Recent Submissions

  • Global Landscape Review of Serotype-Specific Invasive Pneumococcal Disease Surveillance among Countries Using PCV10/13: The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) Project.

    Deloria Knoll, Maria; Bennett, Julia C; Garcia Quesada, Maria; Kagucia, Eunice W; Peterson, Meagan E; Feikin, Daniel R; Cohen, Adam L; Hetrich, Marissa K; Yang, Yangyupei; Sinkevitch, Jenna N; et al. (MDPI, 2021-04-02)
    Serotype-specific surveillance for invasive pneumococcal disease (IPD) is essential for assessing the impact of 10- and 13-valent pneumococcal conjugate vaccines (PCV10/13). The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project aimed to evaluate the global evidence to estimate the impact of PCV10/13 by age, product, schedule, and syndrome. Here we systematically characterize and summarize the global landscape of routine serotype-specific IPD surveillance in PCV10/13-using countries and describe the subset that are included in PSERENADE. Of 138 countries using PCV10/13 as of 2018, we identified 109 with IPD surveillance systems, 76 of which met PSERENADE data collection eligibility criteria. PSERENADE received data from most (n = 63, 82.9%), yielding 240,639 post-PCV10/13 introduction IPD cases. Pediatric and adult surveillance was represented from all geographic regions but was limited from lower income and high-burden countries. In PSERENADE, 18 sites evaluated PCV10, 42 PCV13, and 17 both; 17 sites used a 3 + 0 schedule, 38 used 2 + 1, 13 used 3 + 1, and 9 used mixed schedules. With such a sizeable and generally representative dataset, PSERENADE will be able to conduct robust analyses to estimate PCV impact and inform policy at national and global levels regarding adult immunization, schedule, and product choice, including for higher valency PCVs on the horizon. Keywords: global; invasive pneumococcal disease; pneumococcal conjugate vaccines; pneumococcal meningitis; surveillance.
  • Serotype Distribution of Remaining Pneumococcal Meningitis in the Mature PCV10/13 Period: Findings from the PSERENADE Project.

    Garcia Quesada, Maria; Yang, Yangyupei; Bennett, Julia C; Hayford, Kyla; Zeger, Scott L; Feikin, Daniel R; Peterson, Meagan E; Cohen, Adam L; Almeida, Samanta C G; Ampofo, Krow; et al. (MDPI, 2021-04-01)
    Pneumococcal conjugate vaccine (PCV) introduction has reduced pneumococcal meningitis incidence. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project described the serotype distribution of remaining pneumococcal meningitis in countries using PCV10/13 for least 5-7 years with primary series uptake above 70%. The distribution was estimated using a multinomial Dirichlet regression model, stratified by PCV product and age. In PCV10-using sites (N = 8; cases = 1141), PCV10 types caused 5% of cases <5 years of age and 15% among ≥5 years; the top serotypes were 19A, 6C, and 3, together causing 42% of cases <5 years and 37% ≥5 years. In PCV13-using sites (N = 32; cases = 4503), PCV13 types caused 14% in <5 and 26% in ≥5 years; 4% and 13%, respectively, were serotype 3. Among the top serotypes are five (15BC, 8, 12F, 10A, and 22F) included in higher-valency PCVs under evaluation. Other top serotypes (24F, 23B, and 23A) are not in any known investigational product. In countries with mature vaccination programs, the proportion of pneumococcal meningitis caused by vaccine-in-use serotypes is lower (≤26% across all ages) than pre-PCV (≥70% in children). Higher-valency PCVs under evaluation target over half of remaining pneumococcal meningitis cases, but questions remain regarding generalizability to the African meningitis belt where additional data are needed.
  • Fetal descent in nulliparous women assessed by ultrasound: a longitudinal study.

