LDLR with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in LDLR that have a large effect on LDL cholesterol levels. Methods: We analyzed whole-genome sequencing data from 43 202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions, and duplications were genotyped using whole-genome sequencing-based data. LDL cholesterol associations were carried out in a sample of >100 000 Icelanders with genetic information (imputed or whole-genome sequencing). Molecular analyses were performed using RNA sequencing and protein expression assays in Epstein-Barr virus-transformed lymphocytes. Results: We discovered a 2.5-kb deletion (del2.5) overlapping the 3' untranslated region of LDLR in 7 heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101 851 noncarriers, a difference of 2.48 mmol/L (96 mg/dL; P=8.4×10-8). Del2.5 results in production of an alternative mRNA isoform with a truncated 3' untranslated region. The truncation leads to a loss of target sites for microRNAs known to repress translation of LDLR. In Epstein-Barr virus-transformed lymphocytes derived from del2.5 carriers, expression of alternative mRNA isoform was 1.84-fold higher than the wild-type isoform (P=0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers (P=0.0086). We did not find a highly penetrant detrimental impact of lifelong very low levels of LDL cholesterol due to del2.5 on health of the carriers. Conclusions: Del2.5 is the first reported gain-of-function mutation in LDLR causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of LDLR mRNA as a potent regulator of LDL receptor expression in humans. Keywords: cardiovascular disease; genetics; lipids; microRNA; polyadenylation.
  • Acute Kidney Injury After Acute Repair of Type A Aortic Dissection.

    Helgason, Dadi; Helgadottir, Solveig; Ahlsson, Anders; Gunn, Jarmo; Hjortdal, Vibeke; Hansson, Emma C; Jeppsson, Anders; Mennander, Ari; Nozohoor, Shahab; Zindovic, Igor; et al. (Elsevier, 2020-09-19)
    Background: The aim of this study was to examine the incidence, risk factors, and outcomes of patients with acute kidney injury (AKI) after surgery for acute type A aortic dissection (ATAAD) using the Nordic Consortium for Acute Type A Aortic Dissection registry. Methods: Patients who underwent ATAAD surgery at 8 Nordic centers from 2005 to 2014 were analyzed for AKI according to the RIFLE criteria. Patients who died intraoperatively, those who had missing baseline or postoperative serum creatinine, and patients on preoperative renal replacement therapy were excluded. Results: AKI occurred in 382 of 941 patients (40.6%), and postoperative dialysis was required for 105 patients (11.0%). Renal malperfusion was present preoperatively in 42 patients (5.1%), of whom 69.0% developed postoperative AKI. In multivariable analysis patient-related predictors of AKI included age (per 10 years; odds ratio [OR], 1.30; 95% confidence interval [CI], 1.15-1.48), body mass index >30 kg/m2 (OR, 2.16; 95% CI, 1.51-3.09), renal malperfusion (OR, 4.39; 95% CI, 2.23-9.07), and other malperfusion (OR, 2.10; 95% CI, 1.55-2.86). Perioperative predictors were cardiopulmonary bypass time (per 10 minutes; OR, 1.04; 95% CI, 1.02-1.07) and red blood cell transfusion (OR per transfused unit, 1.08; 95% CI, 1.06-1.10). Rates of 30-day mortality were 17.0% in the AKI group compared with 6.6% in the non-AKI group (P < .001). In 30-day survivors AKI was an independent predictor of long-term mortality (hazard ratio, 1.86; 95% CI; 1.24-2.79). Conclusions: AKI is a common complication after surgery for ATAAD and independently predicts adverse long-term outcome. Of note one-third of patients presenting with renal malperfusion did not develop postoperative AKI, possibly because of restoration of renal blood flow with surgical repair. Mortality risk persists beyond the perioperative period, indicating that close clinical follow-up of these patients is required.
  • Pubertal development and risk of premenstrual disorders in young adulthood.

    Lu, Donghao; Aleknaviciute, Jurate; Bjarnason, Ragnar; Tamimi, Rulla M; Valdimarsdóttir, Unnur A; Bertone-Johnson, Elizabeth R; 1Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 2Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 4Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands. 5Faculty of Medicine, University of Iceland and Children's Medical Centre, Landspitali University Hospital, Reykjavik, Iceland. 6Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA. 7Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 8Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, USA. 9Department of Health Promotion and Policy, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, USA. (Oxford University Press, 2021-01)
    Study question: Is pubertal timing associated with risk of premenstrual disorders (PMDs) in young adulthood? Summary answer: Late pubertal development is associated with decreased premenstrual symptom burden and risk of PMDs in young adulthood. What is known already: PMDs, including premenstrual syndrome and premenstrual dysphoric disorder, may begin during the teenage years. Few risk factors in early life have been identified for PMD development. Study design, size, duration: A prospective cohort study of 6495 female participants during 1996-2013. Participants/materials, setting, methods: We included participants from the Growing Up Today Study (GUTS). Pubertal development was indicated by the timing of menarche, breast and pubic hair growth. Self-reported age at menarche was longitudinally assessed at enrollment (in 1996/2004 for GUTS I/II) and onwards, and classified as early (age ≤ mean - SD, 11.64 years), normative and late menarche (age ≥ mean + SD, 13.95 years). Timing of pubic hair and breast growth were assessed multiple times during follow-up via Tanner scales, and classified into early, normative and late development according to mean ± SD. Using a validated questionnaire based on the Calendar of Premenstrual Experiences, we assessed premenstrual symptoms and identified probable cases of PMDs in 2013. We examined the associations of timing of pubertal development with premenstrual symptom score and disorders using multivariable linear and logistic regressions, respectively. Main results and the role of chance: In 2013 (mean age = 26), 1001 (15.4%) individuals met criteria for a PMD. An inverse association was found between age at menarche and premenstrual symptom z-score (β -0.05 per year, 95% CI -0.07 to -0.03) and risk of PMDs (odds ratio (OR) 0.93 per year, 95% CI 0.88 to 0.99). Compared to individuals with normative menarche, individuals with late menarche had a lower risk of PMDs (OR 0.73, 95% CI 0.59 to 0.91), while individuals with early menarche had comparable odds (OR 0.98, 95% CI 0.81 to 1.18). Moreover, early growth of pubic hair was associated with increased premenstrual symptoms (z-score β 0.09 per year, 95% CI 0.02 to 0.17) and PMD risk (OR 1.28, 95% CI 1.04 to 1.56), independent of age at menarche. No associations were noted for breast development. Limitations, reasons for caution: One major limitation is some misclassification of menarche due to recall. We, however, showed robust association among participants who were premenarcheal at baseline. Wider implications of the findings: Our findings suggest that pubertal timing, particularly timing of menarche, is inversely associated with the risk of developing premenstrual symptoms in young adulthood, and that women with later menarche have significantly lower risk of PMDs. Information on PMDs should be provided to teenage girls and their parents. If these findings are confirmed in independent populations, prevention strategies and early detection programs may be considered for women with early pubertal development. Study funding/competing interest(s): The work is supported by the National Institutes of Health and Swedish Research Council. Trial registration number: N/A. Keywords: menarche; premenstrual disorders; premenstrual dysphoric disorder; premenstrual syndrome; pubertal development.
  • Use of psychiatric medication in three Arctic nursing homes: association with dementia and psychiatric symptoms.

    Gisladottir, Sigurveig; Sigurdardottir, Arun K; Hjaltadottir, Ingibjörg; 1Fossahlid Nursing Home, Health Care Institution of Eastern Iceland. 2University of Akureyri, School of Health Sciences, Akureyri, Iceland. 3Akureyri Hospital, Akureyri, Iceland. 4Faculty of Nursing, University of Iceland. 5Division of Clinical Services Landspítali, National University Hospital, Reykjavik, Iceland. (Taylor & Francis, 2021-04)
    As more people reaches advanced age, more people experience cognitive impairment and dementia. Dementia is a degenerative disease in which behavioural and psychological symptoms frequently occur, resulting in admissions to nursing homes (NHs), where the most common treatment has been medical treatment. The aim was to compare three rural Arctic NHs in Iceland in their use of psychiatric medication, type of dementia among residents, level of cognitive impairment and selected quality indicators, as well as considering national data, for the period 2016-2018. Data from the interRAI-MDS 2.0 evaluation were used. Residents with severe cognitive impairment used more antipsychotic medications, and residents with mild and severe cognitive impairment used more antidepressants than residents with no cognitive impairment did. Diagnoses of Alzheimer's Disease and Related Dementias (ADRD) are more common in the capital area and the national average than they are in the rural NHs. This indicates need for diagnostic assessments of ADRD to be conducted in rural areas. Benchmarking is beneficial for local and national regulatory bodies to find areas for improvement. The NHs did not have a lower quality of care compared with the whole country, but areas for improvement were identified. One of the NHs has already started this process. Keywords: Nursing homes; arctic areas; dementia; psychiatric medication.
  • Mild Stage 1 post-operative acute kidney injury: association with chronic kidney disease and long-term survival.