    Hjartardóttir, Hulda; Lund, Sigrún H; Benediktsdóttir, Sigurlaug; Geirsson, Reynir T; Eggebø, Torbjørn M; 1Department of Obstetrics and Gynecology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland. Electronic address: huldahja@landspitali.is. 2deCODE genetics, Reykjavik, Iceland. 3Department of Obstetrics and Gynecology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 4National Center for Fetal Medicine, Department of Obstetrics and Gynecology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Obstetrics and Gynecology, Stavanger University Hospital, Stravanger, Norway; Institute of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. (Elsevier, 2020-10-08)
    Background: Ultrasound measurements offer objective and reproducible methods to measure the fetal head station. Before these methods can be applied to assess labor progression, the fetal head descent needs to be evaluated longitudinally in well-defined populations and compared with the existing data derived from clinical examinations. Objective: This study aimed to use ultrasound measurements to describe the fetal head descent longitudinally as labor progressed through the active phase in nulliparous women with spontaneous onset of labor. Study design: This was a single center, prospective cohort study at the Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland, from January 2016 to April 2018. Nulliparous women with a single fetus in cephalic presentation and spontaneous labor onset at a gestational age of ≥37 weeks, were eligible. Participant inclusion occurred during admission for women with an established active phase of labor or at the start of the active phase for women admitted during the latent phase. The active phase was defined as an effaced cervix dilated to at least 4 cm in women with regular contractions. According to the clinical protocol, vaginal examinations were done at entry and subsequently throughout labor, paired each time with a transperineal ultrasound examination by a separate examiner, with both examiners being blinded to the other's results. The measurements used to assess the fetal head station were the head-perineum distance and angle of progression. Cervical dilatation was examined clinically. Results: The study population comprised 99 women. The labor patterns for the head-perineum distance, angle of progression, and cervical dilatation differentiated the participants into 75 with spontaneous deliveries, 16 with instrumental vaginal deliveries, and 8 cesarean deliveries. At the inclusion stage, the cervix was dilated 4 cm in 26 of the women, 5 cm in 30 of the women, and ≥6 cm in 43 women. One cesarean and 1 ventouse delivery were performed for fetal distress, whereas the remaining cesarean deliveries were conducted because of a failure to progress. The total number of examinations conducted throughout the study was 345, with an average of 3.6 per woman. The ultrasound-measured fetal head station both at the first and last examination were associated with the delivery mode and remaining time of labor. In spontaneous deliveries, rapid head descent started around 4 hours before birth, the descent being more gradual in instrumental deliveries and absent in cesarean deliveries. A head-perineum distance of 30 mm and angle of progression of 125° separately predicted delivery within 3.0 hours (95% confidence interval, 2.5-3.8 hours and 2.4-3.7 hours, respectively) in women delivering vaginally. Although the head-perineum distance and angle of progression are independent methods, both methods gave similar mirror image patterns. The fetal head station at the first examination was highest for the fetuses in occiput posterior position, but the pattern of rapid descent was similar for all initial positions in spontaneously delivering women. Oxytocin augmentation was used in 41% of women; in these labors a slower descent was noted. Descent was only slightly slower in the 62% of women who received epidural analgesia. A nonlinear relationship was observed between the fetal head station and dilatation. Conclusion: We have established the ultrasound-measured descent patterns for nulliparous women in spontaneous labor. The patterns resemble previously published patterns based on clinical vaginal examinations. The ultrasound-measured fetal head station was associated with the delivery mode and remaining time of labor. Keywords: angle of progression; cesarean delivery; fetal head position; fetal head station; head-perineum distance; transabdominal ultrasound; transperineal ultrasound.
  • Changes in Invasive Pneumococcal Disease Caused by Serotype 1 Following Introduction of PCV10 and PCV13: Findings from the PSERENADE Project.

    Bennett, Julia C; Hetrich, Marissa K; Garcia Quesada, Maria; Sinkevitch, Jenna N; Deloria Knoll, Maria; Feikin, Daniel R; Zeger, Scott L; Kagucia, Eunice W; Cohen, Adam L; Ampofo, Krow; et al. (MDPI, 2021-03-27)
    Streptococcus pneumoniae serotype 1 (ST1) was an important cause of invasive pneumococcal disease (IPD) globally before the introduction of pneumococcal conjugate vaccines (PCVs) containing ST1 antigen. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project gathered ST1 IPD surveillance data from sites globally and aimed to estimate PCV10/13 impact on ST1 IPD incidence. We estimated ST1 IPD incidence rate ratios (IRRs) comparing the pre-PCV10/13 period to each post-PCV10/13 year by site using a Bayesian multi-level, mixed-effects Poisson regression and all-site IRRs using a linear mixed-effects regression (N = 45 sites). Following PCV10/13 introduction, the incidence rate (IR) of ST1 IPD declined among all ages. After six years of PCV10/13 use, the all-site IRR was 0.05 (95% credibility interval 0.04-0.06) for all ages, 0.05 (0.04-0.05) for <5 years of age, 0.08 (0.06-0.09) for 5-17 years, 0.06 (0.05-0.08) for 18-49 years, 0.06 (0.05-0.07) for 50-64 years, and 0.05 (0.04-0.06) for ≥65 years. PCV10/13 use in infant immunization programs was followed by a 95% reduction in ST1 IPD in all ages after approximately 6 years. Limited data availability from the highest ST1 disease burden countries using a 3+0 schedule constrains generalizability and data from these settings are needed.
  • Vitamin D status and association with gestational diabetes mellitus in a pregnant cohort in Iceland.