    Long, Thorir Einarsson; Helgason, Dadi; Helgadottir, Solveig; Sigurdsson, Gisli Heimir; Palsson, Runolfur; Sigurdsson, Martin Ingi; Indridason, Olafur Skuli; 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Internal Medicine Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 3Department of Anesthesia and Intensive Care, Akademiska University Hospital, Uppsala, Sweden. 4Division of Anesthesia and Intensive Care Medicine, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 5Division of Nephrology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. (Oxford University Press, 2020-02-10)
    Pre- and post-operative SCr values were available for 47 333 (42%) surgeries. Of those, 1161 (2.4%) had mild Stage 1 AKI and 2355 (5%) more severe forms of AKI. Mild Stage 1 AKI was associated with both incident CKD and progression of pre-existing CKD (P < 0.001). After exclusion of post-operative deaths within 30 days, mild Stage 1 AKI was not associated with worse 1-year survival in patients with preserved kidney function (94% versus 94%, P = 0.660), and same was true for patients with pre-operative CKD (83% versus 82%, P = 0.870) compared with their matched individuals. Conclusions. Mild Stage 1 AKI is associated with development and progression of CKD, but not with inferior 1-year survival. These findings support the inclusion of a small absolute increase in SCr in the definition of AKI.
  • Body weight changes and longitudinal associations with cognitive decline among community-dwelling older adults.

    Eymundsdottir, Hrafnhildur; Ramel, Alfons; Geirsdottir, Olof G; Skuladottir, Sigrun S; Gudmundsson, Larus S; Jonsson, Palmi V; Gudnason, Vilmundur; Launer, Lenore; Jonsdottir, Maria K; Chang, Milan; et al. (Wiley, 2021-02-20)
    Introduction: We aim to investigate the longitudinal associations between changes in body weight (BW) and declines in cognitive function and risk of mild cognitive impairment (MCI)/dementia among cognitively normal individuals 65 years or older. Methods: Data from the Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study) including 2620 participants, were examined using multiple logistic regression models. Cognitive function included speed of processing (SP), executive function (EF), and memory function (MF). Changes in BW were classified as; weight loss (WL), weight gain (WG), and stable weight (SW). Results: Mean follow-up time was 5.2 years and 61.3% were stable weight. Participants who experienced WL (13.4%) were significantly more likely to have declines in MF and SP compared to the SW group. Weight changes were not associated with EF. WL was associated with a higher risk of MCI, while WG (25.3%) was associated with a higher dementia risk, when compared to SW. Discussion: Significant BW changes in older adulthood may indicate impending changes in cognitive function. Keywords: APOE ε4; body weight changes; cognitive function; dementia; executive function; memory function; mild cognitive impairment; nutrition; speed of processing.
  • 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.
  • 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.
  • Vesicourethral Anastomotic Stenosis After Open or Robot-assisted Laparoscopic Retropubic Prostatectomy-Results from the Laparoscopic Prostatectomy Robot Open Trial.

    Modig, Katarina Koss; Godtman, Rebecka Arnsrud; Bjartell, Anders; Carlsson, Stefan; Haglind, Eva; Hugosson, Jonas; Månsson, Marianne; Steineck, Gunnar; Thorsteinsdottir, Thordis; Tyritzis, Stavros; et al. (Elsevier, 2019-11-09)
    Background: Vesicourethral anastomotic stenosis is a well-known late complication after open radical retropubic prostatectomy (RRP) with previously reported incidences of 2.7-15%. There are few reports of the incidence after robot-assisted laparoscopic radical prostatectomy (RALP) compared with RRP. Objective: The aim was to compare the risk of developing symptomatic stenosis after RRP and RALP, and to explore potential risk factors and the influence of stenosis on the risk of urinary incontinence. Design, setting, and participants: Between 2008 and 2011, 4003 men were included in a prospective trial comparing RRP and RALP at 14 Swedish centres. Clinical data and patient questionnaires were collected before, during, and after surgery. Outcome measurements and statistical analysis: Stenosis was identified by either patients' reports in questionnaires or case report forms. The primary endpoint is reported as unadjusted as well as adjusted relative risks (RRs), calculated with log-binomial regression models. Data on incontinence were analysed by means of a log-binomial regression model, with stenosis as an independent and incontinence as a dependent variable. Results and limitations: Symptomatic stenosis developed in 1.9% of 3706 evaluable men within 24 mo. The risk was 2.2 times higher after RRP than after RALP (RR 2.21, 95% confidence interval [CI] 1.38-3.53). Overall, urinary incontinence was twice as common in patients who had stenosis (RR 2.01, 95% CI 1.43-2.64). Conclusions: This large prospective study found an overall low rate of vesicourethral anastomotic stenosis after radical prostatectomy, but the rate was significantly lower after robot-assisted prostatectomy. The risk of stenosis seems to be associated with the number of sutures/takes in the anastomosis, but this was statistically significant only in the RALP group. Patient summary: We investigated the risk of developing vesicourethral anastomotic stenosis after open and robot-assisted radical prostatectomy. We found that the risk was generally lower than previously reported and lower after robot-assisted radical prostatectomy than after radical retropubic prostatectomy. Urinary incontinence was twice as common in patients with stenosis. Keywords: Anastomotic stenosis; Prostate cancer; Robotic surgery.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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