    Magnusdottir, Kristin S; Tryggvadottir, Ellen A; Magnusdottir, Ola K; Hrolfsdottir, Laufey; Halldorsson, Thorhallur I; Birgisdottir, Bryndis E; Hreidarsdottir, Ingibjorg T; Hardardottir, Hildur; Gunnarsdottir, Ingibjorg; 1Unit for Nutrition Research, Landspitali University Hospital and Faculty of Food Science and Nutrition, University of Iceland, Reykjavik, Iceland. 2Institution of Health Science Research, University of Akureyri and Akureyri Hospital, Akureyri, Iceland. 3Centre for Fetal Programming, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. 4Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavík, Iceland. 5Faculty of Medicine, University of Iceland, Reykjavík, Iceland. (Swedish Nutrition Foundation, 2021-03-23)
    Background: Vitamin D deficiency has been associated with an increased risk of gestational diabetes mellitus (GDM), one of the most common pregnancy complications. The vitamin D status has never previously been studied in pregnant women in Iceland. Objective: The aim of this research study was to evaluate the vitamin D status of an Icelandic cohort of pregnant women and the association between the vitamin D status and the GDM incidence. Design: Subjects included pregnant women (n = 938) who attended their first ultrasound appointment, during gestational weeks 11-14, between October 2017 and March 2018. The use of supplements containing vitamin D over the previous 3 months, height, pre-pregnancy weight, and social status were assessed using a questionnaire, and blood samples were drawn for analyzing the serum 25‑hydroxyvitamin D (25OHD) concentration. Information regarding the incidence of GDM later in pregnancy was collected from medical records. Results: The mean ± standard deviation of the serum 25OHD (S-25OHD) concentration in this cohort was 63±24 nmol/L. The proportion of women with an S-25OHD concentration of ≥ 50 nmol/L (which is considered adequate) was 70%, whereas 25% had concentrations between 30 and 49.9 nmol/L (insufficient) and 5% had concentrations < 30 nmol/L (deficient). The majority of women (n = 766, 82%) used supplements containing vitamin D on a daily basis. A gradual decrease in the proportion of women diagnosed with GDM was reported with increasing S-25OHD concentrations, going from 17.8% in the group with S-25OHD concentrations < 30 nmol/L to 12.8% in the group with S-25OHD concentrations ≥75 nmol/L; however, the association was not significant (P for trend = 0.11). Conclusion: Approximately one-third of this cohort had S-25OHD concentrations below adequate levels (< 50 nmol/L) during the first trimester of pregnancy, which may suggest that necessary action must be taken to increase their vitamin D levels. No clear association was observed between the vitamin D status and GDM in this study. Keywords: cod liver oil; gestational diabetes mellitus; nutritional status; pregnancy; supplements; vitamin D.
  • Effects of intensive upright mobilisation on outcomes of mechanically ventilated patients in the intensive care unit: a randomised controlled trial with 12-months follow-up

    Amundadottir, Olof R.; Jónasdóttir, Rannveig J.; Sigvaldason, Kristinn; Gunnsteinsdottir, Ester; Haraldsdottir, Brynja; Sveinsson, Thorarinn; Sigurdsson, Gisli H.; Dean, Elizabeth; a School of Health Sciences, University of Iceland, Reykjavik, Iceland b Department of Physiotherapy, Landspitali–The National University Hospital of Iceland, Reykjavik, Iceland c Department of Anaesthesiology and Intensive Care Medicine, Landspitali–The National University Hospital of Iceland, Reykjavik, Iceland d Department of Physical Therapy, Faculty of Medicine, The University of British Columbia, Vancouver, Canada (Taylor & Francis, 2021-03-04)
    Objective: To examine effects of intensive upright mobilisation on short- and long-term outcomes in critically ill mechanically ventilated patients. Methods: A randomised controlled trial compared patient outcomes after intensive twice-daily (n = 29) or daily mobilisation (n = 21). Patients in the intensive care unit (ICU), mechanically ventilated for over 48 hours, were randomly assigned to one of the two groups. Outcomes were duration of mechanical ventilation, ICU and hospital lengths of stay; health-related quality of life and physical function. Results: The twice-daily mobilisation group began upright mobilisation on day seven of ICU stay, and were mobilised upright on 31% of ICU days compared with the daily mobilisation group, who began upright mobilisation on day eight (p >= .05), and mobilised upright on 22% of ICU days (p = .03). No difference between groups was observed for any variable of interest across time-points over one year. Conclusions: The intensive twice-daily mobilisation group neither started upright mobilisation early nor yielded superior short- or long-term outcomes compared to the daily mobilisation group. Both groups showed poor physical health-related quality of life and exercise capacity one year after ICU discharge. Our findings support the need for targeted and tailored upright mobilisation in the ICU and after discharge.
  • 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.

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